OBR Daily Commentary

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Merck KGaA, Pfizer's Immunotherapy Fails In Lung Cancer Trial

(Reuters) Feb 15, 2018 - Merck KGaA and Pfizer’s cancer drug Bavencio could not be shown to improve survival in lung cancer patients that had previously undergone unsuccessful chemotherapy, Merck said.

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H. Jack West, MD (Posted: February 15, 2018)

quotesOn its face, the report that a trial of avelumab vs. docetaxel in chemotherapy-pretreated NSCLC seems surprising unless it's a clearly inferior checkpoint inhibitor to the ones that have already demonstrated positive results and similar efficacy in very similar trials -- namely nivolumab, pembrolizumab, and atezolizumab. We have presumed that these agents are all far more similar than different. The JAVELIN Lung 200 trial did note that the cross-over of such a higher proportion of patients to subsequent immunotherapy in this trial (26.4% on docetaxel arm, vs. 5.7% on avelumab arm) vs. other ones that have been positive is likely to be a relevant factor that compromised the ability to detect an improvement in OS in the broad study population. Frankly, I think it's disappointing that only just over 25% of patients received access to clearly very effective immunotherapy that has been a standard of care now for a few years. In my clinic, nearly 100% of patients who were ever eligible for a checkpoint inhibitor receive it over the course of their illness. The only question is whether it is delivered first line, second line, or later. And while this trial was conducted in a different time and place, the evidence should lead us to conclude that only 26% of patients receiving immunotherapy is gross under-treatment. It is also notable that the effects were reportedly greater in those patients with high level PD-L1 expression, as we've generally seen, with a positive survival benefit in that subset. We will need to see the actual data in an upcoming meeting, but I believe that it is premature to conclude that avelumab is a less effective therapy than the similar checkpoint inhibitors that have been approved in this setting already. I think the results may be most instructive in demonstrating that the timing of immunotherapy is not critical for many/most patients to achieve the same overall survival. In the contemporary practice of treating lung cancer, we should expect and aspire to have nearly all eligible patients receive one of these agents at some point over the course of their disease. quotes

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Pivotal Phase 3 CheckMate -227 Study Demonstrates Superior Progression-Free Survival (PFS) with the Opdivo Plus Yervoy Combination Versus Chemotherapy in First-Line Non-Small Cell Lung Cancer (NSCLC) Patients with High Tumor Mutation Burden (TMB)

(BMS) Feb 5, 2018 - Bristol-Myers Squibb Company today announced that the ongoing Phase 3 CheckMate -227 study met its co-primary endpoint of progression-free survival (PFS) with the Opdivo (nivolumab) plus Yervoy (ipilimumab) combination versus chemotherapy in first-line advanced non-small cell lung cancer (NSCLC) patients whose tumors have high (≥10 mutations/megabase, mut/mb) tumor mutation burden (TMB), regardless of PD-L1 expression.

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H. Jack West, MD (Posted: February 05, 2018)

