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    ASCO Guidelines

    ASCO Guidelines features key recommendations from the latest evidence-based clinical practice guidance from ASCO that you can access on the go.
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    Episodes (150)

    Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2023.3 Part 2

    Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2023.3 Part 2

    Dr. Natash Leighl and Dr. Jyoti Patel are back on the podcast to discuss the update to the living guideline on stage IV NSCLC with driver alterations. This guideline includes recommendations for first-, second-, and subsequent-line therapy for patients with driver alterations including: EGFR, ALK, ROS1, BRAFV600E, MET exon skipping mutation, RET rearrangement, NTRK rearrangement, HER2, and KRAS G12C. They highlight the key changes to the recommendations, addition of recent trials, the importance of biomarker testing, and the impact of this guideline for clinicians and patients living with advanced NSCLC. Stay tuned for future updates to this continuously updated guideline.

    Read the full update, “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3” at www.asco.org/living-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02744.   

    Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.   

    My name is Brittany Harvey, and today I am interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3.” Thank you for being here, Dr. Patel and Dr. Leighl. 

    And before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel and Dr. Leighl, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

    So, to start us off on this living clinical practice guideline, Dr. Leighl, this guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being routinely updated. What new data was reviewed in this full update to the living guideline?

    Dr. Natasha Leighl: Thanks so much, Brittany. So, we looked through the literature for publications between February and the end of October 2023, and also any novel agents that were approved, in particular by the United States FDA, to really incorporate this update in the current guidelines. In particular, we had updates in EGFR-driven tumors, BRAF and RET-driven tumors. And we also worked very hard to make this more digestible. In particular, it was turning into a bit of a laundry list of all of the things that we had ever recommended. So we really wanted to shorten things, pare them down, and really make them helpful and very, very current for the treatment of people with lung cancer in 2023 and 2024.

    Brittany Harvey: Excellent. Thank you for providing that overview of the evidence reviewed and the key updates that we will address in this guideline. So then I would like to talk about some of those key updated recommendations from the expert panel. You mentioned both EGFR, BRAF, and RET. So starting with patients with stage IV non-small cell lung cancer with EGFR alterations, Dr. Leighl, what are the key changes to those recommendations?

    Dr. Natasha Leighl: So, as I said, we really started to get quite a long list of things we recommended, including drugs that, to be honest, we no longer think are what we should lead with first-line. So we updated the recommendation to recommend first-line osimertinib in patients with sensitizing mutations. We were also able to capture in this update for patients with EGFR exon 20 insertion mutant lung cancer, the data from the randomized PAPILLON trial, recommending amivantamab plus chemotherapy for progression-free survival benefit. Not yet an overall survival benefit, but we will see how these data mature. 

    The other thing that we did was we moved all of the- I don't want to call them "legacy agents" because, in many countries, these are still very important. But older agents such as gefitinib, approaches such as gefitinib plus chemotherapy, and drugs like dacomitinib and other agents where we truly believe as an international panel that we would prefer a third-generation kinase inhibitor like osimertinib. We moved all of those to our discussion, just to recognize that, around the world, not everybody may have access. And we also specified that things are different in different countries. So, for example, in China, there are other third-generation kinase inhibitors with randomized data to support their use. And those are approved and used in China. And also, for example, in Korea, there are other agents that are used. So, we have really tried to be both inclusive and yet keep things simple at the same time. And hopefully, we have succeeded. 

    One of the challenges was that, with all of the updates that we made, we did not have all of the publications out yet at the end of October to make recommendations about moving beyond osimertinib in the first-line setting. So, please stay tuned for the next guideline update, where we’re going to tackle whether we should give osimertinib alone or combination therapy.

    Brittany Harvey: Excellent. Thank you for providing those updates and clarifications for those patients with non-small cell lung cancer and an EGFR alteration. And we will look forward to the guideline panel's review of that evidence and future updates as well.

    So then, Dr. Leighl, you had previously mentioned that additional recommendations were updated, such as those for patients with BRAF alterations and RET alterations. So, Dr. Patel, what are the other key updated recommendations from the expert panel?

    Dr. Jyoti Patel: Thanks so much, Brittany. So certainly, I think we have seen many of these trials mature over time, which has been fantastic. I think one remarkable achievement was the reporting of a phase III selpercatinib trial. This was a trial in the front-line setting, in which patients who were RET-positive were randomized to selpercatinib versus carboplatin-based chemotherapy. And the selpercatinib significantly outperformed platinum-based chemotherapy, and I think really demonstrated a significant improvement in progression-free survival. So, based on that phase III trial, the recommendation for selpercatinib was elevated. Many of these agents that are used in clinical practice are approved initially on smaller phase I or phase II trials. And so, seeing the maturity of these phase III trials gives clinicians and patients greater certainty that these agents are really effective. And so, the evidence was increased for that, and that's now a preferred agent over another TKI, pralsetinib, in which there is only phase II data. So, certainly, those kinds of real things that we can explain to patients are important in these guidelines. 

    Another thing that we were able to update was another doublet for BRAF V600E non-small cell lung cancer. So, the combination of the two TKIs, encorafenib and binimetinib, was also included in the guidelines. 

    One thing that we tried to help was really identifying the best therapy post-progression on these first-generation TKIs. And again, there is a paucity of data, but often we went back to carboplatin-based doublets, and there is some data regarding whether or not patients with driver alterations should get immunotherapy in the second-line setting. And so, certainly, I think we have a number of randomized studies for patients with classical EGFR mutations, and our recommendation is generally avoidance of immunotherapy for these patients and treating many of these patients with carboplatin and pemetrexed when appropriate. I do not think we have the data for a lot of other subsets of patients. So, again, stay tuned as these data evolve.

    Brittany Harvey: Thank you for reviewing those updated recommendations and the supporting evidence. I think it's helpful for our listeners to understand the level of evidence behind these recommendations as well. 

    So then, Dr. Leighl, what should clinicians know as they implement these new and updated recommendations?

    Dr. Natasha Leighl: It's really important, first of all, to make sure that you have the information that you need to get your patients to these great new treatments as part of the shared decision-making process. So your patients need biomarker testing. You need to get that as quickly as you can. As Dr. Patel has highlighted, you really want to get that before they start their first-line therapy, if at all possible. We also really tried to bring out in this guideline that when things are delayed, I mean, this is the real world that we live in, just to be very cautious of immunotherapy with chemotherapy for that first cycle. That obviously, again, is a discussion with your patient, but this concept that the approach of a cycle of chemotherapy while you wait for the next-generation sequencing testing. And then if the patient does not have a driver alteration, adding any other therapy as appropriate is okay. It's something that people do. We believe it's important as we talk about the balance between benefits and harms. And so I think that's in there for clinicians, and I hope that they and patients can really benefit from that to avoid toxicity and also to really improve the ability to get molecular testing results first line. 

    Also, I think it's really important that when people read the wording of the guidelines, that this really follows GRADE, which is a type of system that we use to develop our recommendations. And so things like "may" do not mean that you shouldn't do it. So sometimes we'll hear back from clinicians and say, "Well, you said that they may use alectinib or lorlatinib, for example, with ALK, and I can only get coverage for one or the other." And so I think it's really important that clinicians and patients recognize that all of the things that we do recommend, even if we do use the word "may" or the recommendation is more conditional, we do think that these agents should be available for patients and clinicians, and that they go through this shared decision-making process together. 

    And so I think that's something that clinicians, we hope, can help take forward as they advocate for their patients to get access to these different and new and emerging treatments that have clearly shown benefit. Even when we say patients and clinicians may use this or that, there may be excellent reasons for using something newer, that’s emerged, perhaps for toxicity benefits or benefits in terms of efficacy, even though we can't compare directly. And so we really want clinicians and patients to be empowered to access these new compounds and these new exciting agents that are in our guidelines.

    Brittany Harvey: Absolutely. Thank you for reviewing those key points. And, yes, that's a great comment that the level of obligation in the recommendations may be based on the evidence quality, but that doesn't mean that clinicians and patients shouldn't have access to all of the recommended treatment options to offer patients based off their individual patient and clinical characteristics. 

    So then, Dr. Patel, in your view, how will these changes affect patients with non-small cell lung cancer, with driver alterations? 

    Dr. Jyoti Patel: A lot of this echoes the points made by Dr. Leighl. I think there are opportunities for patients to assess toxicity or what it means for intensification of therapy. So, particularly for EGFR patients, for example, we have data that chemotherapy with osimertinib can improve progression-free survival, or the incorporation of a bispecific antibody, amivantamab, can improve progression-free survival over the TKI alone. It certainly comes with increased toxicity. And so how we weigh this in the absence of a known survival benefit at this juncture is one that, again, really gives patients the opportunity to prioritize what's important for them. And so I think this guideline affects patients and that we have multiple options, we help with the weight of the evidence so they may be able to better discern what treatment makes sense for them.

    Brittany Harvey: Understood. Yes, this guideline provides lots of options for different patients based off their driver alterations. So it's helpful to have that information for shared decision-making with their clinicians. 

    So then finally, to wrap us up, Dr. Leighl, what current research is the living guideline expert panel monitoring for updates to the guideline recommendations?

    Dr. Natasha Leighl: This process of the living guidelines has really been to help us stay on top of the amazing and incredibly rapid progress that we're making in lung cancer and other cancers. And even with this process, where we're trying to stay up-to-the-minute, there have already been some changes in the literature between the start of November and now. And so we're already working on some additional commentary and options for the first-line treatment of patients with EGFR-mutant lung cancer. Also, the subsequent treatment of patients with EGFR-mutant lung cancer, depending on what they've had before. Also, a great new study in patients with ROS1 fusion-driven lung cancer. And so these are some of the things that we're looking at.  

    Also, a bit more discussion about the importance of molecular testing. In our companion article, the Journal of Oncology Practice, along with Dr. Patel, we're going to be talking a bit more about new ways to genotype, for example, using both liquid biopsy and tumor tissue at the same time, and some of the support for that and how it gets us with our patients to the answers that they need faster. 

    Brittany Harvey: Absolutely. The pace of research in non-small cell lung cancer has moved quite quickly. So we definitely appreciate the panel's efforts to review all of this evidence on a continuous basis and take the time to develop these guideline recommendations for both clinicians and patients with non-small cell lung cancer. 

    So I want to thank you so much for your work to update these guidelines, and thank you for your time today, Dr. Patel and Dr. Leighl.

    Dr. Natasha Leighl: Thanks so much. It's a real pleasure to be here.

    Dr. Jyoti Patel: Thank you. 

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. 

    The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

     

    ASCO Guidelines
    en-usFebruary 28, 2024

    Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2023.3 Part 1

    Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2023.3 Part 1

    Dr. Jyoti Patel and Dr. Natasha Leighl discuss the latest full update to the stage IV NSCLC without driver alterations living guideline. This guideline addresses first-, second-, and subsequent-line therapy for patients according to their histology (squamous cell and nonsquamous cell carcinomas) and PD-L1 expression. They discuss the streamlined recommendations, incorporation of recent evidence, and the highlights for implementation of these recommendations in the treatment of advanced non-small lung cancer. Dr. Patel and Dr. Leighl also point out ongoing trials that will inform this continuously updated guideline as we look ahead. 

    Read the full update, “Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3” at www.asco.org/living-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02746.   

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts  delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all of our shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on “Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.3.” Thank you for being here, Dr. Patel and Dr. Leighl.

    Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel and Dr. Leighl, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. 

    So, to start us off on the content of this episode, Dr. Patel, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is being updated on a regular basis. Could you provide some background information on the process for these living guidelines?

    Dr. Jyoti Patel: The ASCO Living Guideline offers continually updated recommendations based on review of systemic randomized controlled trials. We bring a panel of experts together that includes representatives from Ontario Health as well as ASCO patient representatives. We review phase III studies and other published studies between the times from July 2022 and October 2023 for this most updated guideline. We think about the size of the populations that are being tested, what kind of interventions we have, the outcomes. We certainly look at PFS, as well as OS, but also toxicity, and overall response rates. We prioritize randomized trials and really look for studies that have large sample sizes. We exclude studies that were only meeting abstracts and really look at those that are published in peer-reviewed journals. 

    When we weigh the evidence, we really think about a number of factors. So what is the strength of the evidence, what’s the sample size, and how we can make recommendations for our patients based on the totality of the data. Certainly, because this is such a rapidly evolving field, one of the things we are looking at is how to update in real-time these guidelines. So for this coming year, for example, these guidelines are published and we look forward to quarterly updates and, again, incorporate the latest evidence.

    Brittany Harvey: Great. Thank you for that explanation on the background and how these living guidelines are developed. 

    So, Dr. Leighl, could you describe what the key changes are from the expert panel?

    Dr. Natasha Leighl: So what we try to do in the guidelines for this latest publication, was really try and streamline the way we set up a format to make it much easier for people to use. In terms of new recommendations, we made sure to include more recent studies of additional PD-1 or PD-L1 inhibitors, for example, cemiplimab in combination with chemotherapy, or the combination of durvalumab and tremelimumab with chemotherapy, both of these in unselected patients, so with any PD-L1 expression, of course, this continues with pembrolizumab with or without chemotherapy, atezolizumab with chemotherapy combinations, and, of course,  nivolumab and ipilimumab with and without chemotherapy. And so it really is just an update on all of the potential options. In the discussion, we’ve really tried to go through some of the nuances in the trials just to help when you’re discussing with patients or discussing with your oncologists, how to figure out which of these is best for you.

    Brittany Harvey: Excellent. It's helpful to have all of the recommendations listed out together so that clinicians and patients know all of the available options available to them. 

    So then, Dr. Patel, what should clinicians know as they implement these changes into their clinical practice?

    Dr. Jyoti Patel: I think it's important to stress that our decision-making in the treatment of advanced non-small cell lung cancer is really reliant on adequate biomarker testing. And so the way we approach this is our assumption that all appropriate patients undergo molecular testing and have PD-L1 testing to help us get the best therapies. And the other assumption is that patients and physicians are engaging in a dialogue to better assess patient preferences to have a better understanding of performance status, for example, as we think about allocating therapy. One thing that we’ve been able to do is to take the evidence and break it up by histology as well as PD-L1 expression for patients who don’t have driver alterations. Based upon that, think about the toxicity data with, for example, dual immunotherapy versus chemo-immunotherapy for subsets of patients, and so hopefully get some guidance to clinicians as they are going through this process.

    The other part of the guideline was to, once again, look at second-line and subsequent therapies. So, again, for patients who get immunotherapy alone, the recommendation is that patients get a carboplatin-based doublet in the second-line setting. We still do not know if patients should get immunotherapy after that initial exposure, that is the subject of ongoing randomized studies. We also have stronger evidence than ever that docetaxel is an appropriate second-line agent, but there are other options there, so docetaxel and ramucirumab, as well as other single-agent chemotherapies.

    Brittany Harvey: Understood. Those are key points for informed and shared decision-making and are helpful for clinicians to know. 

    So then, Dr. Leighl, in your view, how will these guideline recommendations impact patients with non-small cell lung cancer without driver alterations?

    Dr. Natasha Leighl: Thanks. So, we’re really hoping that with all of the focus in the first-line setting, that more patients will receive immunotherapy with or without chemotherapy in the first-line setting to really bring it forward and really make sure that patients can start benefiting as soon as possible. As Dr. Patel said, one of the challenges, of course, is to understand who might benefit most with a chemotherapy-free approach and have treatments in sequence versus who really needs everything together. And so, we’ve really tried in the discussion to try and help with that discussion both from a provider and patient perspective. So, we want more people to get immunotherapy to help improve their outcomes and also to potentially get it earlier.

    I think the other thing, and Dr. Patel has brought this up, but when we looked at what happens after first-line therapy, we really have very limited recommendations. And so it’s our real hope that this will spur the community on to do even more studies to help us figure out what’s next and how do we really improve outcomes for our patients after all of these great first-line options have stopped working.

    Brittany Harvey: Absolutely. I appreciate you touching on those key points for improved outcomes for patients with non-small cell lung cancer.  

    Finally, Dr. Patel, you have mentioned some ongoing randomized clinical trials and so has Dr. Leighl. So, what are the ongoing developments that the living guideline expert panel is monitoring for future updates?

    Dr. Jyoti Patel: We will continue to update guidelines based on available literature, but certainly, there are a number of trials that we should be reading out in the next year or so, looking at combinations of immunotherapy in the second-line setting. Certainly comparing novel agents to docetaxel in the second-line settings, and things like antibody-drug conjugates. So certaintly that’s evidence that we hope to incorporate this evidence within the guideline with the idea that  we can really help clinicians and patients recognize or at least identify the best options for treatment for them. 

    Brittany Harvey: Definitely. Well, we’ll look forward to the expert panel's review and interpretation of this evidence as those trials read out. And appreciate all of your work on this guideline update and we’ll hear more as these guidelines are continuously updated. Thank you so much for your time today, Dr. Patel and Dr. Leighl. 

    Dr. Jyoti Patel: Thank you.

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

    The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

    ASCO Guidelines
    en-usFebruary 28, 2024

    Systemic Treatment of Patients with Metastatic Breast Cancer Resource-Stratified Guideline

    Systemic Treatment of Patients with Metastatic Breast Cancer Resource-Stratified Guideline

    Dr. Banu Arun and Dr. Sana Al Sukhun share recommendations from the newest ASCO resource-stratified guideline on systemic treatment for patients with metastatic breast cancer. They describe the importance of this new guideline, the four-tier resource setting approach, key recommendations, and implementation considerations. Recommendations are discussed for systemic therapy for HER2-positive, triple-negative, and hormone receptor-positive metastatic breast cancer, across Basic, Limited, and Enhanced resource settings. Drs. Arun and Al Sukhun highlight the importance of this guideline for clinicians and patients in regions with limited resources to optimize cancer care.

    Read the full guideline “Systemic Treatment of Patients with Metastatic Breast Cancer: ASCO Resource-Stratified Guideline” at www.asco.org/resource-stratified-guidelines."

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at http://www.asco.org/resource-stratified-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the JCO Global Oncology, https://ascopubs.org/doi/10.1200/GO.23.00285 

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Banu Arun from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Sana Al Sukhun from Al Hayat Oncology Practice in Amman, Jordan, co-chairs on “Systemic Treatment of Patients with Metastatic Breast Cancer: ASCO Resource-Stratified Guideline.” 

    Thank you for being here, Dr. Arun and Dr. Al Sukhun.

    Dr. Banu Arun: Thank you for having us. 

    Dr. Sana Al Sukhun: Thank you. Pleasure to join you.

    Brittany Harvey: And before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including the guests who have joined us today on this episode, are available online with the publication of the guideline in the JCO Global Oncology, which is linked in the show notes.  

    Then, to jump into the content of this guideline, Dr. Al Sukhun, can you first provide an overview of the scope and the purpose of this guideline? 

    Dr. Sana Al Sukhun: Sure. And again, thank you, Brittany. Pleasure to join you. This guideline is really interesting and very important. It addresses the care and treatment of the most common cancer worldwide, particularly metastatic breast cancer, taking into consideration different availability of resources, particularly in countries with limited resources. As you know, most of us are aware of the importance of clinical practice guidelines improving outcomes for patients in medicine, not only in oncology, but most of those guidelines are developed in countries that are highly resourced. So their applicability in countries of limited resources that lack infrastructure and resources is definitely limited because they cannot really adopt and adapt to those guidelines, which makes resource adapted or resource stratified guidelines quite important and helpful. First, to clinicians caring for patients so that they can properly allocate resources, prioritize how to use therapy for patients, but also even policymakers to allocate resources and plan graduated implementation of science to improve outcomes for their patients according to the progressive availability of resources. 

    So we're talking about breast cancer, the most common cancer worldwide. And not only is it the most common cancer worldwide, but also more than two-thirds of new cases are diagnosed in countries of limited resources. Unfortunately, they also carry the burden of more than 70% of the mortality attributed to breast cancer. Another challenge is that the median age for the patients affected with breast cancer in countries of limited resources is indeed at least a decade younger than Western societies, which adds to the burden, not only the social, but also the economic burden of cancer. And unfortunately, presentation in these countries is mostly locally advanced, metastatic breast cancer, therefore comes the focus on helping our colleagues in countries of limited resources to care for patients according to the resources available, not only in countries of limited resources, even colleagues practicing in less fortunate areas within countries that are highly resourced.

    Brittany Harvey: Excellent. Thank you for providing that background information for this guideline. 

    So then you've just described how many countries and areas have different resources. So, Dr. Arun, could you describe the four-tier resource setting approach that this expert panel used?

    Dr. Banu Arun: Yeah, Brittany, that's a good question. I think it's important to know where we started and what infrastructure we used. So for developing resource stratified guidelines, ASCO has adopted its framework from the four-tier resource setting approach, which was actually developed by the Breast Health Global Initiative, and we employed modifications to that framework based on the disease control priorities. What this framework emphasizes is also that variations can be present not only between countries, but actually within countries with disparities, for example, differences between rural and urban areas within one country.  

    So the four settings are obviously basic, limited, enhanced, and maximal settings. The basic setting includes core resources or fundamental services that are really absolutely necessary for any public health, primary health care system to function at all. These include services that are typically applied in a single clinical interaction. For example, vaccination is feasible for highest need populations.  

    The next tier would be the limited setting. That includes countries or settings with second-tier resources or services that are intended to produce major improvements in outcomes, such as incidences and cost effectiveness. Unlike the basic setting, it can involve single or multiple interactions with providers or healthcare services.

    Then the third tier is the enhanced setting, where the services are optional but important, and these services should ideally produce further improvements in outcome and increase the number of quality of options and also individual choices, maybe countries having the ability to track patients and links to registries. 

    And then the last one is of course, the maximal setting that includes high-level, state-of-art resources and services that are available in some high-resource countries.

    Brittany Harvey: Thank you for describing that framework and the approach that the panel used.

    So then I'd like to move on and talk about the key high-level recommendations of this guideline for systemic therapy for metastatic breast cancer across those three lower tiered resource settings - the basic, limited, and enhanced resource settings. So, Dr. Al Sukhun, could you start with the recommendations across these settings focusing on HER2-positive breast cancer? 

    Dr. Sana Al Sukhun: Sure. You know, HER2-positive metastatic breast cancer is one of the most aggressive subtypes of breast cancer. However, its outcome has been transformed with the introduction of HER2-targeted therapy. So, apart from patients who suffer from congestive heart failure or limited compromised ejection fraction, which can be evaluated on a case-by-case basis, patients are candidates for HER2 targeted therapy. When we made the recommendations according to the availability of resources, we started in a gradual approach. So, in a maximal setting, you treat patients with HER2-positive metastatic breast cancer in the frontline setting using the combination of trastuzumab, pertuzumab, and taxanes or endocrine therapy if patients have limited disease burden, or if they have the recurrence after a long disease-free interval. Usually, the combination of trastuzumab and pertuzumab with taxane is used. But then again, clinicians can use navelbine, considering good data from the HERNATA trial about its efficacy as compared to taxanes and even also, we recommended platinum therapy according to availability.  

    However, if pertuzumab is not available, you go to the next level where we recommend offering, again, chemotherapy, be it taxane, navelbine, platinum, with trastuzumab, or even without trastuzumab if trastuzumab is not available. So, something to keep in mind, chemotherapy is not without efficacy in this aggressive subtype. It is not as good as when you use the combination with HER2-targeted therapy, but it still works. Patients and clinicians in this era of biologic therapy immunotherapy tend to think only pricey medications are the ones that can be used for treatment and improving outcome. However, definitely adding help with targeted therapy is great whenever it's available. But if it's not available, chemotherapy still could be used in a sequential manner. We listed all possible chemotherapeutic options starting with taxanes, navelbine, platinums, even CMF, capecitabine.  

    When it comes to second-line therapy, including those patients who relapse within 12 months of adjuvant therapy, the optimal line of treatment would be trastuzumab deruxtecan. However, if it's not available, we recommend to be offered with successive or progressive preference, if it's not available, T-DM1 could be used. If it's not available, capecitabine and lapatinib could be used. If it's not available, trastuzumab with chemotherapy could be used. If it's not available, we go back to the sequential use of chemotherapy, including adriamycin, taxanes, platinums, capecitabine, or even CMF. 

    Brittany Harvey: I appreciate you reviewing those recommendations for HER2-positive breast cancer. 

    So then, moving along, Dr. Arun, what are the recommendations for patients with metastatic triple-negative breast cancer?

    Dr. Banu Arun: Thank you, Brittany. Triple-negative breast cancer, of course, is one of the serious subgroups of breast cancer. About 10 to 15% of patients have triple-negative breast cancer. What I will do is I will divide it into the three-tier settings as well as first-, second-, and third-line therapies. 

    For patients with triple-negative PD-L-negative metastatic breast cancer in the limited settings and even enhanced settings, single-agent chemotherapy rather than combination chemotherapy should be recommended as the first-line. However, if patients are symptomatic or have immediate life-threatening disease, combination chemotherapy can be offered. 

