pembrolizumab

A number of groundbreaking and practice-changing studies were presented at the San Antonio Breast Cancer Symposium 2020.

The RxPONDER, ADAPT, and PRIME-2 trials revealed patients who can forgo chemotherapy or radiotherapy, monarchE and PENELOPE-B showed conflicting results with CDK4/6 inhibitors, one study indicated that a new tool can guide adjuvant chemotherapy, and another study suggested that circulating tumor cells (CTCs) can predict overall survival (OS).

Alan P. Lyss, MD, subprincipal investigator for Heartland Cancer Research NCORP, joined host David H. Henry, MD, to discuss these and other studies — their top 10 presentations from SABCS 2020 — in this episode.

1. Abstract GS3-07. Identifying patients whose symptoms are under-recognized during breast radiotherapy: Comparison of patient and physician reports of toxicity in a multicenter cohort. https://bit.ly/2MGCVEH

• This presentation could be one of the most important stories to emerge from SABCS 2020, according to Dr. Lyss.
• The trial included 9,868 breast cancer patients who received radiotherapy over an 8-year period.
• Investigators compared patient and physician reports of toxicity during radiotherapy, assessing four symptoms: pain, pruritus, edema, and fatigue.
• Physicians under-recognized moderate to severe pain 30.9% of the time, pruritus 36.7% of the time, edema 51.4% of the time, and fatigue 18.8% of the time.
• “The bottom line is: We’ve got to do better at this, and the first step in correcting it is to acknowledge that there is a problem. This abstract established that,” Dr. Lyss said.

2. Abstract GS2-03. Prime 2 randomised trial (postoperative radiotherapy in minimum-risk elderly): Wide local excision and adjuvant hormonal therapy +/- whole breast irradiation in women =/> 65 years with early invasive breast cancer: 10-year results. https://bit.ly/3omINAL

• The trial enrolled 1,326 women with histologically confirmed, unilateral invasive, hormone receptor-positive (HR+) breast cancer who were all 65 or older, had a tumor measuring 3 cm or less, had no nodal involvement, and were about to undergo breast-conserving surgery.
• The women were randomized 1:1 to receive adjuvant whole-breast irradiation or no radiotherapy in addition to adjuvant endocrine therapy.
• At 10 years, the rate of ipsilateral recurrence was significantly lower with radiotherapy than without it (0.9% vs 9.8%, P = .00008). The 10-year rate of regional recurrence was significantly lower with radiotherapy as well (0.5% vs. 2.3%, P = .014).
• There was no significant difference in the radiotherapy and no-radiotherapy arms when it came to distant recurrence (3.6% vs. 1.9%, P = .07), contralateral recurrence (2.2% vs. 1.2%, P = .20), non–breast cancer (8.7% vs. 10.2%, P = .41), metastasis-free survival (96.4% vs. 98.1%, P = .28), or OS (81.0% vs. 80.4%, P = .68).
• These results suggest radiotherapy could be omitted in this patient population, but the decision should be discussed and tailored to the individual patient, according to Dr. Henry.

3. Abstract GS1-01. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high-risk early breast cancer. https://bit.ly/38oSHwt

• The monarchE trial enrolled 5,637 women with HR+, HER2- early breast cancer.
  • Cohort 1 included patients with four or more positive nodes, up to three positive nodes and a tumor size ≥ 5 cm, or grade 3 disease.
  • Cohort 2 included women with up to three positive nodes and a Ki-67 index ≥ 20%.
• Patients in both cohorts were randomized to standard endocrine therapy alone or standard endocrine therapy with abemaciclib.
• The 2-year rate of invasive disease-free survival (IDFS) was 92.3% in the abemaciclib arm and 89.3% in the control arm (P = .0009). The 2-year distant relapse-free survival rate was 93.8% and 90.8%, respectively (P = .0009).
• Dr. Lyss said this is the first real advance in HR+ breast cancer adjuvant treatment in many years and has the potential to save thousands of lives. However, these are early data and should be interpreted with caution.

4. Abstract GS1-02. Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancer and with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B. https://bit.ly/2XeQvRs

• The PENELOPE-B trial enrolled 1,250 women who had completed neoadjuvant chemotherapy and locoregional therapy.
• They were randomized to palbociclib plus endocrine therapy or endocrine therapy plus placebo.
• There was no significant difference in IDFS with palbociclib or placebo at 2 years (88.3% vs. 84%), 3 years (81.2% vs. 77.7%), or 4 years (73% vs. 72.4%).