quotesWe’ve eagerly anticipated results from the CheckMate-227 trial, an open-label phase 3 trial of over 2500 patients with advanced NSCLC, either squamous or non-squamous histology, randomized to nivolumab monotherapy or in combination with ipilimumab versus platinum doublet chemotherapy in a comparison of patients with tumors expressing PD-L1 (any level, by the 28-8 pharmDx assay) on part 1a or with tumors expressing no PD-L1 on part 1b. The press release today reflects results for both groups on part 1, noting that there was a significant improvement in progression-free survival (PFS) with nivolumab/ipilimumab (nivo/ipi) compared to platinum doublet chemotherapy in the subset of patients with high tumor mutation burden (TMB) defined as >10 mutations/megabase (mut/MB) on the FoundationOne CDx assay (a liberal threshold capturing approximately 40-45% of patients), though FoundationOne defines high TMB as >20 mut/MB (representing only approximately 13% of patients) (hat tip to Andre Sawyer, Analyst for Equity Research, for noting this point that is easy to overlook). This positive result in patients with high TMB was independent of PD-L1 level. These results are provocative, though we clearly need to see the actual data to get a better sense of the clinical implications. In the meantime, however, we can draw some preliminary conclusions. First, this result adds momentum to the mounting evidence supporting TMB as a relevant biomarker. It is necessary to add the caveat that this was not a prospectively identified endpoint, as well as the fact that this particular threshold of defining high TMB differently than is done by Foundation Medicine undermines some of the convergence toward clinical utility of TMB if there is no semblance of any consensus. Moreover, we should hope and expect to see subset analyses that define whether the results are far stronger in the much smaller subset with the 20 mut/MB cutoff, with the results in the broader population defined by a 10 mut/MB cutoff diluting the effect but expanding the population to be considered good candidates for nivo/ipi. We should ensure that the lower threshold truly defines the group most likely to benefit from nivolumab/ipilimumab and isn’t being promulgated as a reverse engineered result to maximize eligibility while still defining a population in which the positive result for PFS is maintained. Second, I consider a positive effect for PFS to be encouraging but insufficient to change practice unless the absolute difference is absolutely remarkable, particularly in the non-squamous patient population. Despite the FDA approval of the carboplatin/pemetrexed/pembrolizumab combination in May, 2017 based on the phase II KEYNOTE-021g trial, I and many other thoracic oncology specialists, as well as general oncologists, have remained unconvinced that the improvement in response rate and PFS with the addition of pembrolizumab to first line chemotherapy should change practice when a sequential approach may well confer the same overall survival (OS). The widening gap between the OS curves with longer follow-up on KEYNOTE-021g has warmed me to this approach as an increasingly compelling option, as has the recently reported positive results for a PFS and OS benefit with addition of pembrolizumab to cisplatin or carboplatin with pemetrexed in the phase III KEYNOTE-189 trial (actual data still awaited). With a regimen that oncologists are comfortable using and that is FDA approved, carboplatin/pemetrexed/pembrolizumab will be the true comparator as we consider nivo/ipi as a challenger. In contrast, we don’t yet have a first line immunotherapy-based treatment approach for patients with squamous NSCLC who don’t have a tumor with high PD-L1 expression (for which pembrolizumab monotherapy is a clear standard of care and strong option). I think for patients with high PD-L1, pembrolizumab will remain a leading option, and nivo/ipi may emerge as a favorable option compared to doublet chemotherapy for patients with high TMB and low or negative PD-L1. We will need to see the magnitude of benefit and tolerability of nivo/ipi when the actual data are available. In addition, we should expect to see several trials of chemotherapy combined with checkpoint inhibitors in patients with squamous NSCLC that may well be positive for PFS and/or OS in the next 6-12 months. These options will need to be considered alongside nivo/ipi. Though the dose and schedule of nivo/ipi may well be tolerable for a broad population, it will be critical to see the toxicity profile and compare it not only to a platinum-based doublet but to that expected for other alternatives. I remain concerned that nivo/ipi may be challenging for less selected, potentially older and sicker patients, being treated by oncologists with less support and experience than the trial investigators who have been the main ones gaining experience with this combination up to this point. Overall, I think this is encouraging for adding further credibility to TMB measurement and potentially nivo/ipi for a selected subset of patients with advanced NSCLC, but I feel these results should definitely not lead us to adopt either TMB or nivo/ipi in clinical practice without far more information. quotes

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Merck's KEYTRUDA(R) (pembrolizumab) Significantly Improved Overall Survival and Progression-Free Survival as First-Line Treatment in Combination with Pemetrexed and Platinum Chemotherapy for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (KEYNOTE-189)

(Merck) Jan 16, 2018 - Merck, known as MSD outside the United States and Canada, today announced that the pivotal Phase 3 KEYNOTE-189 trial investigating KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with pemetrexed (Alimta®) and cisplatin or carboplatin, for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS).