    For patients with triple-negative breast cancer that are PD-L1 positive, they may be offered in addition to chemotherapy, an immune checkpoint inhibitor, as first-line therapy, most probably in enhanced settings and in basic and limited, of course, chemotherapy. When you move on to the second-line for metastatic breast cancer in patients with or without previous PD-L1 checkpoint inhibitors, clinicians can offer palliative or best supportive care in the basic setting. In the limited setting, chemotherapy with anthracyclines, taxanes, platinums are options. And in the enhanced setting if sacituzumab govitecan is not available, chemotherapy would be an option.

    Now, when we move on to the third-line setting for triple-negative breast cancer, clinicians can actually offer chemotherapy and/or palliative care, depending really on the status of the patient.

    Brittany Harvey: Excellent. Thank you for providing those recommendations for triple-negative breast cancer. As you mentioned, it's one of the rarer forms of breast cancer. So then, Dr. Al Sukhun, I'd like to move into the last section of patients, actually the most common, but hormone receptor-positive breast cancer. What are those recommendations? 

    Dr. Sana Al Sukhun: Thank you, Brittany. As you mentioned, it's the most common subtype worldwide. The rule of the thumb is sequential hormonal therapy, depending on availability. So, whatever you have hormonal therapy, sequential hormonal therapy unless pending visceral crisis or symptomatic disease, it's recommended that you offer sequential single-agent chemotherapy, unless it's a real visceral crisis, where we recommend combination chemotherapy. That's a classic in all our guidelines. 

    When considering frontline hormonal therapy, again, I will start from the maximal level and gradually recommend according to availability. So in enhanced levels in many countries now, we have generic CDK4/6 inhibitors, which increase their availability. So we do recommend hormonal therapy with CDK4/6 inhibitors. Upon progression or when they are not available, on progression, you move to the second line of hormonal therapy. If you have liquid biopsy, check for PIK3CA mutation. Sometimes you do have the liquid biopsy, but you do not have alpelisib to offer to your patients with hormonal therapy, then it's okay, you still can move to second-line fulvestrant with everolimus. Sequentially, you can move forward to fulvestrant by itself if you do not have everolimus. And even you can sequence tamoxifen until your patient stops responding to hormonal therapy then you can offer sequential single-agent chemotherapy. 

    Brittany Harvey: Thank you, Dr. Al Sukhun for providing those recommendations. 

    So then, Dr. Arun, what should clinicians do when we do not have access to receptor assessment? What is recommended for best practices for management of those patients?

    Dr. Banu Arun: So, Brittany, that's an important question. There are some basic settings where unfortunately, immunohistochemistry for ER/PR HER2neu determination is not available. Our group really recommends in these cases that clinicians may presume hormonal receptor positivity and offer tamoxifen in most cases. It is expected that IHC would be available in limited and, of course, enhanced settings.

    Brittany Harvey: Great. Thank you for providing that information. 

    So further, what else should clinicians know as they implement these recommendations, Dr. Arun? 

    Dr. Banu Arun: It's very important that we, all healthcare provider clinicians, really know the data. I think reading the guidelines or knowing about first and second line therapies is obviously important, but the devil is in the details. And I think knowing the publications and subgroup analyses, if needed, because every patient is different and sometimes the recommendations cannot go by the books. You really need to do an assessment of the patient and see in which setting you are and then make the most of the guidelines that are recommended. It's to guide. The name is guidelines. It's to guide. And ultimately, it's the clinician's responsibility to find the best available therapy for the patient. And sometimes that includes no treatment and supportive care.

    Dr. Sana Al Sukhun: Totally agree with Dr. Arun. They are there to support the clinician decision. After all, the clinician is the one who sees the patient, who can evaluate the patient from all aspects — social aspect, physical aspect, the tumor aspect. So it's not just about the tumor, it's about the patient and the environment where the clinician is treating the patient. However, I believe there is support to the clinician not only in treating the patient, but also on addressing priorities for research to improve outcomes for patients in different resource settings. There is also support for the clinicians to help them advocate for improving care for patients in a strategic way, where they prioritize resource allocation. So they are there to support the clinician at all levels, not only when treating patients, but when advocating for patients, when helping patients to make decisions, when they're discussing with their health officials and policymakers.  

    Brittany Harvey: Absolutely. Those are excellent points that you both made about individualizing patient care for the specific person in front of you. So then, finally, Dr. Al Sukhun, how will these guideline recommendations impact patients with metastatic breast cancer globally? 

    Dr. Sana Al Sukhun: The ultimate goal for anything we do, including guidelines, is to improve outcomes for patients worldwide. They are there to support clinician decisions, empower clinicians to optimize care for their patients, to advocate for improving outcomes for patients by strategically allocating resources according to the most impactful strategy. They help clinicians to identify areas for research that are needed according to the resources available to them. They are there to guide policymakers, again, also implementing strategies to implement science that could improve outcomes in an efficient way for their societies. So hopefully, all these, with our research, with our advocacy, with our health policy, with our treatment decisions, hopefully all these will improve outcomes for breast cancer patients and ultimately reduce mortality, particularly in less fortunate, limited resource settings for patients everywhere.

    Brittany Harvey: Absolutely. We hope that these guidelines improve outcomes and quality of life for patients worldwide. 

    So I want to thank you both so much for your work to develop this guideline. There's certainly a large amount of recommendations, so I encourage our listeners to read the full guideline, which is linked in the show notes. And I want to thank you so much for your time today, Dr. Al Sukhun and Dr. Arun.

    Dr. Sana Al Sukhun: Thank you for having us.

    Dr. Banu Arun: Thank you, Brittany.

    Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/resource-stratified-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

    ASCO Guidelines
    en-usJanuary 10, 2024

    Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline

    Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline

    Dr. Isabelle Bedrosian and Dr. Mark Robson discuss the new guideline from ASCO and SSO on germline testing in patients with breast cancer. They discuss the framework for which patients should be offered BRCA1/2 testing, and what additional moderate- and high-penetrance genes may be considered for inclusion in germline testing. They highlight key aspects of personal and family history, recommendations surrounding counseling for genetic testing, and the impact for patients and their families. They close the conversation with a discussion of gaps in the research.
    Read the full guideline, Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02225

    Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts

    My name is Brittany Harvey, and today I'm interviewing Dr. Isabelle Bedrosian from the University of Texas MD Anderson and Dr. Mark Robson from Memorial Sloan Kettering Cancer Center, co-chairs on “Germline Testing in Patients with Breast Cancer: American Society of Clinical Oncology – Society of Surgical Oncology Guideline.” 

    Thank you for being here, Dr. Bedrosian and Dr. Robson.

    Dr. Mark Robson: My pleasure.

    Dr. Isabelle Bedrosian: Thank you, Brittany.

    Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bedrosian and Dr. Robson, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. 

    So then, to jump into the content of this particular guideline, Dr. Bedrosian, could you give us a general overview of both the scope and the purpose of this guideline?

    Dr. Isabelle Bedrosian: Yeah, sure. So, in the last decade or so, the whole area of clinical cancer genetics has become incredibly complicated, driven, I think, predominantly by the development of extended gene testing. And in the midst of this complexity, our goal here was to try to give providers a framework through which they can think about the application of germline testing within their patient population. And really, this framework was to help them think through how testing can best be applied to patients that were both newly diagnosed with breast cancer or had a history of breast cancer, and also to help them think through the scope of that testing as well, be it BRCA testing or testing in a more extended fashion that may help inform longer-term decisions such as risk management.

    Brittany Harvey: Absolutely. We appreciate your efforts to provide recommendations in this framework in this complicated space. 

    So then, I'd like to review the key recommendations of this guideline developed by the expert panel. So first, Dr. Robson, who should be offered BRCA1/2 testing?

    Dr. Mark Robson: Thank you. I think this is perhaps one of the most important things that comes out of the guideline is that we, and the group, are now recommending that anyone who is either newly diagnosed with breast cancer at or before the age of 65, or if they're over 65 and have suggestive personal or family history criteria, or alternatively, if they are eligible for PARP inhibitor therapy, that they all be offered BRCA1 or BRCA2 testing. And the same would hold for women who had a personal history of breast cancer but were not currently under active treatment if their diagnosis had been made at or before 65 or older than that, with certain criteria then they should be offered testing. This is a much simpler way to look at things than the rather complicated existing criteria, which are perhaps a bit both difficult to remember and unfortunately inadequately sensitive in a setting where there is such critical, both therapeutic and risk management implications to the identification of a BRCA mutation.

    Dr. Isabelle Bedrosian: Yeah, I would just also add there's one other, albeit a much smaller group of women for whom BRCA testing could be considered, and those are women who develop a second primary breast cancer. That's another group that I think we can think about offering BRCA1/2 testing to.

    Brittany Harvey: Understood. I appreciate you both reviewing those recommendations for BRCA1/2 testing. 

    So, Dr. Bedrosian, which additional genes does the panel recommend including in germline testing?

    Dr. Isabelle Bedrosian: Yeah. So, in this area, outside of BRCA genes, Brittany, I think the panel didn't make any definitive recommendations or any specific genes that should be tested for. I think the panel felt that the decision to test for additional high penetrance genes and also for some moderate penetrance genes should be guided by the specifics of the individual case, whether the identification of germline mutations makes sense in the context of the patient's personal history and family history. So, in other words, is there a worrisome pattern in the family that might warrant more in-depth testing beyond BRCA, and also considerations around the implications of those test results. Would it change the management for the patient themselves? Either in the treatment of the index malignancy, which, in the case of most of these non-BRCA genes, there really is not changes to the management of the breast cancer that would be offered based on the finding of non-BRCA germline mutations. But potentially, the finding of a non-BRCA germline mutation in a breast cancer patient might help better understand risks of second malignancies that would then be addressed. And certainly for families as well of the patients, identifying those that are carriers could offer opportunities for risk assessment, risk mitigation.

    Dr. Mark Robson: I totally agree with Dr. Bedrosian. One thing I think it's important to understand is that most commercial testing done in the United States now does involve panels of genes. And the group certainly did not intend to suggest that that practice not continue. So, I think if somebody has a history of breast cancer, I think the panel felt that it would at least be reasonable to test for breast cancer susceptibility genes. However, this issue of do you test for all of the high penetrance genes when the family history doesn't suggest it, was certainly something we left open and we did not want to imply that it was obligatory to test for a large number or large panel of genes that weren't related to the patient's personal and family history. So, in other words, didn't want to imply that it was obligatory to do an extremely large panel just as a target of opportunity, if you will.

    Dr. Isabelle Bedrosian: I think really a key part of these guidelines was that we wanted to afford the oncologist flexibility. It's very difficult beyond BRCA to be prescriptive. There are so many considerations about testing, and those considerations will be applied differently in every patient context. So, we really wanted to let providers know that while they have to think about these other genes, and oftentimes there'll be good reason to do these other genes as part of the overall germline testing, again, that it's not obligatory to do so. It's not a fixed set that needs to be tested for. And really, the understanding of the patient's personal history, family history, therapeutic goals, and risk assessment goals should be used to determine kind of the ultimate scope of the testing.

    Brittany Harvey: It sounds like these decisions will be individualized, based on patient characteristics and with working between both patients and their clinicians. So that leads into my next question. But, Dr. Robson, how should patients with breast cancer considering genetic testing be counseled?

    Dr. Mark Robson: With this recognition and emphasis on the therapeutic implications for patients with breast cancer, both surgical and potentially systemic using PARP inhibitors, the approach has gradually moved away from the concept of testing for personal utility, in other words, just wanting to know, and more towards the idea of this being a clinically useful test that's to some extent necessary for the appropriate management of a fair number of patients. And so the counseling is usually- the pre-test counseling is perhaps more educational than we have used in the past, rather than this extensive discussion of whether or not somebody wants to know. Obviously, it's always the patient's ultimate decision whether or not to be tested, and we have to give them the same elements of education that we would have given back in the day. But it can be delivered in a more didactic type of context rather than necessarily the back and forth that takes place with formal genetic counseling. 

    Now, for patients who have complicated or extensive family histories or who have histories that may suggest predispositions other than those for breast cancer, the type of thing that Dr. Bedrosian was talking about earlier, they could certainly benefit, again, from a more formal evaluation by a provider experienced in cancer genetics to help select what the scope of the testing should be, for instance, and also to help interpret those results. And certainly anybody who had a pathogenic variant or a likely pathogenic variant identified should be considered for meeting with somebody who's experienced in clinical cancer genetics both to interpret and also to help with family expansion when appropriate. 

    Brittany Harvey: Excellent. Thank you for reviewing those recommendations from the expert panel. So, Dr. Robson just touched on this a little bit, but Dr. Bedrosian, how will these guideline recommendations affect patients with breast cancer and their families?

    Dr. Isabelle Bedrosian: Yeah, so from a patient perspective, I think there are two ways that these recommendations can impact care. For those women that are identified as germline carriers, specifically with BRCA, it will open the door for receipt of PARP inhibitors, which are currently recommended for patients that are high-risk primary cancer or those with metastatic disease. The other ways that patients will be affected by a germline testing is really in this idea of second cancer risks. Some of these germline mutations are well established to carry risks of either second primary breast cancer or non-breast malignancies. And understanding those risks will allow the patients and their providers to create management strategies, be they surgical or with more intensified screening that will help them mitigate the effects of that germline-driven risk. 

    And I think similarly for the families of patients, the ones the proband has identified, I think that family now has a very real opportunity to better understand their cancer risks and again be able to more effectively manage those risks through either surgical or non-surgical means. And it would really underscore the family component of this. I think oftentimes oncologists are very much focused on the patient and admittedly so that is the person that has the most immediate needs. But I think there's a real opportunity to extend efforts at prevention and early detection by identifying the at-risk family members and allowing them the opportunity to access care that mitigates their cancer risks and hopefully will improve survival outcomes in so doing. So, I think the opportunities for families here to understand risks of germline testing is a really important one to underscore from these recommendations.

    Dr. Mark Robson: Just to expand a little bit on what Dr. Bedrosian was saying, I think this is a very important place for collaboration between the oncology community and the clinical cancer genetics providers because the oncologist is pretty occupied taking care of all of their cancer patients, and the approach to people who are unaffected is a little bit different. People who are unaffected perhaps do need a little bit more pretest counseling to understand the pros and cons of choosing to be tested for the familial mutation. And certainly that idea of family expansion is something that's well known to clinical cancer genetics providers and that's really very much something that they can help the primary oncologists do.

    Brittany Harvey: Absolutely, these recommendations have impacts beyond just the individual patient, but also for their families as well. 

    So then, finally, Dr. Robson, what are the outstanding questions regarding germline testing in breast cancer?

    Dr. Mark Robson: Oh, there are so many. Where should I start? I think over the years we've become, as a community, pretty comfortable managing individuals who have BRCA1 or BRCA2 mutations. There are certainly some questions left, but there's a lot of familiarity with that. I think the challenges expand into these what we call moderate penetrance genes and how to guide people with alterations in those genes. Because except for PALB2, which is relatively uncommon, many of the other genes don't really have the same implications for therapy because it's not clear that they confer PARP sensitivity. It's not at all clear that they have high risks of contralateral breast cancer. And even in the unaffected setting, we know that there's a wide distribution of risk for people who carry these alterations. And some individuals with these alterations probably are not at increased risk at all because they have protective factors. So the management of breast cancer susceptibility genes beyond BRCA1 and BRCA2 is still very much in evolution. They can't be handled exactly the same way as a woman with a BRCA carrier.  

    And then, of course, this issue of how much should we test and what do we do with some of the alterations that we find, if you will, out of context, what are the implications for that and what's the most appropriate management? Those still remain very much open questions. So I think there's still plenty of work to do.

    Dr. Isabelle Bedrosian: Yeah, I agree. I think one of the enormous challenges has been the disconnect between how rapidly our technology has advanced and can sequence alterations, and our ability to really understand the biologic and clinical implications, which really is a time-dependent issue. We need to see over time how patients do for us to understand the implications of some of these germline findings. So that disconnect is a very difficult one to bridge, particularly, I think, for surgical oncologists because they are oftentimes referred patients who don't have a cancer history, necessarily, or have a distant history, and really the concern is “I'm at risk and I would like to reduce my risk.” And it becomes very difficult to counsel patients as to the benefits of risk reduction when we don't have such a great handle on the degree to which they are actually at risk. So that really is a significant gap, I think, for surgeons in particular to have to contend with.

    Brittany Harvey: Definitely. We'll look forward to answering some of those questions as we learn more and get more data to address those gaps.

     So I want to thank you both so much for your work to develop this framework for genetic testing in breast cancer, and thank you so much for your time today, Dr. Robson and Dr. Bedrosian.

    Dr. Isabelle Bedrosian: Thank you, Brittany. 

    Dr. Mark Robson: Thank you for having us.

    Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

    Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

    ASCO Guidelines
    en-usJanuary 04, 2024

    Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Rapid Recommendation Update

    Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Rapid Recommendation Update

    Dr. Rohan Garje reviews the latest rapid recommendation update for the ASCO guideline on systemic therapy in men with metastatic castration-resistant prostate cancer (mCRPC). He reviews what prompted the guideline update and the latest recommendation from the expert panel. Dr. Garje also discusses future updates to the guideline that are currently underway, and outstanding questions regarding systemic therapy for mCRPC.
    Read the latest update, “Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/genitourinary-cancer-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02128 

    Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Rohan Garje from Miami Cancer Institute Baptist Health South Florida, lead author on “Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update. 

    Thank you for being here today, Dr. Garje.

    Dr. Rohan Garje: Thank you so much for having me, Brittany.

    Brittany Harvey: And then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines in ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Garje, who has joined us on this episode today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes. 

    So then, to dive into the content of this rapid update, first, Dr. Garje, what prompted this rapid update to the guideline on Systemic Therapy for Metastatic Castration Resistant Prostate Cancer?

    Dr. Rohan Garje: So, last year, when we did a rapid update on ASCO prostate cancer guidelines, we recommended the addition of 177Lutetium-PSMA-617, also called as PLUVICTO, as a treatment choice for patients who have PSMA-positive metastatic castrate-resistant prostate cancer. After that approval, the primary imaging modality at the time of this initial drug approval was based on gallium-68, which was used in that clinical trial, which was VISION. Since then, we have access to a couple of new radiotracers, one of them being piflufolastat, also called as PYLARIFY, and the newer one called flotuflastat F-18, which is also called as POSLUMA, as additional imaging agents to detect PSMA-positive lesions. So, our expert panel group, along with my co-chairs, we thought to add these additional choices for patient selection because this provides the treating physicians additional options because there really are nuances involved in these imaging agents. So this helps broaden the access to  177Lutetium-PSMA-617 for patients.

    Brittany Harvey: Excellent. I appreciate you providing that background that the panel was reviewing.  

    So then, based on this updated information, what is the updated recommendation from the expert panel?

    Dr. Rohan Garje: So, for the new recommendation, the guideline expert panel recommends use of one of these three radio tracers, that is Ga-68PSMA-11, or piflufolastat F-18, or flotufolastat F-18 as one of the radiotracer choices to screen for PSMA-positive lesions on a PSMA scan, and potentially select the patients for PSMA 177lutetium. This way, we can use one of these three agents rather than previously recommended, as per FDA approval of gallium 68. Now, the reason behind these additional agents, as I was just alluding in my initial comment, is each institution may have access to one of these agents. For example, if a patient had a testing done by piflofolastat or flotufolastat, if they are PSMA-positive, it has shown PSMA-positive lesions as per VISION criteria, we do not suggest the patients to undergo gallium-68 assisted imaging again to have selection for PSMA lutetium therapy. This is unnecessary imaging. We have evidence now, based on the studies which were done with PYLARIFY, which is the piflofolastat, or the flotufolastat, which is POSLUMA, that they are equally good in detecting PSMA-positive lesions. This way we can avoid additional imagings for patients who are being screened for lutetium therapy.

    Brittany Harvey: Understood. Thank you for reviewing the expansion of this recommendation to avoid additional or unnecessary screening. 

    So then, Dr. Garje, the article mentions complete updates to the metastatic castration-resistant prostate cancer guideline are underway. At a high level, could you review what new evidence the panel will look at to update their evidence-based recommendations?

    Dr. Rohan Garje: There have been a lot of developments in the last year, at least, in the treatment strategies for patients with metastatic castration-resistant prostate cancer. Earlier this year, we have seen three big updates about the first-line metastatic CRPC setting, where the combination of PARP inhibitors and androgen receptor pathway inhibitors were tested. For example, in the TALAPRO-2 study talazoparib and enzalutamide, and in the MAGNITUDE study, it was niraparib along with abiraterone. And in the PROpel study, the combination of olaparib and abiraterone was studied. Now, all these combinations have recently received FDA approval with specific nuances with regards to folks who have biomarker positive disease, specifically BRCA1 and BRCA2 mutations. So it is very important to refine this information so that it is utilized by practicing oncologists so that it is widely adapted in their day to day practice.

    Now, in addition, we also are focusing on addressing the need for utilizing biomarkers. The biggest thing for us to offer a biomarker driven therapy is to do biomarker testing. So we are focusing on making sure patients with advanced prostate cancer get biomarker testing so that we can identify who are the patients who get selected. So this particular guideline update is addressing those needs. 

    And then most recently at the recent ESMO meeting, we also noted the positive data from a study called PSMAfore, which evaluated PSMA 177lutetium prior to chemotherapy. This study showed positive data based on progression free survival benefit. So we will review additional data from that and see if a guideline update can be done based on this. So it is very exciting. Now, obviously, we are also waiting on survival data on all the studies. So we are closely monitoring all the updates on these studies so that we can provide more rational guidance based on not only progression-free survival benefit in a specific cohort and also to see if it helps with overall survival improvement.

    Brittany Harvey: Absolutely. We'll look forward to the panel's review of this evidence and then future updates to this full guideline. 

    So then, finally, Dr. Garje, you've alluded to awaiting some data. So could you expand on what are some of the outstanding questions regarding systemic therapy for metastatic castration-resistant prostate cancer?

    Dr. Rohan Garje: I would put that in two boxes. Number one, sequencing. So we are excited that we have a broad spectrum of options; androgen receptor pathway inhibitors, chemotherapy options, radium-223. We have lutetium based options and then biomarker selected patients with PARP inhibitor combinations and select patients with benefit for checkpoint inhibitors. Now, the biggest question we need to answer is how to sequence them, which drug or which combination strategy is ideal for one particular patient. Now, obviously, when we do not have clinical trials which have addressed sequencing, we as an expert panel would want to come up with some mechanism of consensus to identify what treatment sequence would work best for patients. So that is an important question this guideline panel wants to address where we can give some generic information as a consensus, based on the experience of the panel to give guidance for practicing physicians the best sequencing. 

    Now, second thing, very equally important, is biomarkers. This particular guideline update is also focusing on making sure biomarker testing is universal. There has been a lot of evidence that biomarker testing happens very late in the course of the disease, which precludes a lot of patients from these combination strategies. So this particular guideline also is focusing on what biomarkers to be tested and at what time frame, so that they can be optimally utilized for the patient treatment so that the patients will have the best cancer outcomes.

    Brittany Harvey: Definitely, those are important questions for personalized care for people with prostate cancer.  

    I want to thank you so much for your work on this rapid update and your ongoing work on the updates to the full guideline, Dr. Garje, and thank you for your time today.

    Dr. Rohan Garje: Sure, thank you so much.

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/genitourinary-cancer-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

     

    ASCO Guidelines
    en-usNovember 06, 2023

    Systemic Therapy for SCLC: ASCO-OH (CCO) Guideline

    Systemic Therapy for SCLC: ASCO-OH (CCO) Guideline

    Dr. Greg Kalemkerian joins us on the ASCO Guideline Podcast to discuss the newest ASCO – Ontario Health (Cancer Care Ontario) Guideline on systemic therapy for small-cell lung cancer (SCLC). He reviews the evidence-based recommendations from the panel, including guidance on systemic therapy options for resected, limited-stage, extensive-stage, and relapsed SCLC, and NSCLC with an EGFR mutation that has transformed to SCLC, recommendations for older adults with poor performance status, the role of biomarkers, and the use of myeloid supportive agents. Dr. Kalemkerian also highlights future research for systemic therapy options for SCLC, and the impact of guidelines on both clinicians and patients with SCLC.
    Read the full guideline, “Systemic Therapy for SCLC: ASCO-OH (CCO) Guideline” at www.asco.org/thoracic-cancer-guidelines."

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01435 

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts 

    My name is Brittany Harvey, and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, co-chair on “Systemic Therapy for SCLC: American Society of Clinical Oncology – Ontario Health Guideline.” Thank you for being here, Dr. Kalemkerian. 

    Dr. Greg Kalemkerian: Thank you.

    Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Kalemkerian, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. 

    So then, to move into what we're here today to discuss, Dr. Kalemkerian, can you provide an overview of both the scope and the purpose of this guideline?

    Dr. Greg Kalemkerian: So, the guideline is meant to update the systemic treatment for small-cell lung cancer. There have been several changes in the last couple of years. For the first time in quite a few decades, we actually have some newer drugs that have demonstrated benefits in this disease. So we're really focusing on the systemic therapy. And ASCO does endorse the ASTRO guidelines for the radiotherapy involved in patients with small-cell lung cancer.

    Brittany Harvey: Great. That's great to hear that there's new systemic therapy options for patients with small-cell lung cancer. 