5. Abstract GS4-10. Development and validation of a tool integrating the 21-gene recurrence score and clinicopathologic features to individualize prognosis for distant recurrence and prediction of absolute chemotherapy benefit in early breast cancer. https://bit.ly/38htoMD

• The RSClin tool integrates the 21-gene recurrence score and clinicopathologic features, including the grade of the tumor, the tumor size, and the patient's age.
• Researchers found that RSClin could guide adjuvant chemotherapy in HR+, HER2-, axillary node-negative breast cancer with greater precision, when compared with  clinicopathologic features or genomic data alone.
• RSClin is available at https://online.genomichealth.com/.

6. Abstract GS4-08. Clinical utility of repeated circulating tumor cell (CTC) enumeration as early treatment monitoring tool in metastatic breast cancer (MBC) - a global pooled analysis with individual patient data. https://bit.ly/2MGUrZp

• This study included 4,079 metastatic breast cancer patients who had undergone baseline and follow-up CTC measurements in previous trials.
• The investigators analyzed changes in CTC levels between baseline and follow-up to determine whether those levels were associated with OS.
• The median OS was 47 months for patients who were CTC-negative at both baseline and follow-up, 32.2 months for patients who were positive at baseline and negative at follow-up, 29.6 months for patients who were negative at baseline and positive at follow-up, and 17.8 months for patients who were positive at both time points.
• With the negative-negative group as the reference, hazard ratios were 1.52 for the positive-negative group, 1.74 for the negative-positive group, and 3.15 for the positive-positive group (P < .0001 for all).

7. Abstract GS3-00. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder). https://bit.ly/35bK7Px

• RxPONDER included 5,083 adults with HR+, HER2- breast cancer, one to three positive nodes, no contraindications to taxane and/or anthracycline-based chemotherapy, and recurrence scores of 25 or below.
• Patients were randomized 1:1 to receive endocrine therapy or chemo-endocrine therapy using three stratification factors: recurrence score (0-13 vs.14-25), menopausal status, and axillary nodal dissection vs. sentinel node biopsy.
• At a median follow-up of 5.1 years, there was no association between chemotherapy benefit and recurrence score values in the whole study population.
• In postmenopausal patients, there was no difference in 5-year IDFS between patients who received chemotherapy and those who didn’t (91.6% vs. 91.9%, P = .82).
• However, in premenopausal patients, the 5-year IDFS rate was 94.2% with chemotherapy and 89% without it (P = .0004).
• The data also showed an OS benefit with chemotherapy in premenopausal patients (P = .032), although this result is considered early due to few deaths at the time of evaluation.
• “These data really establish that postmenopausal women with between one to three involved nodes and an Oncotype DX score of 25 or less do not need post-operative adjuvant chemotherapy; end of discussion,” Dr. Lyss said. “For physicians who have been giving those women chemotherapy, these data are immediately practice- changing.”

8. Abstract GS4-04. Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), Recurrence Score <26 and Ki67 response after preoperative endocrine therapy: Primary outcome results from the WSG-ADAPT HR+/HER2- trial. https://bit.ly/35edjVY

• In this phase 3 trial, researchers combined static biomarkers (recurrence score in baseline core biopsy) and dynamic biomarkers (Ki-67 response) in an attempt to optimize adjuvant therapy in luminal early breast cancer.
• The trial included 4,691 patients with HR+, HER2-negative, clinically high-risk disease who received about a month of standard endocrine therapy as neoadjuvant treatment.
• Patients with a pretreatment recurrence score of 0-11 continued endocrine therapy alone with no planned chemotherapy at all.
• Patients with a pretreatment recurrence score of 12-25 received their month of endocrine therapy and then had a core biopsy of their residual tumor. If the Ki-67 had dropped to less than 10%, the patient continued endocrine therapy alone. If the Ki-67 remained > 10% or the patient had clinical N2 or N3 lymph nodes, the patient was assigned to receive neoadjuvant chemotherapy.
• The 5-year IDFS rate was 92.6% in patients with a recurrence score of 12-25 and a Ki-67 response and 93.9% in patients with a recurrence score of 0-11.
• The 5-year distant relapse-free survival was 95.6% and 96.3%, respectively. The 5-year OS was 97.3% and 98%, respectively.
• These results suggest Oncotype DX testing could spare the majority of HR+, HER2- patients with zero to three positive lymph nodes from receiving chemotherapy, Dr. Lyss said.

