OBR Daily Commentary

forumImage

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.

Read Article arrow

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

Reply

Add Comment 1 Comment(s)

Meet the Editorial Board

Community Oncology
member photo
Dean Gesme, MD

FACP FACPE FASCO President, Minnesota Oncology...

Breast Cancer
member photo
Debu Tripathy, MD

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

Lung Cancer
member photo
H. Jack West, MD

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

Gastrointestinal Cancers
member photo
Howard S. Hochster, MD

Distinguished Professor of Medicine, Rutgers Robert Woo...

Radiation Oncology
member photo
Howard Sandler, MD, MS, FASTRO

Ronald H. Bloom Chair in Cancer Therapeutics
Pr...

Community Oncology
member photo
Jeff Patton, M.D.

CEO Tennessee Oncology...

Precision Medicine Section Editor
member photo
Jennifer Levin Carter, MD, MPH

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

Financial Sector
member photo
Michael G. King Jr.

Managing Director and Senior Biotechnology Analyst...

Gastrointestinal Cancers
member photo
Richard Goldberg, MD

Director WVU Cancer Institute Director of Cancer Signa...

Editor-In-Chief
member photo
Robert A. Figlin, MD., FACP

Professor and Director, Division of Hematology Oncology...

Health Policy
member photo
Ted Okon

Executive Director Community Oncology Alliance...

Community Oncology
member photo
Thomas Marsland, MD

Vice President Integrated Community Oncology Network ...

Community Oncology
member photo
William Harwin MD

Florida Cancer Specialists President and Managing Part...

Health Policy
member photo
William McGivney, PhD

National Health Policy Expert...

Payer
member photo
Winston Wong, PharmD

President, W-Squared Group...