    So then I'd like to review the key recommendations of this guideline. This guideline reviews eight clinical questions in total, so we can go through the key points of the recommendations for each question. So let's start with what is recommended for adjuvant systemic therapy in patients with resected small-cell lung cancer?

    Dr. Greg Kalemkerian: So, to start with, only fewer than 5% of people have what would be considered resectable small-cell lung cancer, and that's stage I small-cell lung cancer. So tumors less than 5 cm in size without any lymph node involvement, either hilar or mediastinal lymph node involvement. So purely the very early stages, which are rare in small-cell. And if patients undergo surgical resection for such tumors, the recommendation afterward is to provide adjuvant chemotherapy with four cycles of either cis-or carboplatin plus etoposide in order to try and improve longer-term survival for those patients. 

    The other part of the recommendation is we do recommend that treatment be started within eight weeks of surgery. There is little data on timing in small-cell lung cancer, but that's derived from extrapolating from non-small cell lung cancer as well.

    Brittany Harvey: Understood. I appreciate you reviewing those recommendations for resectable small-cell lung cancer. 

    So then, moving along, what does the panel recommend for patients with limited-stage small-cell lung cancer?

    Dr. Greg Kalemkerian: So, the treatment with limited-stage small cell lung cancer unfortunately has not changed in quite some time. We recommend that patients receive four cycles of either cisplatinum or carboplatin and etoposide concurrently with radiotherapy. Preferably the radiotherapy should be given early and concurrently with the chemotherapy, though we do not recommend that people wait for the radiation to get started in order to start the chemotherapy. So we do recommend that the chemotherapy get started as soon as possible and then the radiation can be added in on the second cycle of chemotherapy.

    Brittany Harvey: Then to follow that up, what is recommended for patients with extensive stage small-cell lung cancer?

    Dr. Greg Kalemkerian: So, extensive stage small-cell lung cancer now is probably the most straightforward of the portions of this. Based on the data from two trials thus far, the IMpower 133 trial and the CASPIAN trial, we now recommend chemotherapy with immunotherapy. The chemotherapy should be cisplatinor carboplatin plus etoposide along with concurrently either atezolizumab or durvalumab as the immunotherapy for four cycles of the combined chemo-immunotherapy followed by maintenance with the immunotherapy drug of choice. With regard to the choice of either cisplatin or carboplatin, meta-analysis has demonstrated that there is no significant difference between the two and our belief is that carboplatin is likely the more reasonable drug in the palliative treatment situation based on its better non-hematologic toxicities.

    Brittany Harvey: Appreciate you sharing those recommendations and some of the rationale behind those. 

    So then moving along, what options are available for patients with relapsed small-cell lung cancer?

    Dr. Greg Kalemkerian: So relapsed small-cell lung cancer gets a little more potentially complicated. One of the main drivers of outcome in patients with relapsed small cell lung cancer is the time since they completed their initial chemotherapy. Patients who have had a longer time since chemotherapy do better and have better responses to subsequent therapy. For patients who relapse with a short interval within 90 days or three months of completion of prior chemotherapy, our recommendation is that they be treated with single-agent chemotherapy. There are two drugs that are currently FDA approved for use in relapsed small cell lung cancer, topotecan and lurbinectedin, and either one of those is the preferred agent as a single-agent treatment in this scenario.

    For people with a longer chemotherapy-free interval, so beyond the 90 days or three months, one could either use combination chemotherapy, so reinitiation or re-induction with the regimen such as carboplatin and etoposide, or one could use single-agent chemotherapy with the preferred agents being topotecan or lurbinectedin again. The use of combination chemotherapy has been shown to improve response rates in this situation over topotecan alone. However, we have not been able to demonstrate that there is a significant improvement in overall survival. So one has to look at the individual patient and make some judgment on whether you think that the added potential toxicity of combination chemotherapy is beneficial for that individual. 

    For people who have progression of disease while they are on maintenance therapy with immunotherapy for extensive stage small-cell lung cancer, we do not recommend continuation of the immunotherapy. So if people progress while they're on the immunotherapy, even if they're nine months out on that, then treatment with second-line chemotherapy, either with the combination agent or with single agents, would be what we would recommend, and not continuing the immunotherapy. If patients had previously been treated for limited-stage small-cell lung cancer where immunotherapy is not part of the initial treatment at this time, and they relapse, say, six months or nine months out from their initial chemotherapy and radiation therapy treatment, then it would be reasonable to perhaps initiate carboplatin etoposide and one of the immunotherapy agents as appropriate treatment, because that patient is immunotherapy naive. 

    However, the single-agent immunotherapy does not have a role in the treatment of patients with relapsed small-cell lung cancer. 

    Brittany Harvey: Understood. It sounds like some of the treatment options are individualized to the specific patient then. 

    So the next question also addresses specific groups of patients. So what did the panel recommend for older adults with small cell lung cancer or for those with poor performance status?

    Dr. Greg Kalemkerian: Approximately half of people who have small-cell lung cancer are over the age of 70 years old, so it is a disease of older smokers. Many of these people have comorbidities that can limit our ability to use standard treatments. Many of these individuals also have poor performance status because the disease is an aggressive disease that causes a lot of problems for people. So the issue of older individuals and people of poor performance status is something that we run into on a regular basis in treating people with small-cell lung cancer. 

    For patients with limited-stage small-cell lung cancer who are older and have a performance status of 0 to 2, it is very reasonable to utilize standard treatment with standard chemo and radiotherapy with curative intent. For people with limited-stage small-cell lung cancer who have a performance status of 3 or 4, and this would include people who might be in an ICU with an obstructive airway, then it is reasonable to initiate chemotherapy in order to try and shrink the cancer down and improve their situation.

    Small-cell lung cancer is a disease that is very sensitive to chemotherapy initial treatment, so many of these people will have shrinkage of tumor and improvement of their symptoms. If the poor performance status is due to the small-cell lung cancer, it has potential to get better. So we do recommend for people at limited-stage small-cell lung cancer and a poor performance status that is felt to be due to the disease, the cancer, then it is reasonable to initiate treatment with chemotherapy. And depending on the person’s response and recovery and improvement in their performance status, then one could add radiotherapy later on or do it sequentially with the definitive radiotherapy for the limited-stage small-cell lung cancer. 

    For older individuals with extensive stage small cell lung cancer who have a performance status of 0-2, it is very reasonable to utilize the standard chemotherapy and immunotherapy as we outlined previously in treating that. For individuals who have a poorer performance status, so performance status 3 or 4, one really needs to individualize the situation. If the poor performance status is due to the cancer, then again, it would be reasonable to attempt chemotherapy in an effort to try and shrink the cancer. There is no data on the use of chemo plus immunotherapy in this patient population. But the use of standard chemotherapy, obviously, in the older individuals preferring carboplatin over cisplatinum with etoposide would be a reasonable option, taking into account abnormalities in organ function that may require dose adjustments or reductions.

    Because small-cell lung cancer is a disease that is quite sensitive and responds well to  chemotherapy, then one can individualize in those situations for patients with poor performance status to see if they can improve their overall situation and have some period of time of optimized quality of life. Clearly, it is a very individualized decision-making whether or not to treat these patients. That requires clearly the patient’s input as well, as a primary driver of what is done. 

    Brittany Harvey: Absolutely. That nuance is helpful for patient-clinician shared decision-making, depending on the factors that you mentioned. 

    So then, switching to the next topic that the expert panel addressed, what does the panel recommend for patients with non-small cell lung cancer with an EGFR mutation that has then transformed to small-cell lung cancer? 

    Dr. Greg Kalemkerian: The EGFR mutant non-small cell lung cancer transformation to small-cell lung cancer is relatively rare. I think in the real world, this probably is occurring in 2%-3% of people with EGFR mutant non-small cell lung cancer, but we do see it. Now, these patients are initially being treated with EGFR inhibitor therapy for their mutant non-small cell lung cancer and then they develop a more aggressive progression of disease. It is important to note that when people progress in that situation, it is important to get a biopsy in order to see whether or not transformation has occurred and whether or not there are any other new driver mutations that might be targetable. If the patient has a small cell lung cancer transformation, then the recommendation is to treat them as we treat patients with small cell lung cancer with chemotherapy consisting of platinum and etoposide for four to six cycles, as we usually do.

    It does not appear that there is a role for immunotherapy in this situation, though we clearly have a paucity of data on these patients. So we do not yet have any trials that have looked at the management of this population. We do have several series that have presented these individuals and what their outcomes are with treatment. And their outcomes are very similar to people with de novo small-cell lung cancer. So not a very good situation, but we do recommend that they be treated with standard chemotherapy, platinum plus etoposide. 

    Another question that arises is do you continue with the targeted therapy with the EGFR inhibitor. And the honest answer is we don't know. We don't have data on that. We do know from case reports, the series, and from personal experiences, that some people, in fact, I think many people, if not most of these individuals, have a mix of both EGFR mutant adenocarcinoma and small-cell lung cancer at the time that they transform. So not every tumor in their body is transforming, so that EGFR mutant tumor is still present in their body. So even though the small-cell lung cancer component, because it's progressing, is clearly not responsive to the EGFR inhibitor any longer, the adenocarcinoma component most likely is still sensitive to the EGFR inhibitor. So it is not unreasonable to continue with the EGFR-targeted therapy along with the small cell lung cancer-directed chemotherapy. Even though we don't have any strong data supporting one way or the other.

    Brittany Harvey: I appreciate that guidance, even with the dearth of data in this relatively rare scenario. 

    So then we've talked a bit about individualized treatment, and often in that conversation, biomarkers come up. So what does the guideline say regarding the role of biomarkers for patients with small-cell lung cancer?

    Dr. Greg Kalemkerian: This is pretty straightforward. Thus far, in people with de novo small-cell lung cancer - so we're not talking about the transformed patients from EGFR mutant, we're talking about people who present with small-cell lung cancer - we have no evidence that molecular diagnostic testing would help guide treatment or improve patient outcomes at this time. So we do not support obtaining molecular diagnostic testing for the routine care of patients with de novo small-cell lung cancer. I would love to talk for the next half hour about what's coming down the pipeline in small-cell lung cancer with regard to identifying subsets of patients and trying to identify the vulnerabilities within those subsets of patients that may lead to better-targeted therapy based on molecular diagnostics, but in the current environment, there is no role for molecular diagnostics. 

    Brittany Harvey: Understood. We'll look for that in future guideline updates instead, then. 

    So then the last clinical question that the guideline addressed - what myeloid supportive options may be offered for patients with small cell lung cancer?

    Dr. Greg Kalemkerian: So this has to be couched initially with whether or not one thinks that myeloid suppressive agents are necessary in the treatment of patients with small-cell lung cancer. So in extensive-stage disease with the use of chemotherapy, say, carboplatin and etoposide, the majority of patients likely don't require myeloid supportive agents. However, if one believes that the patient, because of their own individual characteristics, or in a patient who has already developed myelosuppressive problems, then one could either utilize trilaciclib, which was FDA-approved a couple of years ago and was shown to improve the blood counts in people with small cell lung cancer treatment, or one could utilize G-CSF. So either trilaciclib or G-CSF could be utilized to support the patient's bone marrow.

    In patients who have limited-stage disease, for many years, we have recommended against using G-CSF in combination with chemotherapy and radiotherapy due to concerns for increasing toxicities, including thrombocytopenia. Recent data suggests that this may not necessarily be a hard and fast rule and that if one feels that the patient requires or would benefit from some myeloid support, then G-CSF may be offered to patients undergoing chemotherapy and radiotherapy. I do not think that the standard patient that we see who is starting on treatment requires such support, but some subsets of patients or patients who have already proven that they're getting into trouble with their counts, G-CSF could be utilized in this situation. 

    So with regard to this recommendation, overall, it's that for patients with extensive stage disease, trilaciclib or G-CSF could be used if one feels they're necessary. And for limited-stage small cell lung cancer, G-CSF could be utilized if you feel it's necessary. 

    Brittany Harvey: Thank you for reviewing those options and all of these recommendations. The panel was certainly hard at work reviewing the evidence and developing these recommendations. 

    In your view, Dr. Kalemkerian, what is the importance of this guideline for both clinicians and for patients with small-cell lung cancer?

    Dr. Greg Kalemkerian: Well, I think it's not just small-cell lung cancer, but when you look at guidelines overall, I think they are very important to have evidence-based guidelines as well as expert consensus-based guidelines because, quite honestly, the field is moving very quickly, the field of oncology. Now, small-cell lung cancer hasn't moved as quickly as we would like compared to other aspects of oncology, but it's very hard for the clinician who is trying to care for patients with lots of different tumor types to keep up with all of the flood of literature, the flood of new FDA approvals that are coming out every week. So I do think that utilizing the guidelines is important in order to see what the standard approach might be. 

    Now, I also have to couch that with saying that guidelines are never enough. We have to look at the individual sitting across the exam table from us. We have to personalize the treatment to that individual. I will say that in my own practice, there are very few people who walk in the door who are the optimal patient, who are the person who has outstanding physical function. And in lung cancer, that's even more true because patients tend to be older smokers, and they have a lot of comorbidities and other things that you have to personalize therapy towards in them. So the guidelines are a very good starting point in order to know what the optimal treatment might be and then to adjust that accordingly to the person sitting in the room with you. 

    Brittany Harvey: Definitely, we hope guidelines are a place that clinicians can turn to for evidence-based recommendations and succinct recommendations, but individualized patient and clinician decision-making is paramount to each of our guidelines.  

    So then, Dr. Kalemkerian, we've already talked about this a little bit when you mentioned molecular testing advances down the road. So maybe I'll ask what are the most pressing, unanswered questions about systemic therapy for small-cell lung cancer?

    Dr. Greg Kalemkerian: Yeah, so one of them I'll come back to limited-stage small-cell lung cancer. So, obviously, in the extensive stage, we've now incorporated immunotherapy. And yet I didn't talk about immunotherapy in the limited-stage setting, and neither do the guidelines because thus far we don't have any data on the use of immunotherapy in limited-stage small-cell lung cancer. We are expecting data to be coming down the line within the next year hopefully, definitely, within the next two years, because a number of trials that are either ongoing or have recently been completed looking at incorporating immune checkpoint inhibitors into the treatment of limited-stage small-cell either concurrently with chemoradiation or as consolidation after chemoradiotherapy. So that data is anxiously anticipated. And we're hoping that that might move the needle a little bit further in limited-stage small-cell lung cancer and hopefully improve that long-term survival or cure rate that we see in that disease. 

    Other avenues coming down the line – many of us have made a career of doing negative trials in small-cell lung cancer, myself included, and a lot of that has had to do with trying to target therapies to specific molecular abnormalities, and none of those have really panned out thus far. But coming down the line, as we start to molecularly subtype lung cancers, and the best molecular subtyping that we have thus far is not based on mutational analysis, but more based on expression, gene expression analysis, expression of particular transcriptional factors within different subsets of small cell lung cancer, we're now starting to see some vulnerabilities. So one of these subsets in the small cell lung cancer array has a high expression of DLL3, which is part of the Notch pathway, and we can target that. We haven't figured out how to target it as far as its activity goes, but we can target it as a homing device in order to get either drugs delivered by use of antibody-drug conjugates, or to use a BiTE—a T-cell engaging type molecule—that targets both DLL3and T cells in order to try and amplify that immune response in small cell lung cancers. So recently a compound called tarlatamab had data presented at ASCO and also published in JCO that shows some response, about 20-25% response, in people with relapse small cell lung cancer. These were heavily pretreated patients. So that's moving the needle a bit in favor of a specific targeted therapy. And we're hoping that will lead to further avenues to look at the vulnerabilities of different subsets and be able to develop newer targeted treatments for these diseases, trying to amplify that immunotherapy response as well. 

    Small cell lung cancer is a little bit of an outlier in that it does not respond well to immunotherapy compared to other tumors. Not what we expected based on the high tumor mutational burden and the aggressiveness of the disease. But we know that it does not express a lot of PD-L1. We know that it doesn't have MHC class I molecules. So there are a number of reasons why it doesn't respond, and there is work going on to try and amplify that immune response as well. So I think those three things: the use of immunotherapy in limited-stage, the development of targeted therapies based on subsets, and trying to amplify that immune response are the things that I look forward to in the next few years.

    Brittany Harvey: That's great to hear. We'll await the data to provide answers to those outstanding questions. 

    So I want to thank you so much for your work to develop these evidence-based guidelines, and thank you for sharing your perspective with me today, Dr. Kalemkerian. 

    Dr. Greg Kalemkerian: Thank you, Brittany. And thanks to ASCO for getting these guidelines together and getting the outstanding group of people we had to work on it and getting them out in a timely manner so they can help our patients.

    Brittany Harvey: And also, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

    ASCO Guidelines
    en-usOctober 11, 2023

    Management of Metastatic Renal Clear Cell Cancer Rapid Recommendation Update

    Management of Metastatic Renal Clear Cell Cancer Rapid Recommendation Update

    Dr. Eric Singer highlights the recent rapid recommendation update from ASCO on the management of metastatic renal cell cancer (ccRCC), based on the review of evidence from the phase III COSMIC 313 trial. Dr. Singer reviews the discussion from the Expert Panel and emphasizes clinicians should continue to follow the previously issued recommendations for the management of metastatic ccRCC. He also mentions future directions, ongoing clinical trials, and outstanding questions for these evidence-based guidelines.
    Read the latest update, “Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/genitourinary-cancer-guidelines.

    TRANSCRIPT

    Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Eric Singer from the Ohio State University Comprehensive Cancer Center, lead author on the “Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update.” 

    Thank you for being here, Dr. Singer.

    Dr. Eric Singer: Brittany, great to be with you. Thank you for the invite. 

    Brittany Harvey: Great. Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Singer, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. 

    So then, Dr. Singer, to dive into this rapid update, can you tell me a little bit about what prompted this rapid update to the Management of Metastatic Renal Clear Cell Cancer Guideline, which was previously published in 2022?

    Dr. Eric Singer: Sure. One of the big motivators for this was the fantastic work done by Toni Choueiri and colleagues in publishing the COSMIC-313 trial, which looked at triplet therapy for the management of metastatic kidney cancer: a combination of ipilimumab, nivolumab, and cabozantinib versus patients with placebo plus ipi and nivo. And this was a much-awaited trial, and these results came out. And certainly, there was a lot of interest amongst providers as well as patients to help understand the results of this important study and whether or not we should be changing our practice. So, the guideline group who wrote the initial guideline in 2022 felt that this was a significant enough study to warrant a rapid update.

    Brittany Harvey: Understood. So then, based on this new data from COSMIC-313, what is the updated recommendation from the Guideline Expert Panel?

    Dr. Eric Singer: So, the recommendations largely do not change. Unfortunately, while there was some fantastic information gleaned from COSMIC-313, the survival outcomes that were seen at this point, in context with the toxicity signals that were seen at this point, led the Guideline Committee to recommend against adopting triplet therapy as a standard option. However, the Guideline Committee did encourage patients and providers to continue to refer to and accrue to clinical trials that will be again asking similar questions about the combinations that we should be using to treat metastatic kidney cancer going forward. So essentially, we felt that the survival benefit was not adequate to recommend first-line treatment adoption of this triplet regimen in context with the toxicities that were seen in the triplet regimen. 

    Brittany Harvey: Understood. That's helpful to know. 

    So then, what should clinicians know as they implement this guidance into practice? 

    Dr. Eric Singer: I would recommend that we continue to follow the original guideline as published. There are multiple doublet agents or doublet therapeutic combinations that are available, which we found to have strong survival outcomes and more manageable toxicity profiles than the triplet regimen studied in COSMIC-313.

    Brittany Harvey: Great. Additionally, what does this update mean for patients with metastatic renal clear cell cancer?

    Dr. Eric Singer: Yeah, as we all think about how best to manage patients with metastatic kidney cancer, a lot of the things that we're thinking about are, will this treatment make people live longer, and will this treatment make patients live better, balancing both efficacy and also looking at toxicity. And I think in this case, there wasn't the survival endpoints or the survival benefit we were hoping for, again, sort of a surprisingly low number of complete responses seen in this study compared to prior pivotal trials, and quite a bit of toxicity because we're combining three different drugs. And when we do combine medications, we're always hoping for synergy in terms of the efficacy so the combination working better than what we'd expect just by adding those outcomes together. But unfortunately, we also got quite a bit of additive toxicity in the combination as well. So, I think that we still have many excellent options to choose from and that, unfortunately, at this time, there didn't seem to be the survival benefits in light of the toxicity to warrant a change.

    Brittany Harvey: Absolutely. That balance of benefit and harms is crucial. 

    So then, finally, you mentioned that this guideline encourages enrollment in clinical trials, but I want to also ask you, what are the outstanding questions that we're looking forward to regarding the management of metastatic renal cell cancer?

    Dr. Eric Singer: Brittany, I think there's a lot of important questions for us to work on answering. Like we were sort of alluding to in a study like this, we want to know not only which patients are likely to benefit from a combination of therapies, but we also want to begin to learn more about which patients are at an especially high risk of toxicity from combined treatments. So, not only can I counsel a patient about what we think this will do for disease control, but also to identify potential risk factors for adverse events because that can help us choose between the multiple different options we have available. We also have a lot of options at our disposal now in terms of combining different types of therapy: How should we integrate surgery, radiation, systemic therapy? What order should we do them in? What is the best combination to use at each of these steps, so that we can continue to help patients live longer and live better on their kidney cancer journey?

     

    Brittany Harvey: Absolutely. Well, I want to thank you so much for your work to update this guideline very rapidly, and thank you for sharing your insights with me today, Dr. Singer.

    Dr. Eric Singer: Brittany, my pleasure. And again, I really appreciate the work of everyone who's been on the metastatic kidney cancer panel, such fantastic professionals in terms of their clinical expertise, and then also the fantastic ASCO staff, where we really wouldn't be able to do this work without the amazing dedication and hard work of our ASCO team members.

    Brittany Harvey: Definitely a big thank you to the entire expert panel. 

    And also thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. 

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

     

    ASCO Guidelines
    en-usOctober 10, 2023

    Systemic Therapy for Tumor Control in Metastatic Well-Differentiated GEP-NETs Guideline

    Systemic Therapy for Tumor Control in Metastatic Well-Differentiated GEP-NETs Guideline

    Dr. Jaydira Del Rivero and Dr. Kimberly Perez discuss the latest ASCO guideline featuring evidence-based recommendations on systemic therapy for well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). They discuss the recommendations, insights from the guideline expert panel, impact for clinicians and patients, and outstanding questions in the field.
    Read the full guideline update, "Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline” at www.asco.org/gastrointestinal-cancer-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at http://www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology https://ascopubs.org/doi/10.1200/JCO.23.01529  

    Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I am interviewing Dr. Jaydira Del Rivero and Dr. Kimberly Perez, co-chairs on “Systemic Therapy for Tumor Control in Metastatic Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.”  

    Thank you for being here, Dr. Del Rivero and Dr. Perez. 

    Dr. Jaydira Del Rivero: Thank you.  

    Dr. Kimberly Perez: Thank you, Brittany. 

    Brittany Harvey: Then before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Del Rivero and Dr. Perez, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology which is linked in the show notes.  

    Now, to start us off on the content of this guideline, Dr. Del Rivero, can you provide an overview of both the scope and the purpose of this guideline? 

    Dr. Jaydira Del Rivero: Thank you so much, Brittany for the introduction. I would also like to thank ASCO as well for giving us the opportunity, me and Dr. Perez, to discuss briefly the guidelines for gastroenteropancreatic neuroendocrine tumors.  

    In terms of your question of providing an overview of the scope and purpose of this guideline, we wanted to make recommendations about the various systemic therapies and the management of advanced, unresectable, metastatic gastroenteropancreatic neuroendocrine tumors from grade 1 to grade 3. I’m fortunate to be the co-chair with Dr. Perez, but among the different experts and panelists on this guideline, it is important to establish a guide on how to manage patients with gastroenteropancreatic neuroendocrine tumors. And one of the reasons is because there really is not sequencing enough therapy, and there have been a lot of discussions even among the neuroendocrine tumor experts for at the same time provide information and guide to oncologists in the community to understand more about the management of these neuroendocrine tumors as well as provide in a more standardized manner about how a neuroendocrine tumor expert sees or manages a patient with neuroendocrine tumor. 

    Brittany Harvey: Great. Thank you for providing that overview.  

    So, you just mentioned that this guideline covers grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors. So, Dr. Perez, what are the general recommendations that the panel made for grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors? 

    Dr. Kimberly Perez: Thank you, Brittany. I think the biggest take home for treatment for this group of tumors is based on the heterogeneity of the disease. We can classify this very broad group of tumors into grade 1 to 3 based on histologic features, and we use that to guide treatment. But we also take use the functionality of the tumors to direct treatment, and that can be assessed clinically as well as by functional imaging or nuclear medicine-based imaging. And that’s really how our intention is in trying to provide recommendations for the treatment of these various tumor types. So, we, as a group in our discussions, it really came down to approaching the patient's situation, determining whether or not the patient had functional symptoms as a result of hormone excess, and then determining what their radiographic features were, specifically whether or not somatostatin receptor presence was noted and then the grade of the tumor and lastly, the bulk of disease and the rate of growth. And it’s really those features that drive the different treatment options. 