9. Abstract GS3-01. Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. https://bit.ly/394UCVX

• In KEYNOTE-355, 847 patients with locally recurrent, inoperable or metastatic triple-negative breast cancer were randomized to receive pembrolizumab plus chemotherapy or chemotherapy plus placebo. Chemotherapy consisted of nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin.
• The median progression-free survival (PFS) was longer in the pembrolizumab arm, at 7.5 months, versus 5.6 months with chemotherapy alone (hazard ratio, 0.82).
• The PFS was superior with pembrolizumab regardless of the chemotherapy partner.
• However, higher PD-L1 expression was associated with a longer PFS, a higher overall response rate, and a longer duration of response.

10. Abstract GS3-06. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. https://bit.ly/3hQ14nJ

• Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in triple-negative breast cancer.
• Sacituzumab govitecan (SG) consists of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan.
• In the ASCENT trial, patients with metastatic triple-negative breast cancer were randomized to SG or standard single-agent chemotherapy.
• A subgroup analysis of this trial showed that Trop-2 levels correlated with PFS and OS.
• Patients were divided into three groups by Trop-2 levels — low (H-score <100), medium (100-200), and high (200-300).
• In patients with low Trop-2 levels, the median PFS was 2.7 months with SG and 1.6 months without it. The median OS was 9.3 months and 7.6 months, respectively.
• In patients with medium Trop-2 levels, the median PFS was 5.6 months with SG and 2.2 months without it. The median OS was 14.9 months and 6.9 months, respectively.
• In patients with high Trop-2 levels, the median PFS was 6.9 months with SG and 2.5 months without it. The median OS was 14.2 months and 6.9 months, respectively.

*Some of the numbers mentioned in this episode are incorrect, but the correct numbers are reflected in the show notes. The data presented at SABCS 2020 sometimes differed from data included in the abstracts.

Disclosures:

Dr. Henry has no financial disclosures relevant to this episode.

Dr. Lyss writes a column for MDedge Hematology/Oncology called “Clinical Insights.” He has no other conflicts of interest.

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David Henry on Twitter: @davidhenrymd

In this episode, we review how immune checkpoint inhibitors and COVID-19 have changed the management of non-small cell lung cancer (NSCLC).

Jeffrey Crawford, MD, and Susan Blackwell, PA, both of Duke Cancer Institute, join host David H. Henry, MD, to discuss the use of pembrolizumab in NSCLC, two studies of PD-1 inhibitors presented at ESMO 2020, and how COVID-19 has affected NSCLC care, particularly the use of granulocyte colony-stimulating factor (G-CSF).

Diagnosis and treatment of NSCLC

What information should be obtained from a biopsy?

• Is this lung cancer?
• If so, what kind of lung cancer is it: Small-cell lung cancer or NSCLC? Which subtype?
• Molecular studies for targets, including ALK, KRAS, EGFR, PD-L1.

Treatment with pembrolizumab:

• If, for example, a patient has NSCLC and is positive for PD-L1, the treatment of choice is pembrolizumab.
• A multidisciplinary approach is essential to provide comprehensive education and care to patients taking pembrolizumab (and other immunotherapies).
• Pembrolizumab can have many side effects, including itching, fatigue, thyroiditis progressing to hypothyroidism, hypophysitis, or another off-target “-itis.”
• Ms. Blackwell and Dr. Crawford recommend listening to patients, checking the thyroid routinely, and checking cortisol based on index of suspicion.

NSCLC studies presented at ESMO 2020

KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%.

• The 5-year survival is greater than 30% with pembrolizumab in this study.
• Historically, 5-year survival has been 1% to 2% in patients treated with chemotherapy alone, Dr. Crawford said.
• In the control arm of this study, patients received chemotherapy and then crossed over into the pembrolizumab arm, so overall survival was 16% at the 5-year mark.
• The results suggest immunotherapy should be used first-line if patients meet criteria, Dr. Crawford said.
• Source: Abstract LBA51. https://bit.ly/3mMYLTK.

EMPOWER-Lung 1: Phase III first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. 

• Cemiplimab improved overall and progression-free survival in NSCLC patients when compared with chemotherapy alone.
• Abstract LBA52. https://bit.ly/3mLT6xb.

The effects of COVID-19 on NSCLC care

Logistically, it’s more difficult to see patients during the pandemic, Dr. Crawford noted, but the many potential side effects of immunotherapy make it necessary to see patients regularly in person.

How has COVID-19 affected the concern of febrile neutropenia and the use of G-CSF? Dr. Crawford said the pandemic has heightened the concern about infection risk.