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H. Jack West, MD (Posted: January 16, 2018)

quotesThis is a very important result, in keeping with the results of the phase II KEYNOTE-021g trial that led to the FDA approval of the carbo/pemetrexed/pembrolizumab combination that many experts feel was premature, being based on just 123 patients and with only preliminary OS results at the time of the approval. The report of statistically significant positive results for both PFS and OS with initial cisplatin or carboplatin with pemetrexed and concurrent pembrolizumab over the same chemo alone corroborates the KN-021g trial on a larger scale that we really needed to see. I expect that several other trials that present results this year of various chemo backbones +/- various PD-1/PD-L1 checkpoint inhibitors will also demonstrate a significant benefit at least with PFS and likely many with an OS benefit as well. For patients with non-squamous NSCLC, however, a platinum/pemetrexed combination (overwhelmingly more often carbo than cisplatin in the US) is the preferred chemo combination. Based on this and the existing FDA approval of the KEYNOTE-021g regimen, I believe carbo/pemetrexed with pembrolizumab will be the clear pace-setter for this population. Any competing regimen would need to not just be comparable but would need to be significantly superior to this one in order to provide a real incentive to change from carbo/pemetrexed/pembrolizumab at this point. That said, there are several important questions that will modulate the level of enthusiasm for this regimen over a sequential approach. Today, the standard of care for the ~30% of patients with high PD-L1 expression (based on 22c3 antibody as companion diagnostic for pembro) is pembrolizumab monotherapy, based on the compelling benefits seen on the KEYNOTE-024 trial, rather than chemo alone. It will be critical to assess whether the results of KEYNOTE-189 are still compelling once that subgroup is removed, because the most relevant question for 2018 is whether patients with low or no PD-L1 expression should receive concurrent chemo/immunotherapy or sequential chemo followed by immunotherapy. Accordingly, the other critical question is whether patients on KEYNOTE-189 who were assigned to initial chemo have a very high crossover rate to subsequent immunotherapy, as they should when 3 checkpoint inhibitors are FDA approved and have a very clear survival benefit in that setting. Though some are complacent and argue that a 60-75% crossover rate to subsequent immunotherapy is sufficient and represents real world challenges, I would contend that those patients who do not receive a checkpoint inhibitor in second line or later have been denied a therapy with proven benefit and have been under-treated by the health care system. More than 95% of my patients who are eligible for a checkpoint inhibitor receive it at some point in their treatment course -- it is absolutely possible. For KEYNOTE-189 to be truly interpretable, we need to see that first line concurrent chemo-immunotherapy is superior to sequential treatment where nearly all patients benefit from both treatment approaches. A lower crossover rate will only demonstrate that 100% of patients receiving immunotherapy is better than only 2/3 of patients receiving it at some point. Nevertheless, the same could be said for the PARAMOUNT trial's testing of maintenance pemetrexed, which really only demonstrated that the benefit of pemetrexed doesn't max out at 4 cycles, not that it's critical to give maintenance pemetrexed indefinitely. It's a very similar issue here, but we see that our practice patterns in advanced NSCLC have incorporated maintenance pemetrexed as a default because oncologists we will give the heavily marketed message the benefit of the doubt rather than challenge it too critically. I strongly suspect that the evolution of the immunotherapy space in NSCLC will show a similar story and that carbo/pemetrexed/pembrolizumab will be adopted broadly regardless of any lingering questions of whether it is necessarily the best treatment approach for most patients.quotes

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Meet the Editorial Board

Community Oncology
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Dean Gesme, MD

FACP FACPE FASCO President, Minnesota Oncology...

Breast Cancer
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Debu Tripathy, MD

Professor and Chair, Department of Breast Medical Oncol...

Lung Cancer
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H. Jack West, MD

Medical Director, Thoracic Oncology Program, Swedish Ca...

Gastrointestinal Cancers
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Howard S. Hochster, MD

Distinguished Professor of Medicine, Rutgers Robert Woo...

Radiation Oncology
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Howard Sandler, MD, MS, FASTRO

Ronald H. Bloom Chair in Cancer Therapeutics
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CEO Tennessee Oncology...

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Chief Medical Officer and Founder, N-of-One...

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Michael G. King Jr.

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Richard Goldberg, MD

Director WVU Cancer Institute Director of Cancer Signa...

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Robert A. Figlin, MD., FACP

Professor and Director, Division of Hematology Oncology...

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Ted Okon

Executive Director Community Oncology Alliance...

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Thomas Marsland, MD

Vice President Integrated Community Oncology Network ...

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William Harwin MD

Florida Cancer Specialists President and Managing Part...

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William McGivney, PhD

National Health Policy Expert...

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President, W-Squared Group...