    Brittany Harvey: Excellent. Thank you for reviewing those general recommendations to identify those features that lead to specific treatment options.  

    So, Dr. Del Rivero, what systemic therapy options are recommended for first, second, and later line therapies for grade 1 to grade 3 gastroenteropancreatic neuroendocrine tumors? 

    Dr. Jaydira Del Rivero: As Dr. Perez mentioned earlier, neuroendocrine tumors are quite heterogeneous, and it's not a one-size-fits-all in terms of how we manage patients with neuroendocrine tumors. As Dr. Perez also mentioned, too, in terms of how we manage these neuroendocrine tumors, we need to consider the extension of the disease, whether it's low burden tumors versus high burden tumors. What is the pace of growth? Whether it's stable or rapidly progressive, and whether it's widely metastatic as well or if it's only localized in one area, liver-dominant disease. We also need to understand the primary site, and that's why these guidelines, we also divided it in terms of how we see it in terms of first and second line therapies between pancreas and small bowel neuroendocrine tumors. And as Dr. Perez said, the grade differentiation is also important. That's the reason why, when discussing and developing these guidelines, it was important to differentiate between grade 1, grade 2, as well as the grade 3. And also, as Dr. Perez mentioned, whether they are functional tumors, meaning they produce hormones or not and the symptoms related to that.  

    And I just would also like to mention that we are currently working on the symptom management of neuroendocrine tumors, taking into consideration the hormone status of the tumors. That  is something that we’ll follow up in these guidelines as well. And as Dr. Perez mentioned whether they express somatostatin receptors or not. So based on that, the expert panelists as well in developing these guidelines, we divided them into grade 1 and grade 2 GI (or gastrointestinal) neuroendocrine tumors or pancreas neuroendocrine tumors. And that is based on the proliferation index as well. If the proliferation index of the Ki-67 is greater than 20%, we know that this is a grade 3 gastroenteropancreatic neuroendocrine tumor, which that, in itself is a different category in terms of management.  

    Now, for gastrointestinal grade 1 and grade 2 neuroendocrine tumors, the first line of therapy, one of the things that we need to establish is whether the tumor expresses a somatostatin receptor or not, and that we confirm this via 68Ga-DOTA-peptides or 64Cu-DOTATATE scan. If they expressed the receptors, then I would initiate first line therapy or what is recommended in these guidelines is to start with a somatostatin agonist, either octreotide or lanreotide. One thing to mention here is that either octreotide or lanreotide is considered equivalent in terms of efficacy, we don’t have any head-to-head comparison to determine which one may be better. We think it's equivalent, the two of them. And because of that, whichever is available is what we recommend.  

    Now if there is evidence of disease progression after the use of a somatostatin agonist, we need to determine whether they still express somatostatin receptors. And as a second line therapy, we can consider patients as candidates for 177Lu-Dotatate or PRRT with 177Lu-Dotatate. Usually, our recommendations are, if the patient has a functional tumor, if it’s producing hormones and symptoms related to hormone excess, we still continue the somatostatin agonist. But if the tumor is a non-functional tumor after disease progression on a somatostatin agonist, we don’t necessarily need to continue with either lanreotide or long-acting octreotide.  

    Now, sometimes, some of the discussions that were done as well when developing these guidelines is a concern about hematologic toxicity. And if there is any concern of hematologic toxicity, the patient may not be a candidate for 177Lu-Dotatate. In these situations, everolimus can be considered as a second or later line therapy in patients with G1 or G2 gastrointestinal neuroendocrine tumors. If the patient is somatostatin receptor negative, we can consider everolimus as well. As you can see, with GI neuroendocrine tumors, we really need to take into consideration what we discussed earlier today, and also discussed with Dr. Perez. 

    Now, in terms of the grade 1 or grade 2 pancreatic neuroendocrine tumors, similar to what we discussed on the small bowel or gastrointestinal neuroendocrine tumors, we first need to determine whether the tumor is somatostatin receptor positive through scans such as 68Ga-DOTA-peptides or 64Cu-DOTATATE scan. Based on that, the first line is also considered, a somatostatin agonist, either octreotide or lanreotide. If there is disease progression on that, then we can consider other lines of therapy, such as Peptide Receptor Radionuclide Therapy or PRRT with 177Lu-Dotatate or chemotherapy with capecitabine and temozolomide, or everolimus, or sunitinib. Now, one thing to keep in mind whenever we make these recommendations is for those pancreas neuroendocrine tumors that, in addition to being somatostatin receptor positive, are the ones that have a lower volume of disease or without significant symptoms related to tumor burden.  

    Now we have pancreas neuroendocrine tumors with a higher volume of disease and symptoms related to tumor burden, regardless of somatostatin receptor expression, then usually what the panelists have considered as a first line therapy is chemotherapy with capecitabine and temozolomide. And if there is any disease progression after that, then we also need to establish as well whether they still retain somatostatin receptors avidity if it’s positive. Other options to consider will be 177Lu-Dotatate, everolimus, or sunitinib. Those are the FDA-approved agents for the management of neuroendocrine tumors. And if they are somatostatin receptor negative, it will be everolimus or sunitinib. 

    Now, in terms of grade 3 gastroenteropancreatic neuroendocrine tumors, when the Ki-67 is greater than 20%, there are various options as well. And a lot of the treatments that have been recommended for grade 1 to grade 2 neuroendocrine tumors can also be recommended for grade 3 neuroendocrine tumors. But that said, as we discussed earlier, we also need to understand the growth of disease or the aggressiveness of the disease, as well as the symptoms related to that as well as the tumor burden. But based on that, there may be other treatments available for grade 3 neuroendocrine tumors, such as various types of chemotherapy as discussed in the guidelines. There are also ongoing clinical trials that will help us better understand and have more evidence-based therapy for the treatment decisions of patients with gastroenteropancreatic neuroendocrine tumors. 

    Brittany Harvey: Dr. Del Rivero, I appreciate you reviewing those recommendations and the nuance from the panel's discussion.  

    Dr. Perez, is there anything you'd like to add about those recommendations? 

    Dr. Kimberly Perez: Dr. Del Rivero covered everything that we intended to impart to the community about treatment of gastroenteropancreatic neuroendocrine tumors. I think the only highlight I would make and was intentional on our part was separating gastrointestinal and pancreatic neuroendocrine tumors; because there have been clinical trials demonstrating the different efficacy of treatments based on the primary site of disease. 

    Brittany Harvey: Absolutely, that makes a lot of sense. So then, Dr. Perez, in your view, what is the importance of this guideline and how does it impact both clinicians and patients with gastroenteropancreatic neuroendocrine tumors? 

    Dr. Kimberly Perez: I think the importance of the guidelines, I found, was the common theme in our discussions with the other panelists on the group was because of the rarity of the disease and the clinical trials that we are drawing our experience from, there’s a lot of different ways to interpret the data that’s available. And we all spent a lot of time discussing how we've interpreted the data and how we implement it in our practice and how it’s influenced the development of current clinical trials and the ideas supporting future clinical trials. So I think that our intention was to provide community oncologists or general oncologists, who don't see patients with this disease very often, with an algorithm or review of what is available and how you can try to put your patients into the algorithm in a way that would result in best results or best outcomes.  

    Brittany Harvey: Absolutely. We hope this is a resource for community oncologists to help improve outcomes for their patients.  

    You also just mentioned future clinical trials, so I'll turn back to Dr. Del Rivero. What are the outstanding questions regarding systemic therapy for metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors? 

    Dr. Jaydira Del Rivero: Great, thank you for that question. I would like to mention that in the development of these guidelines, there were a few discussions about when to implement observation. Because we know that patients with neuroendocrine tumors, in terms of the biology, they may be very slow-growing tumors. One of the discussions was: when is observation recommended? Usually, what the discussion was based on the consensus from all the panelists is that observation could be considered in patients with low volume or very slow-growing disease in the absence of any symptoms, meaning from either tumor burden or functional tumors. I think this could still be considered in a subset of patients. It's not necessarily for everyone. I think we agree that a lot of the patients with neuroendocrine tumors, when they present to us, they already had metastatic disease and that's when they are sick. The recommendations of medical oncologists is to determine the next line of therapy.  

    One of the other discussions I would like to mention was about the deficiency of MGMT, and that was based on the data report by Dr. Pamela Kunz. This was also presented at the ASCO meeting and recently published in the Journal of Clinical Oncology, the validity of MGMT deficiency in patients with pancreas neuroendocrine tumors and how that correlates with response. That said, I think the consensus was that even though we can consider that as a predictive biomarker, it's still not something that is a primetime to use, but it was something that was recommended, was discussed during the discussion of the development of these consensus statements. Dr. Perez, we would also like to note that, also Dr. Perez, and what other important aspects were discussed during the development of the guidelines. With that said, a lot of the questions will be answered in ongoing critical trials as well from metastatic  neuroendocrine tumors.  

    I think we’re in a very exciting time where we have not seen a lot of more clinical trials for neuroendocrine tumors and a lot of treatment options than where it was more than 10 years ago. I think one of the questions about sequencing, too, and that's something where there's insufficient evidence in terms of what to recommend, a particular sequence of therapy. With that said, there have been ongoing studies presented at the ESMO Meeting as well, and that in terms of some of the trial results in patients with gastroenteropancreatic well-differentiated neuroendocrine tumors. But I say still, that’s an ongoing question too. And ongoing trials are also currently active, not only for pancreatic neuroendocrine tumors, but as well for gastroenteropancreatic neuroendocrine tumors. And that’s an exciting time to also learn more about these studies and looking forward to also learn about  the results of these studies.  

    And Dr. Perez, what are your thoughts? 

    Dr. Kimberly Perez: I agree with all of your sentiments. I think some additional topics of discussion that came up were in regards to: how to define the burden of disease? So we use that as one of the characteristics for determining what treatment option we want to consider. We found that the data really only addressed this when trialists were looking at liver burden of disease. I think that is something as a scientific and clinical community, we need to define a bit better in our future clinical trial efforts.  

    I think the second is this question of Ki-67 and rate of growth. In Jennifer Ead's study, looking at CAPTEM versus platinum and etoposide and the grade 3 group, the delineation made was a Ki-67 of around 55%. As her trials and other trials looking at the therapeutic options in this grade 3 category mature, we will be able to better characterize that, and I think it will be important to provide guidance to patients and providers on how to really define the Ki-67 that requires a certain type of treatment.  

    And then I think the last question I recall was in regards to using somatostatin receptor-based therapy when you don’t yet have somatostatin-based imaging or when you have somewhat of a mixed uptake in somatostatin imaging. I think that too, as the new radiopharmaceuticals are developed and technology improves, this question will be answered. 

    Brittany Harvey: Definitely, those are important questions to determine therapeutic options for patients. We'll look forward to those future developments ahead.  

     

    Thank you both so much for your work to develop this guideline and these recommendations, and I want to thank you so much for joining me here on the podcast today, Dr. Perez and Dr. Del Rivero. 

     

    Dr. Jaydira Del Rivero: Thank you, Brittany. 

    Dr. Kimberly Perez: Thank you so much for having us.  

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. 

    The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experiences, and conclusions. These do not necessarily reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 

    ASCO Guidelines
    en-usSeptember 29, 2023

    Systemic Therapy for Melanoma Guideline Update

    Systemic Therapy for Melanoma Guideline Update

    Dr. Michael Atkins and Dr. Vernon Sondak highlight the latest updates to the systemic therapy for melanoma recommendations in this newest guideline. The discussion covers neoadjuvant and adjuvant therapy for resected cutaneous melanoma, options for unresectable and/or metastatic cutaneous melanoma, and therapies for noncutaneous melanoma. They review the importance of this guideline and the most pressing outstanding questions to help inform better treatment strategies for patients with melanoma.
    Read the full guideline update, "Systemic Therapy for Melanoma: ASCO Guideline Update" at www.asco.org/melanoma-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at http://www.asco.org/melanoma-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO. 23.01136

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.

    My name is Brittany Harvey, and today I'm interviewing Dr. Michael Atkins from Georgetown Lombardi Comprehensive Cancer Center, and Dr. Vernon Sondak from H. Lee Moffitt Cancer Center and Research Institute, authors on “Systemic Therapy for Melanoma: ASCO Guideline Update.”

     

    Thank you for being here today, Dr. Atkins and Dr. Sondak.

    Dr. Vernon Sondak: Happy to be here.

    Dr. Michael Atkins: Yeah, it's a pleasure.

    Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Sondak and Dr. Atkins, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

    So then, to dive into the content here, Dr. Sondak, what prompted this full update to the Systemic Therapy for Melanoma Guideline, which was initially published in 2018?

    Dr. Vernon Sondak: Well, the last 10 years or so have seen enormous advances in the management of metastatic melanoma and localized melanoma with systemic therapy, and the last few years haven't slowed up at all. So since 2018, we've seen new approvals, we've seen key pivotal trials that have shown some amazing results that we'll talk about, and all of these things together weighed into the decision to update the systemic therapy guidelines.

    Brittany Harvey: Great. Thank you for that background on what prompted the update. So then, this guideline provides updated recommendations across four clinical questions. I'd like to review the key updated recommendations for our listeners. So first, Dr. Sondak, what has changed in the updated recommendations regarding neoadjuvant therapy for adults with resectable cutaneous melanoma?

    Dr. Vernon Sondak: Neoadjuvant therapy is one of the most rapidly evolving and exciting parts of the management of melanoma with systemic therapy. The updated guidelines now include neoadjuvant pembrolizumab as a new recommendation for patients with resectable stage IIIB to IV cutaneous melanoma. This is based on the SWOG S1801 clinical trial, which was a very simple and yet incredibly influential clinical trial. It took patients with resectable metastatic melanoma, either metastatic to the lymph nodes or beyond, as long as it could be removed surgically, and randomized all of the patients to either get surgery, followed by a year of adjuvant pembrolizumab, which is very standard, or the same exact surgery and the same total amount of pembrolizumab, but with three of the doses given before surgery. So that simplicity, that ability to just compare the effect of neoadjuvant or preoperative pembrolizumab to entirely postoperative adjuvant pembrolizumab, made this trial a really pure assessment of the value of neoadjuvant pembrolizumab.

     Impressively, this study showed a significant improvement in event-free survival for patients who got those three doses of pembrolizumab upfront. What's event-free survival? That includes relapse-free survival, but also the kinds of events that you can see happening with neoadjuvant therapy, such as progression of the disease prior to surgery that makes the patient unresectable. And the bottom line is that there was really the same number of issues with neoadjuvant pembrolizumab as with surgery, followed by adjuvant therapy, but there were many fewer recurrences among the patients who got neoadjuvant pembrolizumab. So that's why this was put into the guidelines.

    Brittany Harvey: Excellent. I appreciate you reviewing the evidence behind those recommendations and what's new for neoadjuvant therapy.

    So then, Dr. Atkins, moving into adjuvant therapy, for patients with resected cutaneous melanoma, what is new in the recommendations regarding adjuvant systemic therapy options?

    Dr. Michael Atkins: Sure. In the prior version, adjuvant therapy was recommended for patients with stage IIIB, IIIC, and for some patients with stage IV resected to NED. And those were based on studies with adjuvant pembrolizumab, adjuvant ipilimumab, and adjuvant nivolumab compared to ipilimumab. But what's happened since then is some really important adjuvant studies have been carried out in patients with stage IIB, IIC, and IIIA disease who are at slightly lower risk of recurrence, but still have substantial risk of recurrence, and make up a large percentage of the patients who eventually develop stage IV disease.

    And in these studies, one with pembrolizumab compared to placebo, there was about a 40% to 50% reduction in relapse-free survival observed, leading to the FDA approval of pembrolizumab in that setting. And then recently we saw the results of a similar study involving nivolumab that showed maybe even a slightly better reduction in the risk of relapse in that same patient population. Ultimately, this will lead to FDA approval as well. And we felt it was important to put in the guidelines the results of these studies so that people can have informed discussions with their patients about whether they want to receive this therapy going forward. It's important to point out that we don't have good data yet on overall survival. We just have data on relapse-free survival. So we don't, for sure, know that treating patients early, rather than waiting until a subset of them relapse and treating those late leads to an improved overall survival. That's an important discussion to have with patients to provide them with this option.

    In addition, we saw the results of the IMMUNED trial, which looked at nivo-ipi or nivo monotherapy versus placebo or observation in patients with stage IV disease that had been completely resected. And we saw dramatic improvement for the nivo-ipi combination compared to nivo or observation in those patients with stage IV NED. And we felt that, therefore, this was also an important patient population where we should offer guidance

    Brittany Harvey: Absolutely. That shared patient-clinician decision-making is paramount. And then you've both reviewed the options for resected cutaneous melanoma. But Dr. Atkins, what is new regarding systemic therapy options for patients with unresectable and/or metastatic cutaneous melanoma?

    Dr. Michael Atkins: Yes. For patients with unresectable metastatic cutaneous melanoma, there was a new drug combination that was approved combining nivolumab with relatlimab, which is an anti-lag-3 antibody that showed benefit compared to nivolumab monotherapy across almost all subgroups. In particular, the benefit was similar regardless of BRAF mutation status, regardless of elevated LDH, and regardless of patient stage. That led to FDA approval, and this is now an available treatment option, which is associated with less toxicity and similar efficacy to the standard of care nivo-ipi.

    In addition, although nivolumab-ipilimumab had been approved and was in our last recommendation for patients with BRAF-mutated melanoma, we didn't really know whether they should receive BRAF/MEK inhibitors, which were also approved, versus nivolumab-ipilimumab as their initial therapy. And so in the past few years, we saw the results of the DREAMseq trial, which randomized patients with BRAF-mutant melanoma to either nivolumab-ipilimumab, followed by BRAF-MEK inhibitor progression, versus the converse sequence. And we saw that at two years, the starting with a nivolumab-ipilimumab had a 20% improvement in two-year overall survival. This prompted the NCCN to change their guidelines to list nivolumab-ipilimumab or other immunotherapies as a preferred frontline therapy. And we thought that this data was important enough and somewhat validated by a randomized phase II trial, the SECOMBIT, which had a lot smaller numbers to encourage us to change the guidelines.

    Other minor things that we did were to take T-VEC and no longer recommend that as an option for patients with BRAF-wild type disease who had progressed on anti-PD-1 therapy and that ipilimumab and ipilimumab-containing regimens were no longer recommended for patients with BRAF-mutated disease after progression on other immunotherapy. We felt that those patients probably are best served to get BRAF/MEK inhibitors.

    Brittany Harvey: It's good to have clarity on some of those sequencing options for patients and also on which treatments are working better for patients in these subpopulations.

    So then, Dr. Sondak, the last set of recommendations. What has changed regarding options available for patients with noncutaneous melanoma? 

    Dr. Vernon Sondak: There's no question that our patients with noncutaneous melanomas, such as uveal melanoma or mucosal melanoma, have many fewer options and haven't benefited as much from the revolution in treatment that we've seen with our cutaneous melanoma patients, but there have been definite improvements and progress. The full update incorporates new recommendations for uveal melanoma that were published in 2022 as a rapid recommendation update, specifically a new drug called tebentafusp, which is restricted to HLA-A*02:01-positive patients. It's HLA-type restricted, but it is active in patients with metastatic uveal melanoma. And so the new guideline is that previously untreated patients with metastatic uveal melanoma who are HLA-A*02:01-positive should be offered tebentafusp as a treatment option. So that means all our patients with metastatic uveal melanoma should get HLA typed, so they know if they're a person who is eligible for this treatment and it should be considered early on in the treatment paradigm.

    Brittany Harvey: Well, thank you both for reviewing the updates to these evidence-based recommendations. There's a lot that's new in this field. 

    So then, Dr. Atkins, what is the importance of this guideline? And in your view, how will it impact clinicians, and also how will these guideline recommendations affect patients?

    Dr. Michael Atkins: Sure. Well, we have new treatments such as relatlimab and tebentafusp that are available and should be offered to appropriate patients, and new data on how to optimally apply previously approved treatments such as nivolumab-ipilimumab in patients with BRAF-mutated or resected stage IV melanoma, pembrolizumab use in the neoadjuvant setting, and nivo and pembro in earlier stage disease. And with this new information out there and included in the guidelines, hopefully, this will allow practitioners to give the best possible treatments to their patients, and patients to receive treatments which will improve their outcomes.

    Brittany Harvey: Absolutely. It's great to have new data to better inform treatment options for patients with melanoma.  

    So then, finally, Dr. Sondak, what are some of the most pressing outstanding questions regarding systemic therapy for patients with melanoma that may need to be addressed in a future guideline update?

    Dr. Vernon Sondak: Every advance brings up new questions. In neoadjuvant therapy, we have single-agent pembrolizumab with strong data from the randomized trial I spoke about. We anticipate more data about combination immunotherapy, specifically low-dose ipilimumab and nivolumab in the setting of neoadjuvant therapy. There are some trials going on with that. The best neoadjuvant treatment, the best sequence, how long should we treat, and even should we change the surgery based on the results of neoadjuvant therapy, not just the surgery, but the postoperative adjuvant therapy? Those are all questions that are key in the neoadjuvant side. 

    In the adjuvant therapy side, we have much more clarity now about BRAF versus immunotherapy in unresectable disease, but we still don't know always what's the best adjuvant therapy for our BRAF-mutated patients. That's an area we hope will eventually get more clarity, but I think it's going to take a while for that.  

    And finally, we'll learn more about the optimum sequencing of patients with metastatic disease, but especially for the patients who've already failed adjuvant or neoadjuvant therapy. So much of the data that Dr. Atkins and I talked about in metastatic disease, whether cutaneous or noncutaneous, involved previously untreated patients. But so many of our metastatic disease patients today have come to us already with some form of treatment in the adjuvant or neoadjuvant setting. We still have a lot of work to do to define the best treatment strategies for those patients. 

    Brittany Harvey: Definitely. Well, we'll look forward to learning more as new data comes out and as some of that research comes to fruition. So I want to thank you so much for your work to update this guideline and thank you for your time today, Dr. Sondak and Dr. Atkins.

    Dr. Vernon Sondak: Thank you.

    Dr. Michael Atkins: You're very welcome. Thanks a lot.

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/melanoma-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

    ASCO Guidelines
    en-usSeptember 06, 2023

    Integrative Oncology Care of Symptoms of Anxiety and Depression in Adults with Cancer: SIO-ASCO Guideline

    Integrative Oncology Care of Symptoms of Anxiety and Depression in Adults with Cancer: SIO-ASCO Guideline

    Dr. Julia Rowland shares the newest evidence-based recommendations from SIO and ASCO on integrative therapies for managing anxiety and depression symptoms in adults with cancer. Listen in to hear recommended options, such as acupuncture, aromatherapy, hypnosis, mindfulness, music therapy, relaxation, reflexology, Tai Chi and/or Qigong, and yoga. Dr. Rowland also discusses therapies the panel investigated but found insufficient evidence to support a recommendation for use in treating anxiety and depression. We also review how this guideline complements the recent ASCO guideline on conventional therapies for managing anxiety and depression, and the impact for patients and clinicians.
    Read the full guideline, "Integrative Oncology Care of Symptoms of Anxiety and Depression in Adults with Cancer: SIO-ASCO Guideline" at www.asco.org/survivorship-guidelines

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the update and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00857   

    Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts

    My name is Brittany Harvey and today I'm interviewing Dr. Julia Rowland from the Smith Center for Healing in the Arts, Co-chair on “Integrative Oncology Care of Anxiety and Depressive Symptoms in Adult Patients with Cancer: Society for Integrative Oncology American Society of Clinical Oncology Guideline.” 

    Thank you for being here, Dr. Rowland.  

    Dr. Julia Rowland: Lovely to be here, Brittany. Thanks for this opportunity. 

    Brittany Harvey: We're glad to have you on. 

    Then before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including the guest on this episode, are available in line with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. 

    So then I'd like to jump into the content of this guideline. So Dr. Rowland, what is the purpose of this joint SIO and ASCO guideline? 

    Dr. Julia Rowland: The purpose of the joint guideline, Brittany, published in the Journal of Clinical Oncology is to provide evidence-based recommendations to healthcare providers on integrative approaches to managing anxiety and depression symptoms in their adult cancer patients. By integrative approaches, we mean such interventions as yoga, relaxation, hypnosis, mindfulness, acupuncture, music therapy in treating anxiety and depression. Many of these therapies are already being used by people with cancer both during and after their treatment, with rates increasing over time. While use of integrative interventions can serve to improve quality of life, reduce stress, and provide individuals with a sense of control over their health, and they're often reported by patients as doing just that, it's important to note that for the purpose of this guideline, we examine specifically the ability of these interventions to significantly reduce symptoms of anxiety and depression.

    Brittany Harvey: Great. And then, as you just mentioned, this guideline covers both anxiety and depression. So then I'd like to review the recommendations made by the expert panel and we'll go in order of those. So starting with those recommendations for anxiety, what integrative therapies are recommended for managing symptoms of anxiety experienced after diagnosis or during active treatment? 