Prior guidelines for G-CSF:

• Before the pandemic, guidelines suggested routine prophylactic G-CSF in patients with a greater than 20% risk of febrile neutropenia.
• In patients with 10% to 20% risk, the recommendation was to consider the use of G-CSF based on the patient population and risk factors.

Pandemic-specific guidelines for G-CSF:

• The National Comprehensive Cancer Network (NCCN) recommended relaxing guidelines during the pandemic.
• If the risk is greater than 20%, NCCN still recommends giving G-CSF.
• If the risk is 10% to 20%, NCCN recommends giving G-CSF even in the absence of additional risk factors.
• Dr. Crawford noted that lung cancer patients receiving chemotherapy are typically in the 10% to 20% risk category.
• Download the COVID-specific NCCN guidelines: https://bit.ly/3jQIco5.

G-CSF biosimilars

• The most common complaint with biosimilars is bone pain.
• Ms. Blackwell advises first treating bone pain with acetaminophen or ibuprofen and warm blankets.
• For refractory pain, she suggests a low-dose narcotic or dexamethasone.
• Consider an antihistamine for prophylaxis, as patients report this can help with symptoms.

Show notes written by Ronak Mistry, DO, a resident at Pennsylvania Hospital, Philadelphia.

Disclosures:

Dr. Crawford is on advisory boards at Amgen and Merck, makers of Onpro/Neulasta (pegfilgrastim) and Keytruda (pembrolizumab). Ms. Blackwell and Dr. Henry have no conflicts of interest.

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Email the show: podcasts@mdedge.com

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David Henry on Twitter: @davidhenrymd

The combination of pembrolizumab and lenvatinib is a promising second line option for metastatic or recurrent MSS endometrial cancer, although there can be considerable toxicity and choosing appropriate patients is key.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article “Lenvatinib and Pembrolizumab in Patients With Advanced Endometrial Cancer” by Makker et al. My name is Meghan Shea, and I am an Instructor of Medicine at Harvard Medical School at Beth Israel Deaconess Medical Center in Boston, Massachusetts. My oncologic specialty is gynecologic oncology.

Patients with advanced endometrial carcinoma have limited options after receiving the carboplatin and paclitaxel doublet for recurrent or metastatic disease. The study that accompanies this podcast evaluates the combination pembrolizumab and lenvatinib, providing a much needed second-line option for this patient population. The approval of single-agent pembrolizumab for tumors with microsatellite instability (from here on referred to as MSI high) does not have immediate relevance for the majority of patients with advanced endometrial carcinoma who have microsatellite stable disease (from here on referred to as MSS). Makker et al. now report the results of an ongoing phase 1b/2 study of pembrolizumab, an anti-PD1 antibody, and lenvatinib, an oral tyrosine kinase inhibitor that targets the VEGF-receptor, in patients with metastatic endometrial carcinoma. Eligibility criteria included patients with an ECOG 0 to 1 who had confirmed metastatic disease with less than or equal to 2 prior lines of systemic therapy. Notably the majority were not heavily pre-treated; 52.8% of patients in the study had only one prior line of systemic treatment.

Patients received lenvatinib 20 mg once daily orally continuously and pembrolizumab 200 mg intravenously every 3 weeks – with a maximum duration of 2 years for pembrolizumab. All patients had imaging at baseline and then every 6 weeks for first 24 weeks and then every 9 weeks thereafter. The primary end point was objective response rate at 24 weeks. Forty-one of the 108 patients, 38%, had a response at 24 weeks with a median follow up of 18.7 months.  As expected, the MSI high tumors had a higher response rate of 63.6%, although this was a minority of the study population, only 11 patients. Most importantly, the patients with MSS tumors had a response rate of 37.2% with a median duration of response of 21.2 months. The histology did not appear to impact the response rate – the majority of patients had endometrioid (50.9%), although the study population also contained a reasonable proportion of serous and clear cell (38%) compared to the expected frequency in the general population of advanced uterine cancers. The PD-L1 status positive or negative did not correlate with response.

One might question, before accepting a complicated regimen with both oral and IV chemotherapy as a new second-line standard option, whether anyone has studied the activity of either single agent lenvatinib or single agent pembolizumab in a similar population, especially for those with MSS disease. With the caveats of cross study comparisons, it appears that neither single agent is as active as the current combination. For instance, Vergote et al reported results of a phase 2 study of lenvatinib monotherapy for advanced endometrial cancer, where the response rate was only 14.3% with median progression free survival of 5.4 months. Likewise, Ott et al studied single agent pembrolizumab in endometrial cancer with 18 of 19 patients having MSS cancer, resulting in only a 13% response rate and progression free survival of 1.8 months.