    Dr. Julia Rowland: The strongest recommendations in the guideline are for the use of mindfulness-based interventions, which include mindfulness-based stress reduction, meditation, and mindful movement. These interventions were recommended across the board to treat both anxiety and depression symptoms in patients in active treatment, and those post-treatment due to the strong evidence to show their benefits to patients. Yoga was also recommended for patients with breast cancer to treat both anxiety and depression symptoms, although the strength of the evidence was moderate. Data was less compelling for its use during or after treatment in other cancers, likely due to the lack of small numbers of non-breast cancer survivors included in study samples. There was also evidence for the use of relaxation, music therapy, and reflexology for treating anxiety symptoms during active treatment, and that the use of hypnosis and aromatherapy using inhalation were of modest to some benefit during diagnostic or treatment procedures.

    Brittany Harvey: Understood. Thank you for reviewing those recommendations. And you already mentioned a few items that are helpful and recommended for adults with cancer experiencing anxiety post-treatment, but which additional integrative therapies are recommended for this patient population? 

    Dr. Julia Rowland: In addition to mindfulness-based interventions and yoga, acupuncture, Tai Chi, and/or Qigong, and reflexology are recommended for treating anxiety symptoms post-treatment. 

    Brittany Harvey: Excellent. Thank you for that summary of recommendations. So then, moving into the recommendations on depression, what does the expert panel recommend for adults with cancer experiencing symptoms of depression? 

    Dr. Julia Rowland: For depression symptoms during treatment, the panel recommended mindfulness-based interventions, yoga, music therapy, relaxation, and reflexology, while post-treatment mindfulness-based interventions, yoga, and Tai Chi or Qigong were recommended. 

    Brittany Harvey: Excellent. Thank you for reviewing all the recommendations that the panel put forward. So this guideline reviewed a large breadth of integrative therapies. Are there any therapies that the panel reviewed but couldn't make a recommendation for, for this particular guideline? 

    Dr. Julia Rowland: Thank you for asking that question because as people listen to this podcast, they may realize that there are some therapies that may be widely used by their population or in their center or clinic, including such things as natural products and supplements, melatonin, healing touch, massage, light therapy, to name a few. Where the panel found in its review of the literature of over 110 studies or systematic reviews, there was insufficient evidence for the vast majority of these to make any conclusive recommendation. It just means we have a lot more work to do in assessing the efficacy of these, especially in treating anxiety and depression. 

    One intervention stands out in particular that's widely used and that's expressive writing. While this may be very helpful for improving quality of life or making sense of the cancer experience and providing an outlet for self-expression, the data does not support its use for treating anxiety and depression. It may be because it's too brief an intervention for conditions that have more depth and permanence. It doesn't mean you can't use it for other purposes, but the panel did not recommend its use for treating anxiety and depression.

    Brittany Harvey: Understood. That makes sense that there are some integrative therapies that work across different parts of the treatment spectrum and that there are some areas in which we just don't have the evidence yet. So, thank you for reviewing all of those recommendations. 

    So then, how does this guideline complement the recently published ASCO Guideline on the Management of Anxiety and Depression in Adult Survivors of Cancer?

     Dr. Julia Rowland: That's a terrific question. The recently published ASCO Guideline on Management of Anxiety and Depression in Adult Cancer Survivors represents an update of our original 2014 guideline. The ASCO guideline provided recommendations regarding the use of conventional therapies, psychological, behavioral, and psychopharmacologic interventions for managing anxiety and depression. The current SIO and ASCO guidelines sought to expand upon and essentially complement these recommendations by identifying those integrative therapies that might also be effective in the management of anxiety and depression in adults treated for cancer. Further, the SIO and ASCO guidelines attempted to determine when, in the course of care, during diagnosis and active treatment and/or post-treatment, these interventions worked best. Both sets of recommendations strongly endorse the benefits of mind-body interventions in addressing both anxiety and depression, specifically mindfulness-based interventions in this SIO and ASCO guideline and cognitive, behavioral, behavioral activation, and mindfulness-based stress management programs in the ASCO guideline.

    Brittany Harvey: It's great to have these complementary guidelines available at the same time for a complete approach to managing anxiety and depression during treatment and post-treatment. So then, in your view, Dr. Rowland, what is the importance of this guideline and how will it impact clinicians and patients with symptoms of anxiety and/or depression?

    Dr. Julia Rowland: Brittany, cancer takes a significant psychological toll on affected individuals. Research has shown that cancer survivors have a significantly elevated risk of developing mental health disorders compared with the general population. Despite this, their psychological symptoms are often under-recognized and undertreated. As the number of cancer survivors continues to grow, so does the challenge to healthcare providers of meeting their mental health needs. Anxiety and depression symptoms have long been associated with lower quality of life and higher mortality in people with cancer. Treating symptoms of anxiety and depression using evidence-based, integrative therapies has the potential to not only improve patients' quality of life and help them better manage their care but may also improve length of life. 

    With the publication of this guideline, we now know which therapies could have the biggest impact. An added benefit of incorporating, or at least considering, integrative therapies to manage anxiety and depression are that they have few, if any, side effects, can be readily modified to accommodate individuals with multiple comorbidities, are well received by the majority of patients, and can be received in a variety of settings, including at home and online.

    Brittany Harvey: Those are key points that you just made. These recommendations are key for improving quality of life for patients, and it's great to have options for patients, including, as you mentioned, at home.  

    So then finally, what are the outstanding questions for the use of integrative approaches in managing anxiety and depression in patients with cancer?

    Dr. Julia Rowland: As I look at these new guidelines, both the SIO and ASCO, as well as the renewed ASCO guidelines, perhaps the biggest question raised is how to increase the use of recommended care. And I think there are three parts to this challenge. One critical first part is raising awareness about these guidelines, which it's hoped this podcast will help us achieve. A second, equally critical step, however, is identifying available treatment resources. While most treatment clinics and centers have access to mental health resources in a number of settings, this may be quite limited. Further, it's not clear how many such programs include integrative programs and services. 

    In addition to the questions about availability, lack of familiarity with some of these therapeutic modalities may leave clinicians reluctant to refer their patients for such care and raise questions for them about how to assess the training and qualifications of integrative care providers and the rigor of the therapy they provide. An important recommendation made by both ASCO and the SIO and ASCO Anxiety and Depression Management Guideline panels is that oncology clinicians should conduct a landscape analysis of who is and what types of programs are available to provide the recommended therapies to their patients. Arguably, not knowing where to refer a patient suffering from anxiety and depression is the most significant area to that patient's receipt of optimal care. The landscape review should include in-house or affiliated mental health providers, integrative program leads if present, local professionals, and organizations offering this care, as well as access to community-wide and national groups providing integrative care remotely via online and telephone. Asking patients themselves who they have seen and found helpful in improving their emotional well-being can also broaden resource lists generated.  

    A third challenge is how best to identify and refer those patients most in need. Recommendations regarding screening and assessment of anxiety and depression were not within the scope of the SIO and ASCO guidelines. However, in the two published ASCO Guidelines on use of conventional interventions for managing anxiety and depression, both the 2014 original and the updated 2023 revised, the expert panels emphasize the critical need to routinely screen for both anxiety and depression using standardized measures such as the GAD-7 and the PHQ-9. 

    ASCO's QOPI or Quality Oncology Practice Initiative already includes screening for emotional distress early in the course of care as a key practice standard. Other appropriate times for screening include changes in disease or treatment status, transition to palliative and end-of-life care, and when clinically indicated. Screening is the critical and necessary first step to identification and referral for appropriate and timely care of cancer patients and survivors suffering from anxiety and depression. Figuring out how to do this well and systematically should be a priority for reducing the burden of cancer nationally.

    Brittany Harvey: Absolutely. As you mentioned, screening is critical for identifying patients experiencing anxiety and depression, and I appreciate you reviewing those implementation barriers and how clinicians and practices can work to reduce these barriers and increase the uptake of these recommendations. We'll have some of those resources linked in the guideline also on the ASCO website and in the show notes of this episode. 

    So I want to thank you so much for your insights on this guideline and for your time today, Dr. Rowland.

    Dr. Julia Rowland: My pleasure, Brittany. I hope the word gets out and we'll see more uptake of these affected therapies and in broader use. Thank you. 

    Brittany Harvey: Definitely. That's the goal of all of these guidelines. 

    I also want to thank all of our listeners for tuning into the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines.  You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode. 

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of medical conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

    ASCO Guidelines
    en-usAugust 15, 2023

    Management of Stage III NSCLC Rapid Recommendation Update

    Management of Stage III NSCLC Rapid Recommendation Update

    Dr. Navneet Singh joins us again, this time to discuss the rapid recommendation update for stage III non-small cell lung cancer, incorporating updated data presented at the 2023 ASCO Annual Meeting. He discusses the new trials that prompted the guideline update and updated recommendations on adjuvant osimertinib for patients with EGFR exon 19 deletion or exon 21 L858R mutation, and the option of neoadjuvant chemoimmunotherapy for patients with stage III NSCLC.

    Read the update, "Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/thoracic-cancer-guidelines

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01261

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts

    My name is Brittany Harvey, and today I'm interviewing Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, Co-chair on “Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update.” 

    Thank you for being here, Dr. Singh.

    Dr. Navneet Singh: Thank you for having me.

    Brittany Harvey: Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Singh, who is joining us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. 

    So then, to dive into the content of this guideline, first, Dr. Singh, what prompted this rapid update to the ASCO management of stage III non-small cell lung cancer, which was initially published in 2021?

    Dr. Navneet Singh: There have been a number of studies that have involved patients with stage III non-small cell lung cancer since the publication of the stage III NSCLC management guidelines. Of note, three trials deserve special recognition and have actually formed the basis for this rapid update. These include the ADAURA trial for use of osimertinib as adjuvant treatment for completely resected stages Ib to IIIa NSCLC and harboring a sensitizing EGFR mutation. The other two trials have explored the use of PD-1 immune checkpoint inhibitor therapy in combination with chemotherapy as neoadjuvant treatment of potentially resectable stages I to III NSCLC. And these are the CheckMate 816 trial with nivolumab and the KEYNOTE-671 trial with pembrolizumab.

    Brittany Harvey: Great, thank you for that background. So then, based off these three new trials that you just mentioned, what are the updated recommendations issued in this rapid recommendation update?

    Dr. Navneet Singh: The first updated recommendation is based on the overall survival benefit observed in the ADAURA trial. And this recommendation is that patients with dissected stage III NSCLC and harboring an EGFR exon 19 deletion or an exon 21 L858R mutation should be offered adjuvant osimertinib after platinum-based chemotherapy. The second important update is that in the absence of contraindications, patients with stage III non-small cell lung cancer who are planned for surgical resection should receive a neoadjuvant combination of a platinum doublet chemotherapy, and immunotherapy. Now, both of these are based on high-quality evidence and have a strong strength of recommendation.

    Brittany Harvey: Understood. I appreciate you reviewing both the level of evidence and the strength of the recommendation for those as well. So then, what should clinicians know as these new recommendations are implemented?

    Dr. Navneet Singh: Now, it's very important for clinicians involved in the management of lung cancer to realize the importance of biomarker testing, something that was initially believed to have relevance only for metastatic disease. But now, with the availability of data indicating the benefit of immunotherapy and targeted therapy not just in metastatic disease but also in early-stage as well as locally advanced disease, clinicians need to ensure that biomarker testing, especially EGFR mutation and PD-L1 expression by approved and validated methods is performed in all patients with stages I to  III non-small cell lung cancer. This is important to decide and select patients for the appropriate biological therapy, which is either targeted therapy or immunotherapy that can be used in conjunction with or following chemotherapy. I need to clarify here that the spectrum of biomarker testing that is recommended for metastatic disease is much larger than what is currently being advocated for early or locally advanced NSCLC.

    Brittany Harvey: Great, and I appreciate that clarification. So then you've just described what this guideline means for clinicians, but how does this rapid update impact patients diagnosed with stage III non-small cell lung cancer?

    Dr. Navneet Singh: Well, for patients with stage III non-small cell lung cancer, all the three trials that form the basis for this rapid update indicate very encouraging developments. The neoadjuvant chemo-immunotherapy approach is now the standard of care for potentially resectable stage III disease, as this combination has been shown to be superior to chemotherapy alone in terms of higher probability of achieving a complete or major pathological tumor response, as well as improving recurrence or event-free survival following surgical resection. Similarly, adjuvant osimertinib for resected stage III NSCLC patients having a sensitizing EGFR mutation has been shown to significantly improve overall survival compared to placebo. It is important to highlight here that osimertinib treatment in stage III NSCLC should be initiated following the completion of adjuvant chemotherapy.

    Brittany Harvey: Understood. So then this panel works to rapidly update this guideline, turning it around after the ASCO Annual Meeting. But what are the ongoing research developments that the panel is monitoring for future guideline updates?

    Dr. Navneet Singh: Well, the expert panel is eagerly awaiting overall survival data from the neoadjuvant chemo-immunotherapy trials. We have several unanswered questions which ongoing research will attempt to answer. And some of these questions include number one, whether adjuvant immunotherapy is beneficial for patients who have already received neoadjuvant chemo-immunotherapy, and if so, what is the optimal duration for the same? Second, is the three-year adjuvant osimertinib duration appropriate? Can lesser duration of treatment suffice for a subgroup of patients? And if so, it would lead to a reduction in both treatment costs as well as a reduction in potential treatment-related adverse effects. On the other hand, other patients in whom stopping at three years may not be warranted, and should patients with exon 19 deletion be treated differently from those with exon 21 L858R mutation? Third, does a similar adjuvant targeted therapy approach be warranted for ALK-rearranged NSCLC that has been surgically resected? And fourth, are there specific subgroups of patients undergoing neoadjuvant treatment in whom immunotherapy as a neoadjuvant treatment may not be effective? Examples are those with EGFR mutations or ALK rearrangements, or even those with no PD-L1 expression.

    Brittany Harvey: Absolutely. We'll look forward to finding the answer to those questions for future guideline updates. So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Singh.

    Dr. Navneet Singh: Pleasure.

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store

    If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

    ASCO Guidelines
    en-usJuly 20, 2023

    Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy Guideline Update

    Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy Guideline Update

    Dr. Supriya Mohile , Dr. William Dale, and Dr. Heidi Klepin discuss the updated guideline on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy. They highlight recent evidence that prompted the guideline update, and share the updated evidence-based recommendations from the panel, focusing on geriatric assessment-guided management. Dr. Mohile also reviews what the expert panel recommends should be included within a geriatric assessment, and Dr. Dale highlights the Practical Geriatric Assessment tool, aimed at helping clinicians implement a geriatric assessment. Dr. Klepin comments on the impact for both older adults with cancer and their clinicians, and reviews outstanding questions and challenges in the field.
    Read the full guideline, "Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the update and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00933. See also the Practical Geriatric Assessment tool and associated videos (How to do a Geriatric Assessment, What to do with the Results of a Geriatric Assessment) mentioned in the podcast episode.

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts

    My name is Brittany Harvey, and today I'm interviewing Dr. William Dale from City of Hope National Medical Center, Dr. Heidi Klepin from Wake Forest Baptist Comprehensive Cancer Center, and Dr. Supriya Mohile from University of Rochester Medical Center—co-chairs on “Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update.” 

    Thank you for being here, Dr. Dale, Dr. Klepin, and Dr. Mohile.

    Dr. William Dale: Nice to see you. Thanks for having us.

    Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensures that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests joining us on this podcast episode today, are available online with the publication of the guideline in the Journal of Clinical Oncology linked in the show notes. 

    Diving into the content of this guideline first, Dr. Dale and Dr. Mohile, can you speak to what prompted an update of this ASCO guideline on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy, which was previously published in 2018?

    Dr. William Dale: Sure. Yes. In 2018, that was the very first guideline for older adults that ASCO had created, and that was based on work that had been done up to that time, focused on chemotherapy toxicities. And to summarize what was put out at that time, the evidence was thought to be strong enough for doing geriatric assessments. And these are specialized assessments across a number of domains, including functional impairments, cognitive losses, social impairments, etc. But to do these kinds of geriatric assessments with validated tools; that a certain selection of these domains to cover everything that was relevant; to conduct non-cancer prognostication so that for decision-making purposes, if someone were to have their cancer cured, what would be their prognosis, and help make decisions about giving chemotherapy and what doses; and then to enact geriatric assessment-guided target interventions was the fourth recommendation. And so that's where we were in 2018. 

    In 2020 at ASCO, there was an oral session that had four randomized controlled trials that enrolled older adults. And in that was kind of the signal that there was more coming. And in 2021, two big trials that are practice-changing were published. One led by Dr. Mohile in Lancet that we call the GAP70+ study, and another one was published in JAMA Oncology. And they essentially showed the same thing, which was that GA-guided interventions could change the primary outcome, which was to reduce chemotherapy toxicity up to 20%, and also to affect a number of other outcomes.

    That, along with a number of other trials that have since come out and are included in the upcoming guidelines, and made it a high priority to update these guidelines. So that's where we got from there to here. And I think it's worth saying a few words about these new trials, particularly the GAP and GAIN studies.

    So the GAIN study included patients who were 65 and older who were starting systemic chemotherapy and looked at the likelihood of having chemotherapy toxicity as described and looked at a number of other outcomes. Most importantly, it showed that chemotherapy toxicity could be reduced with these interventions based on the geriatric assessment from about 60% to about 50%. It also showed that the likelihood of completing advanced directives would go up by around 25%. And importantly, there was no impact after all of the use of the geriatric assessments on mortality. So patients were living just as long, but they were having less toxicity and they were having more goal-concordant care. And at almost the same time, the GAP study came out, which I would hand over to Dr. Mohile to describe.

    Dr. Supriya Mohile: Thank you, Dr. Dale. I agree that it was time for an update, and I'm glad ASCO partnered with us to do this. I'll also just mention that Dr. Dale, Dr. Klepin, and I lead the Cancer and Aging Research Group, and many of the original predictive models that showed that geriatric assessment could help us identify patients at highest risk for toxicity were designed by Cancer and Aging Research Group investigators. And that's what informed the first guideline. I'll mention Dr. Arti Hurria, who unfortunately passed away a few years ago, and she led some of the first large studies that developed these predictive models. We built on that data in both GAP and GAIN studies to show that the geriatric assessment—when you assess and provide management—can reduce chemotherapy toxicity.  

    Like GAIN, GAP70+ implemented a geriatric assessment intervention that both assessed and provided management to older adults. There were some key differences. In GAP70+, the patients had advanced cancer, whereas, in the GAIN study, it was a more generalizable population of patients with both curative intent and advanced cancer. And in the GAP70+ study, we enrolled patients who already had geriatric assessment domain impairments, meaning that these patients were more vulnerable because of those aging-related conditions. We were trying to enroll patients who are traditionally excluded from therapeutic clinical trials. The GAP70+ study was done in oncology offices by Community Oncology practices. 

    So this was what I think was really interesting, in that geriatricians were not involved in implementing the geriatric assessment in this study. Oncologists received the assessment information from their team, and they're the ones that implemented the recommendations. We found in GAP70+ that not only chemotherapy toxicity was reduced, that we were able to reduce the prevalence of falls and reduce the incidence of polypharmacy, which are important geriatric outcomes for older adults. We included patients who were receiving chemotherapy, but also patients who are receiving high-risk targeted agents in GAP70+, which also leads us to believe that these interventions are important for patients who are receiving treatments other than chemotherapy. 

    So we believe these two trials, plus others, really inspired the ASCO guidelines.

    Brittany Harvey: Absolutely. I appreciate you both for providing that context and background and some of the new evidence that's informed this latest update. So then I'd like to move into some of the updated recommendations of the guideline. So, Dr. Mohile, what is the updated recommendation from the panel regarding the role of geriatric assessment in older adults with cancer?

    Dr. Supriya Mohile: So the first guideline really focused on the assessment piece, what should be assessed, and why, which we still incorporate in this new guideline. This guideline extends now because of the randomized controlled trials into management. And when we think about geriatric assessment, we think about two pillars of management. One is how geriatric assessment influences cancer decisions, that includes what treatments to provide, what dose to provide. And then the second is how geriatric assessment can influence management recommendations that are supportive care based that address some of the geriatric assessment domain impairments. 

    I’ll just give you an example of both. So when we see patients with advanced cancer who have geriatric assessment domain impairments who are presenting for treatment, often the doses of chemotherapy may be overtreatment because those doses were developed in therapeutic clinical trials in younger, more fit patients. And in our geriatrics world, we often think about going slow and starting low, and we may do a first cycle that’s dose reduced a touch, to kind of see how the patient does physiologically with that first cycle. There are therapeutic clinical trials like FOCUS2 in patients with metastatic colon cancer that show the benefits of being careful with dosing in the first cycle. 

    So, in GAP70+, the oncologists who received information from the assessment were more likely to reduce the dose of the treatment in the first cycle which led to less toxicity but did not lead to a difference in survival, so do not compromise survival. And I think this is because we don’t know the right doses for patients who have significant aging-related impairments. So that’s one example of decision-making. 

    As examples for geriatric management recommendations that are supportive care, this can be done in almost like an algorithmic approach. So, if a patient has an impairment on a physical function test, then through the geriatrics literature we know of management recommendations that can improve outcomes like physical therapy, home safety evaluations, balance, training, fall prevention information. And if we implement those supportive care recommendations through that patient who’s at risk for falls, we may prevent falls and we were able to show that in addition in GAP70+ as well as other trials showed benefits in some of those outcomes.

     And so those are the two pieces that I think are newer with this guideline than with the previous guideline. We know more about how those management recommendations can improve outcomes.   

    Brittany Harvey: Understood. Yes. It's helpful to understand those examples of how integrating this geriatric assessment can help improve the management of care for these patients. So then you've mentioned some of the geriatric assessment domain impairments. So, Dr. Mohile, what does the guideline recommend should be included within a geriatric assessment?

    Dr. Supriya Mohile: This was a really great question for us to rise and think about, as part of this guideline and as a panel, we went back and forth with all of the authors to try to think about what is the most streamlined number of domains that should be assessed? What are the highest priority domains that, if you could only do a few things in a busy oncology clinic, which are the ones that oncologists should have to do because without doing them, they won't have relevant information to inform treatment decisions or to improve the outcomes of their patients? 

    And so when we think about geriatric assessment, there has been literature to show that almost all of the domains we do are important in identifying patients who are at risk of poor outcomes. These include physical function, cognitive function, emotional health, comorbidities, polypharmacy, nutritional status, and social support. That sounds like a lot, but we do many of those assessments sort of naturally in oncology clinics. There are just a few that are not done as standard. For example, it is not standard for oncologists to assess cognition using a validated screening test for cognition. And we know that recognizing patients who may have cognitive impairment is really important in identifying vulnerabilities and providing support systems in place so patients who are receiving treatment can go through treatment safely.  

    Other things, like just doing a formalized nutritional assessment, really bringing in the caregiver, are done not in a standard way. And so what the geriatric assessment allows is for us to assess each of those domains in a standard way. When we're communicating to our colleagues and tumor boards, we can describe vulnerabilities in a standard way. And we're moving now past the eyeball test, which is different for different clinicians, and having more objective ways of describing health status to be able to have a common language across studies and in clinical care.

    Brittany Harvey: That's helpful to understand moving past the less formal approach to geriatric assessment and making it more standardized. 

    So then, Dr. Dale, this guideline offers a specific tool, the Practical Geriatric Assessment, as an option for clinicians conducting a geriatric assessment. What is this tool and where can clinicians access it?

    Dr. William Dale: Very good question. Just to set the context a bit, after hearing about all the evidence that we've just described. We did do some work as a task force through ASCO and through some work that Dr. Klepin and her colleague have done to understand now that the guidelines in 2018 had come out, they weren't really being used. So when we asked, about 25% of people would say they were using them very much, even though we saw in these large studies that we did, that those who were using the guidelines were changing their practice significantly in the ways that Dr. Mohile mentioned. And this was among a large group of community oncologists. 

    So we have been breaking down the geriatric assessment into the most concise, most straightforward, and easiest-to-use version of the geriatric assessment, maintaining its validity and maintaining the number of domains. We really tried to make it simple. So the Practical Geriatric Assessment is not the only tool, but it is a tool that accomplishes this practical charge to make it accessible to community oncologists while also being valid. So those domains that Dr. Mohile mentioned physical function, functional status, nutrition, social support, psychological considerations, comorbidities are all in the Practical Geriatric Assessment.  

    But what we've done is boil it down to here's a very specific tool that we think is valid but easily applied. Here are the very specific thresholds that tell you when a deficit has been identified and then gives recommended actions to be taken, whether it's in decision-making or in other interventions like a referral to somebody, perhaps physical therapy, or a cognitive specialist, all of which come from the GAP. So this tool is designed to be very straightforward and practical, but still cover all the relevant domains. And it will be made available through both the ASCO website and through the Cancer and Aging Research Group website so that people can access it easily.

    Brittany Harvey: That sounds like a real challenge that the ASCO working group took on to create a comprehensive yet practical tool for clinicians to use. We'll also provide some links for people to access this in the show notes of this podcast episode.  

    So then I want to move on. Dr. Klepin, in your view, how will this guideline update impact both clinicians and older adults with cancer? 