             So you may be wondering, what’s the catch? The issue is the potential toxicity of this doublet regimen, with 66.9% or 83 of 108 patients, having a grade 3 or 4 treatment-related adverse event. Overall 17.7% of the patients discontinued one or both drugs. Notably, pembrolizumab was never dose reduced - only dose held or discontinued. Most strikingly, 62.9%, roughly two thirds of patients, required a dose reduction of lenvatinib. Only 11 patients (that is 8.9%) stayed on full dose 20 mg of lenvatinib for greater than 6 months. The average dose for lenvatinib was 14.4 mg daily. The toxicity profile of lenvatinib may be related to the fact that it is a multi-targeted tyrosine kinase inhibitor that targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, platelet-derived growth factor receptor alpha, RET and KIT.

There were 51 deaths during this study; the majority occurred during follow up due to progression of disease. However, there were 16 deaths while on study, 4 considered treatment emergent adverse events and 2 judged to be treatment related.  The four deemed treatment emergent were due to gastrointestinal perforation, intestinal obstruction, general health deterioration and metabolic encephalopathy. The two deemed treatment related were from septic shock and intracranial hemorrhage.

The National Comprehensive Cancer Network (NCCN) guidelines have added the combination of pembrolizumab and lenvatinib to their list of second line therapeutic options, and it also has been approved by the Food and Drug Administration (FDA). This recognizes the fact that this combination has the highest response rate of the available drugs listed, and thus should be a strong consideration for second line therapy for patients with MSS endometrial carcinoma. However, ensuring that this treatment is appropriate for a given patient is of the utmost importance.  First the patient must be a candidate for immunotherapy – ideally not on chronic prednisone and/or have an active autoimmune disease. In contrast to prescribing single agent anti-PD-1 or anti-PD-L1, a performance status of 0 to 1 is important with this combination. The most appropriate patient should have controlled blood pressure prior to initiating drug, be able to monitor their blood pressures, take their oral chemotherapy as prescribed, and readily report any new symptoms. I avoid prescribing this drug combination if the patient has a bleeding disorder, recent clotting, uncontrolled hypertension, or is at high risk of a fistula or bowel obstruction. Lenvatinib is a renally-cleared drug, and thus patients with a reduced glomerular filtration rate (GFR) require renal dosing. This is especially relevant for patients with recurrent uterine cancer, whose kidney function is dynamic, especially in the setting of hydronephrosis. In my practice, I consider starting patients with normal renal function at 14 mg lenvatinib daily, given that the vast majority of patients on study were eventually dose-reduced. Furthermore, I might start the lenvatinib dosing even lower for patients with dynamic renal function and for those who have a baseline GFR lower than 30.

Overall this study provides a promising second line option for metastatic or recurrent MSS endometrial cancer, with responders having a durable response.  Patient selection and dose adjustments are key considerations to avoiding and managing toxicity.

This concludes this JCO Podcast. Thank you for listening.

This podcast reviews the results of KEYNOTE 164 investigating the use of pembrolizumab for mismatch repair deficient metastatic colorectal cancer, the place of this agent in the current clinical paradigm, and future directions to identify which patients are most likely to benefit from this treatment strategy.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article 'A Phase II, Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164' by Le et al. My name is Dustin Deming, and I am an associate professor at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin. My oncologic specialty is gastrointestinal oncology.

Microsatellite instability high status or mismatch repair deficiency is found in approximately 15% of early stage colorectal cancers, but only 3-4% of metastatic colorectal cancer. The mechanisms by which these cancers acquire their DNA repair aberrations can vary, including germline mutations, somatic mutations and promoter methylation, which is often observed in the setting of the hypermethylation phenotype associated with BRAF mutations. This distinct colorectal cancer subtype is of particular interest for immunotherapy strategies as the lack of adequate mismatch repair can lead to 1000s of mutations and also fusions leading to the potential for expression of more neoantigens.

This world-wide phase 2, open-label study enrolled 124 patients with microsatellite instability high or metastatic mismatch repair deficient colorectal cancer following 2 or more lines of standard therapy in cohort A and following 1 or more lines of therapy in cohort B. Patients received pembrolizumab 200 mg every 3 weeks, up to 2 years, until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review and secondary endpoints included duration of response progression-free survival, overall survival, safety and tolerability.