    Dr. Heidi Klepin: Yes. Thank you. As was mentioned, for clinicians, the guidelines provide an overview of new evidence and concrete recommendations to address the challenge experienced every day in practice, that of providing personalized care in the context of age-related conditions to maximize benefits and minimize the risk for older adults with cancer. The evidence summary will educate clinicians on key outcomes that can be positively impacted by use of geriatric assessment, including decreasing treatment toxicity, enhancing decision-making, and improving communication and patient-caregiver satisfaction. 

    And this information on outcomes is really critical to informing the use of geriatric assessment in practice. We hope that the evidence-based recommendations with the provision of the practical geriatric assessment and the associated trigger table to guide management strategies will empower clinicians to incorporate geriatric assessment into their workflow by helping them overcome some of those known barriers that Dr. Dale mentioned, such as lack of time and uncertainty about which measures to use and what to do with the information once you have it. So, we anticipate that providing clear recommendations and accompanying readily available materials to support the implementation that clinicians in both community and academic practices will be able to use the geriatric assessment and incorporate it into routine care.

    For patients, we anticipate that the guideline recommendations would translate into increased use and access to this type of assessment as part of their routine oncology care. So, we hope that our patients will actually be able to access this regardless of whether they're receiving care at a specialized academic center versus a community oncology clinic. So, by doing this, we would extend the proven benefits of geriatric assessment, including lower rates of side effects, experiencing fewer hospitalizations, and improving satisfaction to older adults regardless of where they receive treatment.  

    And we feel like this is critically important, since currently, most older adults receive cancer care in community oncology clinics without access, as was mentioned, to any geriatric specialty care. So, as more older adults have the opportunity to participate in this type of assessment as part of routine care in their oncology clinics, they'll be able to discuss the results of the assessment with their healthcare providers, which can help them make better-informed decisions and engage, I think, more completely in what we would consider patient-centered decision making. And ultimately, we would hope that the guidelines would provide an evidence-based and practical strategy for improving the quality of care received by older adults with cancer.  

    Dr. Dale, would you be interested in commenting a little bit more on the patient perspective informed by our patient partners on the guideline panel?

    Dr. William Dale: Yeah. Thank you, Dr. Klepin. Very well said. Yeah, our guideline panel, just to fill out the picture of that, included our patient partners, along with a wide diversity of perspectives. We had experts in geriatric oncology, but we had community oncologists who take care of cancer patients. We have people from across the country. We had different backgrounds and different levels of experience. But to focus on the patients for a group that we've worked with for some time called SCOREboard, and they were some of the strongest voices on this. 

    Whenever people said, “Well, do we really need to require this?” The patient partners were insistent that this be included as a requirement as much as possible for what happens. I think one of the most important roles they've played is as advocates for this. If I can, when the community oncologists are having some concerns about how hard this would be or how difficult it might be, the patient partners have been the first to say, we need to find a way to do it and insist that we empower the patients to ask for it. So, one of the hopes for all of these guidelines is also that it get disseminated to patients who can self-advocate as they go forward and have tools that will be made available for them to use in this self-advocacy.

    Brittany Harvey: Definitely, that self-advocacy is important and the geriatric assessment is critical for optimal care for older adults. 

    So, then we've talked a lot about the new evidence regarding geriatric assessment and also making it easier for clinicians to implement the geriatric assessment, but Dr. Klepin, what are the outstanding questions and challenges regarding geriatric assessment in older adults with cancer?

     Dr. Heidi Klepin: Thanks. So, while there's strong evidence and clear rationale to incorporate geriatric assessment into routine clinical care, there are outstanding questions and challenges that we have to consider. First and foremost, still remains a challenge of implementation. As mentioned, we hope that the Practical Geriatric Assessment, the detailed recommendations, and the associated educational materials on what to do with the geriatric assessment information will help overcome implementation barriers for many. But we recognize that more work needs to be done to both train providers to facilitate behavior change as well as to tackle clinic and healthcare system barriers to routine use. 

    And along these lines, we also recognize that it's important to educate patients and caregivers about the role of geriatric assessment and its value in order to optimize uptake in community clinics. We want all of our patients to be as enthused and recognize the importance of the geriatric assessment, as our colleagues on the recommendation panel did. Another consideration is the challenge of tailoring use of geriatric assessment to specific disease and treatment settings. And more research is underway testing geriatric assessment and management strategies in varied disease settings, as well as with varied treatment types and intensities. 

    And finally, I would suggest that another challenge is the lack of routine incorporation of geriatric assessment measures into cancer clinical trials. And this will really be necessary to interpret clinical trial data for older adults optimally and to reinforce the value of routine geriatric assessment in clinical care.

    Brittany Harvey: Absolutely. These are key points for moving forward and looking forward to additional research in this area and maybe future guideline updates down the line. 

    So, I want to thank you all so much for your work on updating this guideline and for your time today. Dr. Dale, Dr. Klepin, and Dr. Mohile. 

    Dr. Heidi Klepin: Thank you for having us. 

    Dr. William Dale: Yeah, thanks for having us here. We're delighted to be talking about this. 

    Dr. Supriya Mohile: Thank you. 

    And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store

    If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 

    The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

    ASCO Guidelines
    en-usJuly 17, 2023

    Cancer Cachexia Rapid Recommendation Update

    Cancer Cachexia Rapid Recommendation Update

    Dr. Charles Loprinzi shares the latest update to the management of cancer cachexia guideline. Dr. Loprinzi discusses the evidence that prompted the rapid update to the guideline and reviews the new evidence-based recommendations, including the addition of low-dose olanzapine as a treatment option for patients with advanced cancer to improve weight gain and appetite. Dr. Loprinzi reviews the limitations of the update, and outstanding research questions in the domain of cancer-associated cachexia.

    Read the latest update, "Cancer Cachexia: ASCO Guideline Rapid Recommendation Update" at www.asco.org/supportive-care-guidelines

    TRANSCRIPT
    This guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01280 

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Charles Loprinzi from Mayo Clinic, Co-Chair on “Cancer Cachexia: ASCO Guideline Rapid Recommendation Update.” Thank you for being here today, Dr. Loprinzi. 

    Dr. Charles Loprinzi: It's a pleasure to participate.

    Brittany Harvey: Then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Loprinzi who has joined us here today, are available in line with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  

    Then, to get into the content of this rapid recommendation update, first, Dr. Loprinzi, what prompted this rapid update to the ASCO management of cancer cachexia guideline, which was previously published in 2020?

    Dr. Charles Loprinzi: The impetus for the updated guideline was a recent JCO publication regarding the results of a randomized controlled trial looking at olanzapine. This prompted the expert panel to revisit this topic. The trial, conducted in India, involved 124 patients with stomach, hepatopancreatobiliary, or lung cancers as they initiated chemotherapy. Weight gain greater than 5% occurred in 60% of patients in the olanzapine arm versus 9% of the patients in the placebo arm with a p-value of 0.001 or less. Substantially improved appetite was seen in 43% versus 13%, with placebo also a p-value of less than 0.001. Grade 3 or greater chemotherapy toxicity was less common with olanzapine 12% versus 37%, with placebo with a p-value of 0.002. No substantial olanzapine-associated toxicity was apparent. There was one evidence of this with olanzapine versus two for placebo. So that was the reason for going ahead with this update.

    Brittany Harvey: I appreciate that background information. So then, based on this updated study on olanzapine, what are the updated recommendations from the expert panel for treating cancer cachexia?

    Dr. Charles Loprinzi: So, let me start to address this question by reviewing what the 2020 ASCO guidelines published said regarding the management of cancer cachexia in adults with advanced cancer. It concluded that evidence was insufficient to strongly endorse any pharmacologic agent for established anorexia/cachexia. Nonetheless, the guideline recommendation supported that clinicians could offer a short-term trial of a progesterone analog such as megestrol acetate or a corticosteroid such as dexamethasone to patients experiencing weight loss and/or appetite stimulation. These drugs stimulated appetite and caused weight gain, but they did not improve quality of life, they did not improve survival, and there was toxicity associated with these agents and therefore it was not strongly recommended. 

    The expert panel thoroughly discussed a potential role for olanzapine because of a couple of trials suggesting it was beneficial but concluded that the evidence was insufficient for a recommendation. Now, there was evidence from two randomized trials that supported olanzapine was an effective alternative for treating cancer-associated anorexia/cachexia. Thus, olanzapine was considered promising, but the data were not conclusive enough to support a guideline treatment recommendation. The new JCO publication was the impetus for making this guideline change.

    Brittany Harvey: Understood. So then, based off this new change to the recommendations, what is the breadth of these recommendations and what do these options mean for patients with advanced cancer?

     Dr. Charles Loprinzi: The updated guidelines recommended that for adults with advanced cancer, clinicians could offer low-dose olanzapine once daily to improve appetite and cause weight gain. It was noted that the majority of the evidence for this recommendation came from patients with lung or GI cancers, and the largest study enrolled patients who were receiving cytotoxic chemotherapy concurrently. Having said this, there's evidence from the other two randomized trials noted above that olanzapine is helpful in patients with a wide variety of cancers and regardless of whether patients were receiving concomitant chemotherapy.  

    Of note, extensive data support that olanzapine leads to significant appetite stimulation and weight gain in patients without cancer who were taking olanzapine for psychiatric reasons. This was known from a long time ago in patients in that situation, who don't necessarily want to gain weight, would gain 10-20-30-40 pounds, get prediabetes, and get diabetic sort of troubles. The guideline update continues to support that clinicians may offer a short-term trial of a progesterone analog or a corticosteroid to those experiencing weight loss and/or appetite when there's a good reason for not using olanzapine. 

    Brittany Harvey: Understood. I appreciate you reviewing those two updated recommendations from the guideline panel. 

    So then you've talked about this a little bit already in describing the study details, but what is exciting about olanzapine in this setting and what should clinicians know as they implement these updated recommendations? 

    Dr. Charles Loprinzi: It's exciting that olanzapine is now the best-studied established treatment available for patients suffering from cancer-associated anorexia/cachexia in different oncologic situations, for prevention and/or for treatment of cancer-associated or cancer treatment-associated nausea and/or vomiting, and for treatment of cancer-associated anorexia/cachexia. Varying daily doses of olanzapine have been used, ranging from 2.5 to 10 milligrams per day. Data support that it is quite appropriate to use the 2.5-milligram per day dose for the initial treatment of cancer-associated appetite and/or weight loss. For patients who do not appear to benefit and have no apparent olanzapine toxicity, it seems reasonable to me to try a higher dose. Another thing to note is that olanzapine is a generic drug which is relatively inexpensive. While this drug has been noted to cause sedation, such sedation is usually short-lived despite drug continuation.

    Brittany Harvey: So then, it's great to hear that recent data have caused an update to these guidelines. But in your perspective, Dr. Loprinzi, what are the most pressing outstanding questions regarding the management of cancer cachexia?

    Dr. Charles Loprinzi: My goodness, you're putting pressure on me. I've been involved with a large number of cancer anorexia/cachexia trials for the better part of four decades, which did not support as strong an ASCO guideline recommendation as we now have with olanzapine. Noting that I was involved with one of the trials that supported that olanzapine was helpful for treating cancer-associated anorexia/cachexia. This is one of the trials. It was a short trial. We were mainly looking at nausea and vomiting treatment for advanced cancer, but we saw a marked increase in appetite in over just a day or two of using olanzapine. Having said this, there's always room for improvement, and a number of drugs are under development for treatment of cancer-associated anorexia/cachexia.  

    Recent discussions regarding the topic of olanzapine for treating cancer-associated anorexia/cachexia noted that the primary endpoint of the current trial was weight gain and that this was felt to be a more objective endpoint than appetite would be. As noted in the earlier part of the discussion, substantial improvement was seen both in weight gain and appetite, both with p-values of less than 0.001. My own opinion is that appetite improvement is as important, if not more important than is weight gain in the study population. Given that the trial was double-blinded and placebo-controlled, appropriate questionnaires regarding appetite should be able to be considered as an objective evaluation of a subjective symptom in the same way that appropriate questionnaires regarding a patient's pain can be considered an objective evaluation of a subjective symptom. For some of these subjective symptoms, you just don't have other good ways we can figure these things out by a blood test or something like this. So it's what the patient says which is most important. 

    Brittany Harvey: Absolutely. Incorporating how the patient feels is key to achieving better outcomes for patients. 

    So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Loprinzi.

    Dr. Charles Loprinzi: You're welcome. Pleasure to participate.

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

    The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

    ASCO Guidelines
    en-usJuly 12, 2023

    Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2023.2

    Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2023.2

    Dr. Navneet Singh highlights the latest evidence-based recommendation updates from the ASCO living guideline on stage IV non-small cell lung cancer with driver alterations. This update focuses on new second-line options for patients with advanced NSCLC and an EGFR exon 20 insertion, including amivantamab and mobocertinib. Dr. Singh also discusses updated results from CodeBreaK 200 and the option of second-line therapy with sotorasib for patients with advanced NSCLC and a KRAS-G12C mutation.

    Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.2” and view all recommendations at www.asco.org/living-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01055 

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts.  

    My name is Brittany Harvey, and today I am joined by Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2023.2.”

    Thank you for being here, Dr. Singh. 

    Dr. Navneet Singh: Thank you for having me, Brittany.

    Brittany Harvey: Before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the Guideline panel, including Dr. Singh, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. 

    So then, to dive into this living clinical practice guideline, Dr. Singh, this living guideline for systemic therapy for stage IV non-small cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations in this version?

    Dr. Navneet Singh: So for this 2023 version 2 update, three trials were included. These include two studies which involved patients with exon 20 insertion mutations, who had received prior platinum-based chemotherapy and subsequently were treated with either amivantamab in the CHRYSALIS trial or with mobocertinib in the EXCLAIM trial. The third trial which formed the basis for this update was one which involved patients with KRAS G12C mutation who had previously received systemic therapy and subsequently were treated with sotorasib. And this was the CodeBreaK 200 trial.

    Brittany Harvey: Understood. So then, based on these three new trials that you've just mentioned, what are the updated recommendations from the expert panel for patients with advanced non-small cell lung cancer?

    Dr. Navneet Singh: For patients with advanced NSCLC with an EGFR exon 20 insertion mutation and an ECOG performance status of 0 to 2 who have received prior platinum-based chemotherapy, clinicians may offer amivantamab or mobocertinib as monotherapy. It is important to mention here that in the absence of head-to-head comparison of amivantamab or mobocertinib with each other or with other standard second-line therapies, no recommendation for sequencing can be made and therefore treatment should be individualized. Now, use of either of the two drugs is based on low-quality evidence and has a weak strength of recommendation. And the updates for treating KRAS G12C-mutated NSCLC is largely similar; that patients who have received prior systemic therapy may be offered sotorasib. 

    Brittany Harvey: Thank you for reviewing those updated recommendations. So what should clinicians know as they implement these new recommendations and how do they interface with the existing recommendations?

    Dr. Navneet Singh: It is important for clinicians involved in the management of EGFR mutant lung cancer to realize that exon 20 insertions are the third most common group of EGFR mutations and comprise approximately 5% of all EGFR mutations. Now, historically, the EGFR targeted drugs which have been the first, second, or third generation tyrosine kinase inhibitors have largely shown efficacy for the two common types of EGFR mutations, namely the exon 19 deletions and the exon 21 L858R point mutation.

    Exon 20 insertion mutations thus did not have any effective targeted therapy so far. But now, both of these drugs, amivantamab and mobocertinib, have shown very promising results for pretreated patients with this molecular aberration and therefore may be used in view of standard second line therapy. Similarly, in the case of KRAS G12C mutation, before this, there was no effective targeted therapy, but now sotorasib, based on the CodeBreaK 200 trial, appears to be a very valid option in view of standard second-line therapy. 

    Brittany Harvey: Excellent. So then, what do these new treatment options mean for patients with stage IV non-small cell lung cancer and an exon 20 insertion or a KRAS G12C mutation?

     Dr. Navneet Singh: For patients with stage IV NSCLC and harboring an EGFR exon 20 insertion, the availability of two specific targeted drugs will improve the treatment options available following standard first-line therapy. Furthermore, ongoing trials for these agents in the treatment-naive setting may eventually lead to a scenario wherein such patients may be treated upfront with targeted therapy rather than chemotherapy or chemoimmunotherapy, analogous to how patients with the common EGFR mutations are treated. The ultimate aim of precision medicine is to offer the most effective treatment based on biomarker expression and targeted therapies in comparison to chemotherapy because these lead to better treatment outcomes and lesser side effects.

    Brittany Harvey: Absolutely. The goal of better outcomes with less side effects is what we're looking to achieve here. So then, finally, as this is a living guideline, what emerging therapies or targets is the panel monitoring for future guideline updates?

    Dr. Navneet Singh: As was already said, the expert panel eagerly awaits data from ongoing trials which are assessing the efficacy of drugs targeting the EGFR exon 20 insertion mutations, namely amivantamab and mobocertinib as first-line therapy, as also the drugs which target the KRAS G12C mutations which is sotorasib and adagrasib in the treatment-naïve setting. Ultimately, the optimal sequencing of therapies needs to be established in advanced and metastatic non-small cell lung cancer for several of the oncogenic driver alterations other than classical EGFR mutations and ALK and ROS-1 rearrangements. These include the EGFR exon 20 insertions and other uncommon EGFR mutations, the BRAF V600E, KRAS G12C, the HER2, and the MET exon 14 skipping mutations as well as the RET and NTRK fusions. 

    Brittany Harvey: It sounds like the living guideline expert panel will be busy moving forward then. So I want to thank you so much for your work to update this living guideline and thank you for your time today, Dr. Singh. 

    Dr. Navneet Singh:  Thank you so much, it was a pleasure being here.

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

    ASCO Guidelines
    en-usJuly 11, 2023

    HER2 Testing in Breast Cancer: ASCO-CAP Guideline Update

    HER2 Testing in Breast Cancer: ASCO-CAP Guideline Update

    Dr. Antonio Wolff and Dr. Kim Allison discuss the latest ASCO-CAP guideline update on HER2 testing in breast cancer. This guideline update affirms previous recommendations, and provides commentary based on data from the DESTINY-Breast04 trial. Dr. Wolff and Dr. Allison review the questions from the oncology and pathology community raised by these results, and provide commentary on patients with HER2 IHC 1+ and 2+ and ISH-negative metastatic breast cancer.
    Read the guideline update, "Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update" at www.asco.org/breast-cancer-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.22.02864 

     Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. 

    My name is Brittany Harvey, and today I am interviewing Dr. Antonio Wolff from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Dr. Kim Allison from Stanford University School of Medicine, co-chairs on ‘Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update’. Thank you for being here, Dr. Wolff and Dr. Allison.

    Dr. Antonio Wolff: Thank you.

    Dr. Kim Allison: Thanks for having us. 

    Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in developing its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the full guideline panel, including our guests on this episode today, are available online with the publication of the guideline and the Journal of Clinical Oncology, linked in the show notes. 

    So now jumping into the content, to start us off, Dr. Wolff, what prompted the update expert panel to revisit the 2018 ASCO-CAP recommendations on HER2 testing and breast cancer, and what is the scope of this update?

    Dr. Antonio Wolff: Thank you, Brittany. We appreciate the opportunity of being with you today, and it's great to be here with my colleague, Dr. Kim Allison, as well.  

    What triggered this informatory update was the release from data in trial DESTINY-Breast04, which tested the antibody-drug conjugate trastuzumab deruxtecan in patients who in the past would have been considered to have HER2-negative disease. This ADC, trastuzumab deruxtecan, has a topoisomerase inhibitor payload that is linked to the antibody trastuzumab. And in the past, from all the previous data we had, trastuzumab alone, or in combination with chemotherapy, or as part of another antibody-drug conjugate T-DM1 was essentially active in patients with HER2-positive disease, which is traditionally defined as having overexpression of the HER2 protein, which almost by default is a result of gene amplification of the HER2 gene. 

    And what data from initial studies appear to suggest is that patients who would not be traditionally considered HER2-overexpressed or HER2-amplified were potentially benefiting or having evidence of clinical activity against this disease in the study of metastatic disease. And this was a randomized clinical trial for patients with metastatic breast cancer whose tumors were centrally determined to have IHC 1+ or IHC 2+ expression and would not have been called HER2-positive, would not have been called HER2-overexpressed. And for the tumors that were HER2 2+, they also had to have absence of gene amplification by an in-situ hybridization assay. 

    And what was very interesting is that there was a meaningful, clinically significant improvement in survival for that patient population. And that has some clinicians to begin asking whether there is a different subset of patients who would have in the past been called as having HER2-negative disease that now could potentially be a candidate for this drug. And is there a difference between these patients and patients who, in the past, would have been called as HER2-negative on the basis of IHC 0? And so what complicated things for us a little bit is that patients with IHC 0 were not eligible for this trial. And what is left unanswered by this clinical trial is whether all patients who don't have HER2 protein overexpression or HER2 gene amplification would potentially have benefited from this drug. Kim?

    Dr. Kim Allison: Yeah, agree. I think the main impetus for the update was the exciting results from the DESTINY-Breast04 trial and the questions then that the pathology community and the oncology community had about whether this should change HER2 testing guidelines.

    Brittany Harvey: I appreciate that background on what prompted the panel to revisit this guideline. So then, Dr. Allison, how did the panel come to the conclusion that the previous recommendations are current and valid?

    Dr. Kim Allison: Right. So, as Antonio mentioned, the whole reason HER2 testing was first initiated was HER2-targeted therapies that showed response in the overexpressed or amplified tested population. And so guidelines have really been fine-tuned and crafted around distinguishing the HER2-positive for over-expression and amplification from negative. And this trial really questioned that in that maybe we can target lower levels of the HER2 protein, but this assay really wasn't designed for that. So we looked at the data from the trial and some of the limited other data that's out there and really came to the conclusion that, look, everyone in DESTINY-Breast04 benefited. The whole population benefited, whether you were 1+ or 2+. And because 0s were excluded from the trial, we don't know if they benefited. 

    So we thought it was premature to create a new category, a new result category, and change our current reporting to a HER2-low category, mainly because we don't know that there's a new predictive threshold for response to treatment. So essentially, what we've got is a trial that showed great benefit but didn't create a new biomarker that is predictive or prognostic. Instead, it repurposed this older test as a trial entry criteria. And so now we're kind of stuck with 1+ or 2+ ISH negative as their trial entry criteria that gives you eligibility for trastuzumab deruxtecan. So essentially, we reaffirmed our prior recommendations with acknowledgment that what these categories: positive, equivocal, and negative, refer to is for protein overexpression or gene amplification and that we should continue to use the same scoring criteria, 1+, 2+, 0, and interpretation as were used in DESTINY-Breast04 for their clinical trial criteria. But awareness is important.

     Dr. Antonio Wolff: Yeah, the other thing that I would add, Brittany, I think we need to go back to what was the purpose of HER2 testing back in 1998 when we identified the survival benefit from trastuzumab in metastatic disease. And then, in 2005, when we had evidence of adjuvant benefit in improving disease-free and then overall survival for patients with early-stage disease. And the immunochemistry assays at that time were developed to differentiate between patients who had HER2 overexpressing disease or HER2 gene amplified disease versus not. At that moment, it was clearly identified that patients were considered as having HER2-positive disease that defined a biological entity, a tumor subtype, a group of patients who had worse prognoses in the absence of therapy. But then when they were treated with, for instance, chemotherapy with anthracyclines at that time, but then with HER2 targeted therapies with antibodies, these patients that otherwise would have a poor prognosis now were having an improved outcome. 

    HER2 was a marker of poor prognosis but also a marker of a good chance of deriving clinical benefit, so there was a predictive benefit. And everything else, IHC 0, 1 or 2+, ISH-negative, there has been no evidence that targeting the HER2 pathway was clinically important. Or even more meaningful, there was no evidence that these patients have– within the subset of patients that don't have HER2 positive or overexpressing disease - there has been no evidence that those patients have a different outcome based on low levels of expression of HER2.

    A couple of years ago, in terms of trastuzumab, the NSABP reported findings in the data from NSABP B-47 where the antibody trastuzumab was added to chemotherapy to patients who were considered to have low levels of IHC expression, and in that case, was IHC 1+ or IHC 2+ gene non-amplified. And that settled the issue for sure, that there was absolutely no benefit in the adjuvant setting from the addition of trastuzumab. So we know that there's something different going on here. We know that if you now combine trastuzumab with a specific payload, in this case, the drug deruxtecan, which is a topoisomerase inhibitor, we are potentially targeting the HER2 protein. But these are tumors that are not considered HER2 addicted. These are not tumors whose biology is dependent on the HER2 pathway, so this is simply a better drug delivery. 

    And in this sense, data and evidence from Michael Press, a pathologist at USC that has done some seminal work with HER2 and HER2 testing, he once proposed that the vast majority of breast cancers have some level of HER2 present. And a lot of what is considered IHC 0 is an artifact related to suppression of the detection of the HER2 protein. So there's a chance that the tumors that are truly HER2 negative or HER2 0 are going to be a very small proportion. And IHC assays were never optimized to measure very low levels of HER2. They just don't have the dynamic range for that. And then, from a clinical standpoint, there is no evidence that different levels of HER2 when, in the absence of overexpression, identify groups of patients that have disease that have a different biologic behavior.