At the time of this report the median follow-up for cohort A was 31.3 months and 24.2 months for cohort B. The objective response rate was 33% for both cohorts. This includes 7 patients who achieved a complete response. The median PFS was 2.3 months for cohort A and 4.1 months for cohort B. For those patients that developed an objective response the duration of response was quite prolonged with the median duration of response not reached in either cohort. The median overall survival was 31.4 months for cohort A and not reached in cohort B. This treatment was well-tolerated in this population with the most common toxicities being fatigue, pancreatitis, and increased alanine aminotransferase or lipase.

Overall pembrolizumab is an exciting addition to the treatment strategy for patients with metastatic mismatch repair deficient cancers. Based on these results, in part, this agent is now FDA approved for patients with previously treated microsatellite instability high or mismatch repair deficient metastatic colon cancers after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients also for non-colorectal solid tumors following at least one prior therapy, regardless of tumor type or origin. This was the first FDA approval of a tumor histology agnostic anticancer therapy.

Long-term follow-up from this, and similar cohorts, is required to further define the duration of response for these patients, as there is hope that some of these patients could even be cured. Unfortunately, it is only a minority of patients that seem to benefit from this approach as demonstrated by the short median progression free survival in both cohorts. A better understanding of which patients are likely to benefit from immunotherapy approaches are clearly needed. 

The presence of Lynch syndrome was not captured in this study to evaluate for differential response in this setting. The BRAF mutation status was collected and across both cohorts 14 patients had BRAF mutant cancers. The response rate for these patients was 43%. A similar benefit was also observed in KRAS or NRAS mutant and wild-type cancers. This study was limited in its ability to further assess those factors that could influence pembrolizumab response given the relatively small sample size and limited biospecimen collection.

Further clinical trials are investigating the use of anti-PD1 therapies for these patients in the first-line and adjuvant settings, in combination with chemotherapy and with other immune checkpoint agents, such as CTLA4 and LAG3, among others. This includes Checkmate 142, which is a phase II study that is examining nivolumab and ipilimumab in a cohort of 46 patients with microsatellite instability high or mismatch repair deficient colorectal cancer in the first-line setting. Preliminary results were presented at the 2018 European Society of Medical Oncology meeting demonstrating a 60% objective response rate and a 12 month progression free survival of 77%. These early results are promising, but further investigation is needed.

As we look forward to which factors could be leading to a lack of clinical benefit from these agents it is important to consider those factors that are intrinsic to the cancer cells, tumor microenvironment, and patient specific factors. Tumor cell intrinsic factors include important cell attributes for the immune response such as the tumor mutation burden, MHC class I expression, including beta-2-microglobulin expression, the mutation profile, including alterations in WNT signaling shown to be important for immunotherapy resistance in metastatic melanoma, and tumor heterogeneity. There is also a growing understanding of factors that are important within the tumor microenvironment for tumors to be permissive to immune cell infiltration. These factors include differences in the immune and fibroblast cell subtypes present and also the presence of certain matrix proteins. This includes a matrix proteoglycan called versican that my laboratory and others have demonstrated has immunosuppressive properties, but can be cleaved by ADAMTS proteases to an immunostimulatory fragment. Additionally, patient specific factors need to be considered such as the microbiome, immunosuppression and adverse event management.

In summary, the results of KEYNOTE 164 are a significant advance for patients with microsatellite instability-high and mismatch repair deficient cancers. Long-term follow-up from this study and further studies into the most efficacious clinical setting to use these agents will continue to advance the clinical use of immunotherapy options for these patients.

This concludes this JCO Podcast. Thank you for listening.

Deze week worden de Nobelprijzen uitgereikt. De eerste, de Nobelprijs voor de Geneeskunde, ging naar James Allison en Tasuku Honjo voor hun onderzoek naar immuuntherapie. Medisch redacteur Sander Voormolen schuift aan en vertelt over deze vierde pijler in kankerbestrijding (naast operaties, bestraling en chemotherapie).

De winnaars van de Nobelprijzen voor Natuurkunde en Chemie worden respectievelijk dinsdag en woensdag bekend gemaakt. Ook die zullen de Onbehaarde Apen in een bonusaflevering bespreken. Abonneer je om niets te missen!

Benieuwd naar waarom het winnende onderzoek zo bijzonder is of heb je een andere vraag? Mail ons op podcast@nrc.nl.

Presentatie: Lucas Brouwers en Gemma Venhuizen

Productie: Mirjam van Zuidam

@lucasbrouwers // @hendrikspiering // @SanderVoormolen

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