     And I think, as Dr. Allison just mentioned, we don't have any evidence from the DESTINY-Breast04 trial that there is a differential benefit between IHC 1+ versus IHC 2+, ISH-negative. Those patients appear to equally benefit from therapy.

    Brittany Harvey: Understood. That context is helpful in understanding this updated guideline.

    So then you've both mentioned the category of patients who are HER2 IHC 1+ and 2+, and ISH-negative. So, Dr. Allison, this article includes a special commentary on those patients, those with HER2 IHC 1+ or 2+, and ISH-negative metastatic breast cancer. What are the essential points of this commentary?

     Dr. Kim Allison: Yeah. So some of them we've brought up already that this test for HER2 IHC wasn't really designed to detect the low levels of protein expression that may be present in some breast cancers, including the all-important issue that the IHC 0s may not be truly null for HER2, that we may just not be sensitive enough to detect it, or there may be fixation and ischemia, time issues that are very subtle and create a false negative result, essentially by IHC that, and that in addition to not being necessarily predictive or prognostic, the 0 versus 1+ threshold, which really is a threshold that hasn't been tested yet. 

    But since eligibility for trastuzumab deruxtecan essentially now hinges around that 0 versus 1+ threshold, since these were clinical trial entry criteria, what can pathologists do to make best practice efforts to distinguish 0 from 1+? Because we felt like we should make some helpful recommendations, at least since this does appear to be a current status point that pathologists are going to be struggling with in practice. So the points we come up with in that commentary are to follow best practices, like making sure you're using the standardized ASCO-CAP Guidelines criteria. Making sure you pay attention to pre-analytic conditions of the tissue sample and that you're using controls with a range of protein expression, including 1+, to help ensure you've got an assay that's really looking at the right limit of detection since that has shifted somewhat in this instance. 

    And then for interpretation side, for pathologists to be sure to look on high power, so discriminating at 40x when you're trying to score a 0 versus 1+ stain since that's now relevant, you're going to need to go on high power and really distinguish from those two. And then, consider a second pathologist review in borderline or challenging cases or perhaps using additional tools. There's some additional tools online. There are learning sets that are out there to help with that distinction.

    Dr. Antonio Wolff: What I would add to that is that I think, and Kim, I'm thinking of the pathologist now getting phone calls from oncologists saying, “Hey, Doctor Pathologist, you report this cancer as being IHC 0, and are you sure that this is truly IHC 0?” And I think we need to be careful not to put pathologists in an unfair situation. And I think we also need to be careful based on our behavior as oncologists that we could almost cause the extinction of the diagnosis of IHC 0 if pathologists feel somehow compelled to “try to help the oncologists” and potentially call a tumor that they would otherwise have called IHC 0, that they call that tumor IHC 1+. 

    And I think the reason for being cautious, as Kim mentioned, is these assays were not optimized for the ability to truly distinguish between IHC 0 and 1+. And we do not know if tumors that are IHC 0 clinically behave differently from tumors IHC 1+. Right now, that does not appear to be the case. And I think to a degree, we are being forced, based on the decision by the study sponsors to launch a study that excluded patients of IHC 0. We are left, I often say, twisting ourselves into pretzels, trying to come up with a way to discriminate between IHC 0 and 1+ simply because of the eligibility of the clinical trial and now the resulting FDA label for the study. 

    Because it is plausible that what if patients who had tumors that were IHC 0 had been included in this clinical trial? And what if we had determined that those patients also benefited from this new exciting antibody-drug conjugate? In that case, we would not be talking about creating new categories of HER2 low versus HER2 “ultra-low” and HER2 0, HER2 null. Because essentially, we would have identified a new clinical use for this exciting antibody-drug conjugate for patients who have tumors that are HER2 not overexpressed and HER2 not amplified. So, in fact, it is entirely plausible that the population of patients that could benefit from this antibody may go well above the original intent of DESTINY-Breast04. We just don't have the evidence at this point to say that those patients who would be called IHC 0 don't benefit. It's just that they were not included in the clinical trial.

    Brittany Harvey: Well, your points there from both of you lead nicely into my next question, in that you've talked a little bit about how this impacts both oncologists and pathologists. So, Dr. Wolff, what does this guideline and commentary mean for both clinicians and patients with breast cancer?

    Dr. Antonio Wolff: So I think what I would try to reassure oncologists, pathologists, and also patients and their caregivers and loved ones, over the last 20 years, I think we have seen a meaningful improvement in the quality of HER2 testing. And I think pathologists and oncologists recognize that breast cancer biomarkers, in general, in the past, were used purely for prognostic reasons or to complement anatomic pathology from a diagnostic standpoint. But now, many of these assays, especially ER and HER2, are used as the sole determinant of therapy selection in a binary fashion. If you are positive for ER, you can be a candidate for ER-targeted therapy. If you're positive for HER2, you may be a candidate for HER2-targeted therapy. And I think even though the current generation of IHCs were not equipped to make a differentiation between very low levels of HER2 expression from potentially no levels of HER2 expression, with all the limitations we just said, I think pathologists are today doing a very good job. They understand the importance of the work they do in helping us clinicians take care of patients in the clinic. As I often joke, pathologists are wearing the stethoscope with us. So I think we need to be kind to pathologists and not put them under the microscope, if you will, pun intended, or putting a lot of pressure on them. And I think I tend to trust the quality of the work they do. 

    I think there are two things that I would like to see happening. Number one, I would love to see the study sponsor allowing investigators to use a new generation of assays that are more quantitative to be able to back on DESTINY-Breast04 and test specimens of the patients that were triggered on the trial and see if there is a differential benefit in the observed outcomes of patients treated with trastuzumab deruxtecan according to levels of HER2, but that can be measured using a truly quantitative assay. And there are a lot of new assays out there. And I think the sponsors, they do have an obligation to all the patients who are participating in the trial to allow those things to happen. And the second piece is obviously to develop assays that are more quantitative than a traditional IHC.

    And Kim, along these lines, a question that often comes up is what to do with patients who may have had a previous test that was IHC 0. And what should we, I guess, recommend to clinicians that they do with this situation?

    Dr. Kim Allison: Yeah, I think this is a common question, and because of the unreliability of a 0 versus 1+ result, and we do see them change when you look at metastatic, or core versus primary surgical excision, 0 versus 1+ results shift around much more so than you'd expect if this was a true biologic difference. So I would look at a spectrum of samples across the metastatic progression. So if any of them are not 0, I think that's a result worth looking at. And considering that either there's heterogeneity there potentially or the 0s were false negatives and not consistent over time, so I would test the metastatic sample again. If you have a new sample, if that's 0, I would still consider treating based on a prior 1+ result or a different sample that's metastatic. 

    Dr. Antonio Wolff: Yeah, the one thing that I haven't done yet is actually for patients who have had– Let's say, that I have a primary term that was IHC 0, and then, they had, unfortunately, metastatic disease, and the diagnostic tissue that confirmed that they had metastatic disease also tested IHC 0. And now they are– unfortunately, disease has progressed after first or second-line therapy, be it anti-estrogen if they had ER-positive disease or chemotherapy if they had ER-negative disease. What I have not done is to request a new biopsy exclusively for the purpose of doing another HER2 test because in case the tumor had changed expression from 0 to 1+. Because what we don't know because of the variability, etc., Dr. Allison was just describing whether that change is real or not. 

    Again, it's really unfortunate that patients who were IHC 0 were not allowed for this study. There are other studies taking place right now looking at tumors that are more than IHC 0 and less than IHC 1+; that’s DESTINY-Breast06. And those patients are being called by the study sponsor as “ultra-low”. Although I am not a pathologist, but I have no idea how a pathologist can truly try using immunohistochemistry today; really reliably differentiate between it's not 0, it's not 1+, it’s in between. I am just concerned that I think we may be asking or putting pathologists in a hard spot, asking them to do something with an assay that was not designed to perform that way. 

    Dr. Kim Allison: Even if we could get the interpretation perfect, to have digital tools to help us with interpretation, I think at that low level, IHC is just really sensitive to pre-analytics and analytic factors that are subtle. Even having a slide that's been sitting unstained for a week or so might change a 1+ to a 0 result. So it really is sensitive, maybe too sensitive, to those kinds of factors. 

    Brittany Harvey: Absolutely. Well, thank you both for those insights on what's facing clinicians and patients and the commonly asked questions today.

     So then we've spent a lot of time talking about what's happened recently in this field. But, Dr. Allison, what are the ongoing developments and outstanding questions you're all facing regarding HER2 testing and breast cancer?

    Dr. Kim Allison: Yeah. I mean, I think we've covered some of those. Is IHC 0 truly 0? Would it be responsive to T-DXd or other antibody-drug conjugates targeting HER2? And so if that is relevant, then there's a lot of work looking at maybe more sensitive or quantitative assays that are really designed to detect those lower levels of expression, unlike the current assays. And then digital image analysis to standardize interpretation if they are leading to differences. And then new standards to help us calibrate. 

    Brittany Harvey: Great. Well, I want to thank you both so much for all of your work to review and update this guideline on HER2 testing in breast cancer. And thank you for your time today, Dr. Wolff and Dr. Allison. 

    Dr. Kim Allison: Thanks for having us.

    Dr. Antonio Wolff: Our pleasure. It’s fun. Thank you. 

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode. 

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

    ASCO Guidelines
    en-usJune 07, 2023

    Testing for ESR1 Mutations to Guide Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer Rapid Recommendation Update

    Testing for ESR1 Mutations to Guide Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer Rapid Recommendation Update

    Dr. Angie DeMichele and Dr. Lynn Henry present the latest rapid recommendation impacting two ASCO guidelines. This update focuses on testing for ESR1 mutations in patients with hormone receptor-positive, HER2-negative metastatic breast cancer, and presents treatment recommendations for patients with a detectable ESR1 mutation. Dr. DeMichele and Dr. Henry review the recent data from the EMERALD trial, discuss it's implications for practice, and ongoing developments they're monitoring for more effective therapeutic options.
    Read the latest update, "Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update at www.asco.org/breast-cancer-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the update and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.2300638 

    Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. 

    My name is Brittany Harvey, and today I'm interviewing Dr. Angie DeMichele from University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, authors on ‘Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update’. 

    Thank you for being here, Dr. DeMichele and Dr. Henry.

    Dr. Angie DeMichele: It's a pleasure. 

    Dr. Lynn Henry: Thank you. 

    Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this podcast episode today, are available online with a publication of the rapid recommendation update in the Journal of Clinical Oncology, which is linked in the show notes. 

    So then, getting into the content of this rapid recommendation first, Dr. Henry, what prompted this rapid update, which provides updated recommendations for two ASCO guidelines? First, the ‘Biomarkers for Systemic Therapy and Metastatic Breast Cancer Guideline’, last published in 2022, and the ‘Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer Guideline’, which was last updated in 2021.

    Dr. Lynn Henry: Thank you, Brittany. There's been a lot of exciting news for the treatment of metastatic breast cancer in the last few years. This particular update reflects the results of the phase III EMERALD trial. This trial compared the new oral selective estrogen receptor degrader, elacestrant, to standard-of-care endocrine therapy with either fulvestrant or an aromatase inhibitor in patients with hormone receptor-positive, HER2-negative metastatic breast cancer that had previously progressed during treatment with a CDK4/6 inhibitor in combination with endocrine therapy. Compared to standard-of-care, in this trial, they showed improved progression-free survival in both the overall study population as well as specifically in the patients who had a detectable ESR1 mutation in their circulating tumor DNA. These findings were published in the Journal of Clinical Oncology in 2022, and the drug was subsequently approved by the US Food and Drug Administration in January 2023. Therefore, we felt that it was important to update the guidelines to reflect the results of this trial and the new drug approval. 

    Brittany Harvey: Excellent. Thank you for describing the results of that trial and the new approval.

     So then, based on this data, Dr. DeMichele, what is the updated recommendation from the guideline expert panel for testing for ESR1 mutations? 

    Dr. Angie DeMichele: So, the guideline panel has now recommended that ESR1 mutation testing occur for any patient who develops a recurrence or progression on endocrine therapy. And this is specifically in reference to the development of ESR1 mutations that can occur after a patient has been exposed to aromatase inhibitors. The guideline itself recommends that this testing be done on either tumor or blood, but blood is preferable because there is increased sensitivity using ctDNA testing over tumor testing. So this was an important component of the change in the recommendation because it's linked to the approval of elacestrant as a therapy. Patients are only eligible to receive elacestrant if they harbor an ESR1 mutation.

    Brittany Harvey: Understood. I appreciate that explanation.  

    So then, Dr. Henry, following that recommendation for testing, what is the new recommendation for treatment for patients with a detectable ESR1 mutation?

    Dr. Lynn Henry: Yes. So patients who have a detectable ESR1 mutation and who have previously received treatment with endocrine therapy in combination with the CDK4/6 inhibitor for advanced breast cancer now have multiple treatment options. The newest option is this new drug, elacestrant, which is given 345 milligrams orally daily. There are still the other options that we already knew about, which include a different endocrine therapy alone, such as fulvestrant or an aromatase inhibitor, or possibly an endocrine therapy in combination with a targeted agent, such as alpelisib or everolimus. And those decisions really need to be based on what other mutations are present in the patient's cancer. 

    Importantly, at this time, there are no safety or efficacy data to support using elacestrant in combination with targeted agents. Therefore, to date, it has only been approved to be used as monotherapy. But really, this is an exciting new potential option for treatment for patients whose tumors have a detectable ESR1 mutation.

    Brittany Harvey: Yes, this is an exciting option, and I appreciate you describing how this fits in with the existing treatment paradigm for these patients.  

    So then, Dr. DeMichele, as these new recommendations are implemented, what should clinicians know?

    Dr. Angie DeMichele: I think this is a really important new step in breast cancer in testing for ESR1 mutations. We've not previously had a medication that required the existence of an ESR1 mutation for patients to be eligible for therapy. So obtaining ESR1 mutation testing may be new for some clinicians. As I stated earlier, this can be done either on a tumor biopsy or on blood testing using the Guardant360 ctDNA test, which is the test that was used in the clinical trial. And it was stated that the ctDNA test is more sensitive than the tumor test. But what's really important here is that the testing occur at the time that the clinician is considering switching therapies, because it's important to find that ESR1 mutation prior to starting the next therapy. ESR1 mutations don't typically exist in a tumor at the time it's diagnosed. They only emerge over time after patients have been exposed to different endocrine therapies, particularly aromatase inhibitors. It's also possible that at the time of a recurrence after aromatase inhibitor therapy or progression on an aromatase inhibitor, there will not be any detectable ESR1 mutation. However, with subsequent therapy, an ESR1 mutation can occur. So a patient may need serial testing over time to determine whether an ESR1 mutation has developed.

     Brittany Harvey: Understood. Those are important clinical implications.

     So then, Dr. Henry, Dr. DeMichele just described some of the testing implications for patients. But in your view, how does this rapid update impact patients with hormone receptor-positive, HER2-negative metastatic breast cancer?

    Dr. Lynn Henry: So as Dr. DeMichele mentioned, this update specifically highlights approval of a new drug, oral SERD elacestrant. This is an exciting new option for treatment of patients whose tumors have an ESR1 mutation. So previous data have demonstrated that cancers with ESR1 mutations do not respond as well to previously available standard-of-care treatments such as aromatase inhibitors. It's nice to have a drug that may be a better option than some of the previously existing treatments for hormone receptor-positive, HER2-negative metastatic breast cancer.

    Brittany Harvey: Definitely. That's great to hear. 

    So then, finally, Dr. DeMichele, are there ongoing research developments that the panel is monitoring for future updates to these guidelines?

    Dr. Angie DeMichele: We certainly are monitoring additional research developments, Brittany. Specifically, there are numerous other selective estrogen receptor degraders that are being tested, and these also may ultimately require ESR1 mutation testing and detection for therapies. So we'll be monitoring the results of those clinical trials. We'll also be watching for additional trials that help us understand how to best utilize elacestrant and whether it can be combined with other therapies. And then, finally, I think we have to think about how to place this in the context of other types of molecular changes that we may detect in metastatic breast cancer, such as PIK3CA mutations and others. And as we move forward, I anticipate that we will have additional therapies that are specifically targeted to molecular changes in the tumor. And I think this is a really exciting development because this is a major step forward toward precision medicine, where we're really tailoring the therapy to the specific biology of the patient's tumor and actually responding to the ways in which the tumor is evolving over time and in response to treatment. So as tumors become increasingly resistant to therapies, we can actually take advantage of those resistance mechanisms to develop therapies that will be more effective.

    Brittany Harvey: Yes, we'll look forward to those new therapies and research developments and then updated guidelines in the future. 

    So I want to thank you both so much for your work on this rapid recommendation update and for your time today, Dr. DeMichele and Dr. Henry.

     Dr. Angie DeMichele: Thank you. 

    Dr. Lynn Henry: Thank you very much. 

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guidelines, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 

    The purpose of this Podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

    ASCO Guidelines
    en-usMay 17, 2023

    VTE Prophylaxis and Treatment in Patients with Cancer Guideline Update

    VTE Prophylaxis and Treatment in Patients with Cancer Guideline Update

    Dr. Nigel Key and Dr. Anna Falanga join us for a conversation on the updated ASCO VTE prophylaxis and treatment in patients with cancer guideline. They discuss recent evidence assessing apixaban for VTE treatment in patients with cancer and evaluating direct factor Xa inhibitors for extended postoperative prophylaxis. Based on this new evidence, they present updated evidence-based recommendations from the guideline expert panel. Dr. Key and Dr. Falanga also discuss outstanding questions regarding VTE prophylaxis and treatment in patients with cancer.

    Read the full guideline update, “Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update” at www.asco.org/supportive-care-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00294. 

    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at ASCO.org/podcasts.

     My name is Brittany Harvey, and today I'm interviewing Dr. Nigel Key from University of North Carolina, and Dr. Anna Falanga from University of Milan Bicocca, co-chairs on ‘Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update’.

     Thank you for being here, Dr. Key, and Dr. Falanga.

     Dr. Nigel Key: Thank you.

     Dr. Falanga: Thank you.

    Brittany Harvey: Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology, linked in the show notes.

     So then, jumping into this guideline update, Dr. Key, what prompted an update to the ‘ASCO VTE Guideline’, which was last updated in 2019?

     Dr. Nigel Key: Okay, well, thank you, Brittany, for that question. Well, first of all, ASCO has been providing this guideline since 2007 with iterations and full reviews of the data, the last complete one being in 2019. This update was really triggered by ASCO's signals approach, which relies on experts in the field suggesting an update to the guidelines based on recent publications that may be practice-changing. So, in this case, the signals were really a randomized control trial assessing apixaban for VTE treatment, venous thromboembolism treatment, in patients with cancer called the CARAVAGGIO trial, and we'll discuss that a little bit later. There were also a couple of randomized control trials which evaluated direct factor Xa inhibitors for extended postoperative prophylaxis, and these were new areas subsequent to the 2019 guidelines. So, a systematic review was carried out in the relevant topics for randomized control trials published between November 1, 2018, and June 6, 2022. And what you'll hear today is the result of that process.

     Brittany Harvey: Great. And then you just described that guideline recommendations were updated both for prophylaxis and for treatment. So then, Dr. Falanga, what is the updated recommendation for perioperative VTE prophylaxis?

    Dr. Falanga: Thank you for this question. For this update, actually, there were two randomized trials addressing the extended thromboprophylaxis in cancer patients. This is an important question, and direct oral anticoagulants had never been included in the previous guidelines. So this new data indicating safety and in some way efficacy of these drugs were important to be in some way included. Actually, the two trials, one tested laparoscopic surgery in patients with colorectal cancer, so major surgery in colorectal cancer and tested the drug rivaroxaban against the placebo after one week of low molecular weight heparin. And the other trial tested in a different type of cancer, gynecological cancer surgery, apixaban versus a placebo after a short course with low molecular weight heparin.

     So the two trials are very different, and the recommendation, after all, is weak. But the panel felt it was important to split the previous recommendation 3.5 into three recommendations. The 3.6 specifies which are the cancer patients that really need extended prophylaxis, or the recommendation addresses this population in particular at high risk, which means patients with laparoscopic or laparotomic abdominal pelvic surgery for cancer who have high risk characteristics, including restricted mobility, obesity, previous history of thrombosis, and other additional risk factors. So the recommendation is limited to this population. As I said, there is a weak recommendation because the two trials differ in the type of surgery, the type of the number of patients, the timing of prophylaxis, and one tested rivaroxaban and one tested apixaban.

    But in any case, the recommendation now reads that prophylaxis with these two direct oral anticoagulants may be offered in addition to the previous recommendation with the low molecular weight heparin for this indication, although the low molecular weight heparin indication remains a strong recommendation where these other two drugs are added. But still other research is needed to strengthen this recommendation.

    Brittany Harvey: Understood. Thank you for describing where there is evidence and where future research is needed to strengthen those recommendations and the qualifying statements for who is appropriate to receive this VTE prophylaxis.

    So then, Dr. Key, what did the expert panel update regarding treatment of patients with cancer with established VTE to prevent recurrence?

     Dr. Nigel Key: Yes. First of all, I want to make it very clear that this particular recommendation deals, as you say, with patients with established venous thromboembolism. This is quite distinct from recommendations regarding primary prophylaxis in ambulatory patients, which is dealt with in a separate recommendation. That's number two in the 2019 guideline, and those have not been updated. But in terms of treatment of established venous thrombosis, there were three randomized control trials considered. They essentially all addressed the possible role of apixaban, which had not been included in the 2019 guideline. In this revised recommendation, the data looked at both the initial treatment of patients presenting with venous thrombosis as well as extended treatment, which what we know at present, really extends out to six months in terms of using non-vitamin K antagonists, preferably for extended prophylaxis.

     So, in 4.1, the CARAVAGGIO trial that I mentioned earlier was a very large trial involving almost 1200 patients with cancer who had symptomatic or incidental acute proximal DVT or pulmonary embolism. And these patients were randomized to six months of treatment with either apixaban or dalteparin. And, in a nutshell, apixaban was non-inferior to dalteparin for the primary outcome of a recurrent VTE during the six month trial period. There was also a similar rate of major bleeding, 3.8 versus 4% in the two arms. So this was strong evidence that initial treatment could include apixaban in addition to what was already in the recommendations. And for those choosing to treat with heparin for initial five to ten days, as before, the recommendation is for low molecular heparin over unfractionated heparin.

     So, the second part of this took into account the CARAVAGGIO trial, which I've already mentioned the result of, as well as two smaller trials. They had a VTE trial which had almost 300 patients, and again compared apixaban to dalteparin. And then there was a third smaller study comparing apixaban to lovenox in about 100 patients. But, essentially, the net outcome of the systematic review was that the recommendations 4.1 and 4.2 for, respectively, initial and extended treatment of established VTE, gave high quality evidence with a strong recommendation to include apixaban both for initial treatment and for extended treatment.

    Brittany Harvey: Understood. So then you've both discussed this a bit by describing the randomized trials supporting these recommendations. But Dr. Falanga, what should clinicians know as they implement these updated recommendations?

     Dr. Anna Falanga: Well, clinicians should know that there are more options to offer to their patients for long-term treatment of VTE, as Dr. Key said, up to six months. This is an important expansion of the spectrum of choices for a more personalized treatment on the basis of the patient's characteristics and the drug characteristics. So this is very important to know. Also, for the postoperative prophylaxis, this update is relevant because of the recommendation. Although we are open to the perspective of using new drugs based on oral intake as an alternative to low molecular weight heparin, and knowing this drug appears to be safe in the specific setting where they were tested in the trial is important.

    Brittany Harvey: Definitely, it's great to have more options for patients.

    So then in your view, Dr. Key, how will these guideline recommendations impact patients with cancer?

     Dr. Nigel Key: Well, I think that with more information that Dr. Falanga just presented, essentially we're looking at two different situations here, both the extended thrombosis prophylaxis after surgery and the choice of agent does need to be individualized with a discussion with a physician. There are still remaining concerns about increased bleeding with direct Xa inhibitors in patients with GI and GU malignancy, for example. So this needs to be taken into account, patients' creatinine values and so on, and what other drugs there are in terms of interactions with direct Xa inhibitors. So I think what you're looking at though is the ability to be confident for that patient that oral agents are, for the most part, as safe and effective as low molecular weight heparins. And hopefully, this will be something that is seen as a positive and maybe somewhat liberating effect for patients.

     Brittany Harvey: That's great to hear.

     So then finally, Dr. Falanga, you've already mentioned a few areas in which more research would be helpful to strengthen the recommendations. But are there other outstanding questions regarding VTE prophylaxis and treatment in patients with cancer?

     Dr. Anna Falanga: Yes, there is a lot of work to be done ahead for prophylaxis. As we already mentioned, it's important to improve the evidence for direct oral anticoagulant safety and efficacy for extended, postoperative prophylaxis. In the medical setting, we have open questions about how to improve the management of patients with VTE beyond six months; we don't know for the treatment of VTE beyond six months, and identify better what are the best drugs and the best strategies to be utilized in this interval.

     Then I think that we need to understand, in collaboration with cardiologists and neurologists, whether arterial thrombosis associated with the cancer may need a different treatment compared to subjects without cancer, and understand how to manage anticoagulant together with antiplatelet drugs in these patients who are often thrombocytopenic.

     Finally, it is, of course, important to test new drugs for VTE treatment with potentially reduced bleeding risk, such as the new inhibitors of factor XI and factor XII. I think these are the major points that we need to address in the near future possibly.

     Brittany Harvey: Absolutely. Well, we'll look forward to future updates of this ASCO guideline to discuss that research as it comes along.

     So I want to thank you both so much for your work to update this guideline and thank you for your time today, Dr. Falanga and Dr. Key.

     Dr. Anna Falanga: Thanks a lot. Bye bye.

     Dr. Nigel Key: Thank you. You’re very welcome. Bye bye.

     Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

    Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

     

    ASCO Guidelines
    en-usApril 19, 2023

    Management of Anxiety and Depression in Adult Survivors of Cancer Guideline Update

    Management of Anxiety and Depression in Adult Survivors of Cancer Guideline Update

    Dr. Barbara Andersen delves into the newly updated guideline for management of anxiety and depression in adult survivors of cancer in this ASCO Guidelines podcast episode. This guideline affirms prior guidance regarding screening and assessment of anxiety and depression, and updates evidence-based recommendations for management of both anxiety and depression. Dr. Andersen reviews the principles of the recommended stepped-care model, along with recommended treatments, including options such as cognitive behavior therapy, cognitive therapy, behavioral activation, structured physical activity and exercise, and mindfulness-based stress reduction. Challenges regarding managing anxiety and depression in adult survivors of cancer are also discussed.
    Read the full guideline update, “Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update” at www.asco.org/survivorship-guidelines.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00293.

    Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.

     My name is Brittany Harvey, and today I'm interviewing Dr. Barbara Andersen from the Ohio State University, lead author on “Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update.”

     Thank you for being here, Dr. Andersen.

     Dr. Barbara Andersen: Thank you. Thank you for the invitation.

    Brittany Harvey: And then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Andersen on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

     So then, to jump into the content of this guideline, Dr. Andersen, what prompted an update to this guideline, and what is the scope of this updated version of the guideline?

     Dr. Barbara Andersen: Well, as your listeners probably know, guidelines are routinely updated, primarily due to new accumulated evidence that suggests a change in diagnostic or treatment procedures. The first guideline from ASCO was in 2014. They made this important first step, which alone made that an important advance. The prior scope was on assessment, that is, which measures at what time points were important for assessing patients' depressive or anxiety symptoms. We then provided treatment pathways thereafter, noting currently available evidence for treatment. But a systematic review of the literature wasn't done at that time. So what this guide does is first affirm the prior recommendations regarding the measures to use for assessment, the PHQ-9 and the GAD-7. But the departure for these guidelines is based on a systematic review of the intervention and treatment literature, and from that review, we recommend particular treatments.

    Brittany Harvey: Understood. So, focusing on that intervention and treatment aspect of this updated guideline, I'd like to review the key recommendations starting with, what are the key general management principles for people with cancer and anxiety and/or depression?

     Dr. Barbara Andersen: Well, one key principle is that of education. Your listeners probably are familiar with the fact that many hospitals or centers provide patient-tailored cancer treatment-related information, treatment information on surgery, chemotherapy, immunotherapy, and other topics. But we recommend that general first-level materials on coping with stress, anxiety about treatment, and depression be routinely provided as well. What that does is for individuals with elevated symptoms, it validates what they're experiencing and normalizes the patient experience. So we hope that all patients with cancer and any patient-identified caregiver, family member should be offered the information. We have so many ways we can give information to patients these days. Verbally, material, whatever mode is easy for you and the patient, but please choose one to give information to patients.

     Another characteristic of the guideline is our recommendation that treatment follow the principle of stepped care. So what this means is you match the assessment of the severity, level of depression or anxiety, and you match that data to the selection of treatment contexts. This is most clearly seen in the recommendation that group treatment formats be used for those with moderate severity of symptoms versus individual or face-to-face therapy for those with severe symptoms. And this is the case for both anxiety and depressive disorders. This is a principle that's cost-effective and tailors the treatment recommendations. Another principle that we offer is when making a referral of a patient for further evaluation or psychological care; we plead with you to make every effort to reduce the barriers and facilitate patient follow-through. We say it's essential because low motivation, for example, is a symptom of depression. And that low motivation and low mood can conspire to reduce the likelihood that patients will pursue treatment. So just keep that in mind when referring patients.

     Brittany Harvey: Absolutely. Those are key points for general management across anxiety and depression symptoms. So, moving beyond those principles, what are the recommendations from the expert panel for treatment and care options for patients with depressive symptoms?

     Dr. Barbara Andersen: For depressive symptoms, we recommend cognitive behavior therapy or cognitive therapy, behavioral activation, psychosocial interventions using empirically supported components, and moderate structured physical activity and exercise. All of those are efficacious, empirically supported treatments for moderate depressive symptoms. And it might be easiest to offer group therapy for individuals with these problems.

     Brittany Harvey: Great. Thank you for reviewing those recommendations for patients with depressive symptoms.

     So, in addition, what does the expert panel recommend for treatment and care options for patients with anxiety symptoms?

     Dr. Barbara Andersen: Many of the same treatments are used. Cognitive therapy, cognitive behavior therapy are the most efficacious treatments out there for cancer patients or individuals without cancer coping with anxiety symptoms or depressive symptoms. Again, behavioral activation would be useful. Mindfulness-based stress reduction has garnered significant support in the recent years, as well as interpersonal therapy.

     Brittany Harvey: Understood. So thank you so much for going through each of those recommendations.

     But in your view, Dr. Andersen, what is the importance of this guideline, and how will it impact both clinicians and patients with cancer and symptoms of anxiety and/or depression?

     Dr. Barbara Andersen: An important element to this guideline is it names the specific empirically supported standard therapies for treatment of anxiety and depression. There's a departure, though, from our prior guideline, and in this one, pharmacotherapy is not recommended as a first-line treatment, neither alone nor in combination. It's simply not supported by the evidence. However, clinicians might consider pharmacotherapy when there's low or no availability of mental health resources. Perhaps a patient might have responded well to pharmacotherapy in the past, and patients with severe neurovegetative, or agitated symptoms of depression, those patients, as well as patients with psychotic or catatonic features, would be ones for which pharmacotherapy might be appropriate.

     Brittany Harvey: Understood. And then you've just mentioned that sometimes there is no or low availability of mental health resources, so that leads to my next question. But what are the both outstanding research questions and challenges regarding managing anxiety and depression in adult survivors of cancer?

     Dr. Barbara Andersen: The largest challenge is that we're in the midst of a mental healthcare crisis, and COVID has made that abundantly clear. There are problems with access to psychological care due in part to workforce problems, maybe organizational ones, but there is a shortage of mental health professionals, and that, in turn, limits referral networks from managing depression and anxiety. So that's one significant issue that is in place right now.

     Since the 2014 guideline, screening is a care aim that has been disseminated, but the principles and procedures remain to be fully implemented. I was just looking at a 2022 article in the Journal of Oncology Practice. It was a study examining screening for lung and ovarian cancer patients, two very important groups because the frequency of depressive and anxiety symptoms is perhaps highest of any other groups. So they looked at more than 20 CoC-accredited facilities that studied the electronic records to see if there was screening for the patients. And the troubling finding, from my perspective, was that there was no screening for 45% of the patients in this study. So we know that there are disparities in the use of screening and its management. Those disparities exist across race, ethnicity, cancer type, stage, and facilities. And so, that remains a challenge for many sites, including CoC hospitals, to achieve a rigorous screening program.

    Having said that, I want to say what some might disagree with, but from my standpoint, it's a myth that screening takes a long time. The measures that we recommend probably would take a patient maybe five, maybe ten minutes to complete. But what's time-consuming or what's troublesome in many places is the infrastructure is not in place to do the screening and interpret it in an efficient manner. The other perspective on screening is that it is the effort thereafter, which is, in fact, time and resource intense - that is, finding referral sources, making referrals. But that's the most important step because when that's not done, when patients continue with symptoms, it really incurs the greatest cost for the patients.

    Brittany Harvey: Absolutely. Screening and then further management of anxiety and depressive symptoms is key for maintaining quality of life.

     So I want to thank you so much, Dr. Andersen, for coming on today and sharing your insights and also for all your work you did to update this guideline.

     Dr. Barbara Andersen: Thank you so much.

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast.

     To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.

     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

     

    ASCO Guidelines
    en-usApril 19, 2023

    Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2023.1 Part 2

    Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2023.1 Part 2

    Dr. Dwight Owen is back on the ASCO Guidelines podcast, discussing the latest updates to the ASCO living guidelines for stage IV NSCLC. In Part 2, Dr. Owen presents the update for stage IV NSCLC with driver alterations. He reviews new evidence from KRYSTAL-1, and reviews a new recommended option for patients with stage IV NSCLC with a KRAS G12C mutation, adagrasib.


    Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.1” and view all recommendations at www.asco.org/living-guidelines.

    Listen to Part 1 for recommendations for patients with stage IV NSCLC without driver alterations.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00281 

    Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast, one of ASCO’s podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts

    My name is Brittany Harvey, and in our last episode, we addressed the living guideline updates for therapy for stage IV non-small-cell lung cancer without driver alterations. Dr. Dwight Owen from Ohio State University in Columbus, Ohio, has joined us again to discuss the updates for therapy for stage IV non-small-cell lung cancer with driver alterations, as a co-chair on ‘Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.1’. 

    Thank you for joining us again, Dr. Owen.

    Dr. Dwight Owen: Thanks for having me, Brittany.

    Brittany Harvey: Then, before we discuss this update, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Owen, who's joined us on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology linked in the show notes.  

    So then, jumping into the content here, this living clinical practice guideline for systemic therapy for stage IV non-small-cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations? 

    Dr. Dwight Owen: Yeah. Thank you, Brittany. For this update, the panel and committee felt that it was important to review the KRYSTAL-1 trial. This was a phase I/II open-label study of adagrasib in patients with KRAS G12C mutation-positive solid tumors, which included multiple expansion cohorts, including a cohort of patients with non-small cell lung cancer. Importantly, the data that was presented in this recent publication included only patients treated at the phase II dose of 600 milligrams twice daily. The study included 160 patients with a primary endpoint of a response rate, which was evaluated in 112 of those patients. The confirmed response rate was 43%, including one complete response, with the remaining being partial responses. The median progression-free survival was six and a half months, and the median overall survival for this pretreated patient population was approaching one year. 

    One thing of note is we saw similar toxicities as we have seen with other KRAS G12C inhibitors, which included predominantly GI side effects such as diarrhea, nausea, vomiting, but also hepatic side effects including transaminitis, some renal dysfunction as well. Dose interruption was common in over 60% of patients, and dose reduction was required in over half of patients. Overall, given the efficacy seen in this cohort, again, even though it was a phase I/II trial, it was a substantial number of patients, and we felt that it met the criteria for us to be able to include this as an additional recommendation in our guidelines.

    Brittany Harvey: I appreciate you reviewing that data. So then, based off this data from KRYSTAL-1, you just mentioned that there's a new recommendation from the panel. So what is this new recommendation for patients with advanced non-small cell lung cancer with a KRAS G12C mutation?

    Dr. Dwight Owen: For patients with stage IV non-small cell lung cancer with KRAS G12C who have received prior treatment with a chemotherapy and/or immunotherapy with a PD-1 therapy, we have added that clinicians and oncologists may consider treatment with adagrasib to our current recommendations for these patients.

    Brittany Harvey: Great. And then you just mentioned this is an addition onto current recommendations. So what should clinicians know as they implement this updated recommendation, and how does it fit in with those previous recommendations for patients with previously treated non-small cell lung cancer with a KRAS mutation?

    Dr. Dwight Owen: That's a really important point, is this is now our second option for these patients, including sotorasib, which many of us have been familiar with so far. Of course, we don't have a head-to-head trial comparing these two, but looking at the efficacy and toxicity data, they do seem quite similar. We have some more data for sotorasib from the CodeBreaK 200 study, which we'll be reviewing in a future update. However, at this point, looking at the monotherapy studies that have been done, the toxicity profiles seem fairly similar, the efficacy profiles seem fairly similar, so we don't yet have a clear differentiator that we can see, again, in the absence of a head study. 

    The other thing I would note is that the inclusion criteria for these studies, for the most part, excluded patients with active brain metastases, which, unfortunately, is something that we see quite commonly in patients with lung cancer. And although we have seen some case reports and some anecdotal data for CNS activity with these compounds, we're still waiting for defined cohorts, which there were defined cohorts in these studies that included patients with asymptomatic but untreated brain metastases. And I think that will be something that we are actively looking for and looking forward to. Because I think having a better understanding of potential CNS activity of either or both of these compounds would really alleviate a lot of concerns that we have that those patients who really are the patients that we see in clinic were just not represented in the studies that we reviewed to date. 

    Brittany Harvey: Understood. I appreciate that additional context around these recommendations. 

    So what does this new therapeutic option mean for patients with stage IV non-small cell lung cancer with a KRAS G12C mutation? 

    Dr. Dwight Owen: The end result is that we have more treatment options for patients. Again, both of these compounds seem active. There are clearly patients who benefit and, in some cases, for a substantial period of time because of these options, which were not available as of just recently and until the very recent past, KRAS was, of course, considered an undruggable target. So it's really incredible that we have these treatment options and that they're coming to clinic so quickly. I think there are some areas that we still don't understand yet in terms of the sequencing of treatment. Right now, these treatments are only approved as a subsequent treatment. In most of the studies, the vast majority of patients had received both chemotherapy and immunotherapy. We don't really know how that sequence might affect the tolerability or efficacy of the KRAS inhibitors. We do know that toxicity is an issue, and with both agents, dose reductions are frequently utilized to try to assist with tolerability. There is a slight difference in terms of how these are administered, whether it's daily with a higher pill burden versus twice daily. 

    And so there are some nuances that clinicians can discuss with patients. But again, absent a

    head-to-head study, it's really important to have a discussion with your patient about what the toxicity profiles of these agents are and what the likelihood of benefit is. And we look forward to seeing more data as these get combined with other therapies and potentially have more insight into the optimal sequence of therapies for patients with KRAS G12C non-small cell lung cancer.

    Brittany Harvey: Absolutely. It's great to have additional treatment options for patients, and those are key points for discussions about personalized therapeutic regimens. So then, finally, are there emerging therapies or targets that the panel is considering for future living guideline updates? 

    Dr. Dwight Owen: As I mentioned in the last podcast, the data coming out is happening so quickly that we are working to make sure that the guidelines are as up-to-date as possible based on the most recent published literature where we can actually take time to delve into the data and be transparent about the evidence based from our recommendations. We are very interested in the subsequent studies in the KRAS G12C pathway. I mentioned the CodeBreaK 200 study that we’d be including in a future publication, as well as in some of the emerging data in KRAS non G12C non-small cell lung cancer. 

    As of now, it's very important to keep in mind that the only inhibitors we have are dependent on the G12C on the cysteine, and therefore those are the only patients that are currently able to benefit from these treatments. But in the future, we hope that that patient cohort becomes expanded, and we continue looking for new therapies for patients with other alterations, including subsequent therapies for EGFR non-small cell lung cancer and, of course, other actionable alterations as well.

    Brittany Harvey: That's great to hear. We'll look forward to that future research and the review of that evidence by the panel and future guideline updates. 

    So thank you so much for your work on these updates and thank you for your time today, Dr. Owen. 

    Dr. Dwight Owen: Thanks very much, Brittany.

    Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/living-guidelines. There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer without driver alterations available there and in the JCO. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store

    If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

    Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

    ASCO Guidelines
    en-usApril 06, 2023

    Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2023.1 Part 1

    Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2023.1 Part 1

    Dr. Dwight Owen is back on the ASCO Guidelines podcast, discussing the latest updates to the ASCO living guidelines for stage IV NSCLC. In Part 1, Dr. Owen presents the update for stage IV NSCLC without driver alterations. He reviews new evidence from EMPOWER-Lung3 and POSEIDON and discusses new recommended options for patients with squamous cell carcinoma and non-squamous cell carcinoma, and PD-L1 tumor proportion score 0-49%.

    Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.1” and view all recommendations at www.asco.org/living-guidelines.

    Listen to Part 2 for recommendations for patients with stage IV NSCLC with driver alterations.

    TRANSCRIPT

    This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors’ disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00282 

    Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO’s podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts 

    My name is Brittany Harvey, and I'd like to welcome back Dr. Dwight Owen from Ohio State University in Columbus, Ohio, co-chair on ‘Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline Version 2023.1’.  

    Thank you for being here, Dr. Owen.

    Dr. Dwight Owen: Thanks for having me, Brittany.

    Brittany Harvey: Then, before we discuss this update, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Owen on this episode, are available online, with a publication of the guideline in the Journal of Clinical Oncology linked in the show notes.  

    So then, diving into this update, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is being updated on a regular basis. What was the new evidence identified by the expert panel through routine literature searches to prompt an update to the recommendations?

    Dr. Dwight Owen: Yeah. Thanks, Brittany. I think it's really important to point out that these living guidelines are evidence-based. And so, we are constantly reviewing the literature to find new data to support recommendations for treatment options for clinicians to choose for their patients with metastatic non-small cell lung cancer. Clinicians these days, and physicians and oncologists are faced with so much information coming from abstracts to press releases to publications of new clinical trial results that it can be sometimes overwhelming to keep track of all the latest breakthroughs and nuances in the literature for non-small cell lung cancer. 

    So for this specific update, the panel and the committee reviewed two papers, including the

    EMPOWER Lung-3 Study and the POSEIDON Study. The EMPOWER Lung-3 study was a double-blind, placebo-controlled phase III study investigating cemiplimab plus platinum doublet chemotherapy as the first treatment for patients with either locally advanced stage III or stage IV non-small cell lung cancer without either an EGFR, ALK, or ROS1 alteration. And this is a mode of treatment that we've seen before, which is a PD-1 plus chemotherapy or PD-L1 plus chemotherapy compared to a chemotherapy control. And indeed, we did see an improvement in median overall survival in this study with the addition of cemiplimab to chemotherapy of almost 22 months versus 13 months with the placebo. This was accompanied by a higher rate of grade 3 or higher toxicities. But overall, these data were consistent with what we have seen with other studies of checkpoint inhibitor therapy plus chemotherapy in the first-line setting, which is now the current standard of care. 

    The second study we reviewed was the POSEIDON Study, and this was an open-label phase III study of combination checkpoint inhibitors. So this was PD-L1 plus CTLA-4, durvalumab + tremelimumab with chemotherapy versus chemotherapy alone, and these patients were metastatic non-small cell lung cancer without EGFR or ALK alterations. The interesting thing about this study is there was a cohort of patients treated with durvalumab plus chemotherapy alone. But it was really the cohort of patients treated with tremelimumab, durvalumab, and chemotherapy who had a significant improvement in median survival of 14 months versus 11.7 months with chemotherapy alone, with a hazard ratio of 0.77. In this study, the tremelimumab was only given for a total of five cycles, so it was not continued during the maintenance phase with durvalumab, which is a slight difference from other combination checkpoint inhibitor therapies, which are approved based on CheckMate 227 and CheckMate 9LA, which is nivolumab + ipilimumab. 

    So, overall, neither of these two studies present a new paradigm of treatment. But they present new treatment options for patients as a first-line treatment for non-small cell lung cancer in the form of either PD1/L1 plus chemotherapy or combined checkpoint inhibitor with a PD-L1 plus CTLA-4 plus chemotherapy, again showing improved survival compared to chemotherapy alone.

    Brittany Harvey: I appreciate you reviewing the details of those two trials. So then, based off this new data from the trials that you mentioned, EMPOWER Lung-3 and POSEIDON, what are the updated recommendations from the expert panel?

    Dr. Dwight Owen: So we felt it was important to update our prior recommendations for patients, especially with low to intermediate PD-L1 expression from 0% to 49%, that patients may offer cemiplimab plus chemotherapy as an additional treatment option in addition to the recommendations that have already been in place, regardless of histology. And then, based on the POSEIDON data, we felt that this was also a treatment option for those similar patients, especially with PD-L1 negative or up to 49%. 

    We do feel that the patients with PD-L1 TPS scores of 50% or higher still seem to benefit the most from checkpoint inhibitor monotherapy and multiple studies that have been done there. And so we did not make any changes to the recommendations for those patients with PD-L1 high non-small cell lung cancer. 

    Brittany Harvey: Understood. And then you just mentioned that neither of these therapies represent a paradigm change for treatment options. So what should clinicians know as they consider these new options in addition to previously recommended therapies?

    Dr. Dwight Owen: Yes. So I think when clinicians are looking at these studies, things to keep in mind are the size of the study, the cohorts included, the endpoints. The comparison arm, for now, remains chemotherapy alone, which again is no longer the standard of care. So we are sort of looking backwards at a historical standard of care that we no longer really confront other than for patients who have some contraindication to immunotherapy.  

    The other thing to keep in mind is, of course, when you add more treatments together, you expect more toxicities. And that is certainly the case when we see the dual combined checkpoint inhibitor therapies plus chemotherapy. Regardless of whether it's nivolumab + ipilimumab and chemotherapy or whether it's durvalumab + tremelimumab plus chemotherapy, we do expect a higher rate of toxicities when we do add the CTLA-4 to the PD1/L1 backbone.  

    And so this is a conversation that's really important to have with your patients. We don't have a head-to-head trial, so we are inferring differences in terms of response and benefit using the same comparison of chemotherapy but from different studies and also different populations. So that is probably one of the more important lessons to take from all of these studies is that we know that the toxicity rate does change depending on how you add therapies for these patients. And we also know that there are patients who may not need that additional therapy. So patient selection is key.  

    And I think one of the most unmet needs right now is for patients with PD-L1 negative tumors who don't seem to benefit from checkpoint inhibitor monotherapy or even in long term data when checkpoint inhibitor therapy is given just combined with chemotherapy, these patients seem to be the ones who don't benefit as much. And so I think that would be the patient population that really warrants that extra discussion where you may consider a more aggressive treatment depending on a patient's preference in terms of susceptibility, in terms of toxicity.

    Brittany Harvey: Absolutely. Considerations of the toxicity profiles of these agents is key for patient quality of life. That leads nicely into my next question, but what do these new recommended therapies mean for patients with stage IV non small cell lung cancer without driver alterations? 

    Dr. Dwight Owen: Well, I think, of course, it is beneficial to have more treatment options, but when we have more treatment options, the decision can actually become more challenging because how do you select from any of the treatment options that we have? And in the absence of direct head-to-head trials for now, we really need to look at the toxicity data, look at the outcome data, and see how the patient in front of you fits into the studies that have been done in order to make an inference and to have that informed discussion with the patient about what to expect from a specific treatment.  

    And I think the higher rates of immune toxicities that we see when we use combination checkpoint therapy needs to be a discussion with patients, and also the type of chemotherapy backbone and how long that chemotherapy will be continued. Whether it's two cycles like Checkmate 9LA, whether it's four cycles like POSEIDON, whether we have a non-chemotherapy option to offer patients, these are all nuances that right now lead to a really robust conversation with our patients up front. And really trying to guide patients through these discussions because the information can be so overwhelming when it's given at one time. So, really trying to have that meaningful conversation in a way that the patient can help advocate for themselves in the clinical decision-making. 

    Brittany Harvey: Definitely, those nuances are important for those individual discussions. So then, finally, you've mentioned that the panel is reviewing literature on an ongoing basis. So, what ongoing developments is this panel monitoring for future updates? 

    Dr. Dwight Owen: So, I think all of us are very excited about the announcements that we have been hearing, both in terms of press releases, in terms of abstracts at the upcoming ACR meeting, and of course, ASCO later this year, where we expect to have a wealth of new data for patients with non-small cell lung cancer, both in the metastatic setting but also in the early stage setting. And I think one of the challenges for us in this committee and for practicing oncologists every day is the speed at which this information is coming out and making sure that we have time to really review each study and give each study the time needed to understand how it can impact our treatment selection based on what's already an accepted practice and what maybe is something that we should reconsider. 

    And so I think it's very rewarding work to work with the committee members and the panel and ASCO. But it is also something that we take very seriously, just because data can come out so quickly at varying levels of detail. And we really want to make sure that when we make a guideline recommendation, that we are very clear that it is evidence-based and what that evidence is.

    Brittany Harvey: Absolutely, we appreciate the panel's evidence-based approach to developing these recommendations. 

    So, I want to thank you for your time working on this update and for coming on the podcast to speak with me today, Dr. Owen.

    Dr. Dwight Owen: Thanks very much, Brittany. 

    Brittany Harvey: And thank you to all of our listeners for tuning into ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/living-guidelines.  There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer with driver alterations available there and in the JCO. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store

    If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode.  

    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

     

    Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

     

     

     

     

    ASCO Guidelines
    en-usApril 06, 2023
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