Expert Point of View: Michael J. Overman, MD

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Michael J. Overman, MD

Michael J. Overman, MD

INVITED STUDY discussant Michael J. Overman, MD, Professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, is a co-investigator on CheckMate 142, which led to the approval of another immunotherapy doublet—nivolumab plus ipilimumab—in patients with microsatellite instability–high (MSI-H)/DNA mismatch repair–deficient tumors. In CheckMate 142, this combination produced a 55% response rate, a 1-year progression-free survival rate of 71%, and a 1-year overall survival rate of 85%.1

Studies in microsatellite-stable tumors, on the other hand, have been negative, including IMblaze370 (atezolizumab plus cobimetinib),2 MODUL (atezolizumab plus bevacizumab),3 and KEYNOTE-028 (pembrolizumab).4 “Even if you select for programmed cell death ligand 1 (PD-L1) positivity and treat with anti–programmed cell death protein 1 (anti–PD-1), as was done in KEYNOTE-028, we’ve seen no responses. Selection of patients for treatment with a single agent has not been successful in this population,” he noted.

Microsatellite-Instable vs Microsatellite-Stable Cancers

“NOW WE are looking at anti–PD-1 plus anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4),” he said, noting that these two approaches accomplish different tasks in modulating the immune environment. “The potential difference [between the drugs] is that anti–CTLA-4 agents can generate and activate new T cells, thus broadening the T-cell repertoire, and this is possibly of importance in microsatellite-stable colorectal cancer,” he said. “We have had success with this combination in a nonrandomized fashion, vs monotherapy, but that’s been in MSI-H colorectal cancer, which is a very different disease entity than microsatellite-stable cancer.”

In patients with microsatellite-stable cancer, “very small data sets” have found “limited signs of activity” by combining nivolumab and ipilimumab, he said, “but now we have a much larger data set for anti– PD-1/anti–CTLA-4 targeting.”

Study Praise and Limitations

DR. OVERMAN applauded the investigators for using a novel approach, circulating tumor DNA, to test for microsatellite stability status. “As clinical investigators and members of the gastrointestinal cancer community, we have to obtain this (MSI status) in all our trials. We cannot interpret low-level activity without this information,” he said.

“CCTG CO.26 is a positive trial statistically, but there are caveats,” he said. He cited the lack of placebo control and blinding; the “small amount” of protocol-required additional follow-up in the active treatment arm compared to the best supportive care arm (which may or may not have made a difference); the alpha of 0.1 (which allowed for a 10% potential risk of false-positive results); and the lack of information about subsequent treatments (acknowledging that further treatment would be atypical for a population in which best supportive care is the standard).

Discordance was also shown between the overall survival benefit and the lack of improvement in progression-free survival, although other trials of immunotherapy have also shown discordant outcomes, he indicated. “To be confident” about the results in light of such discordance, added Dr. Overman, studies should not only be randomized, but also blinded and placebo-controlled.

Key Question: Who Will Gain Substantial Benefit?

“ALTHOUGH THIS study has a small hint of activity, going forward the key question is what group of patients is potentially gaining a more substantial benefit,” he added. Efforts are underway in the field to substratify microsatellite-stable colorectal cancers (based on differences in gene expression and so forth). “The current study has a robust correlative plan, with mandatory blood and tissue sampling, and I’m looking forward to the results regarding subsets that are benefiting,” he said.

Meanwhile, Dr. Overman concluded, “Before we incorporate these data into clinical practice, we clearly need confirmation.”

DISCLOSURE: Dr. Overman is a consultant/advisor for Bristol-Myers Squibb, Gritstone Oncology, MedImmune, and Roche-Genentech; and has received research funding from Bristol-Myers Squibb, Merck, MedImmune, and Roche.


1. André T, Lonardi S, Wong M, et al: Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer: First report of the full cohort from CheckMate-142. 2018 Gastrointestinal Cancers Symposium. Abstract 553. Presented January 20, 2018.

2. Bendell J, Ciardiello F, Tabernero J, et al: Efficacy and safety results from IMblaze370, a randomised phase III study comparing atezolizumab + cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol 29(suppl 5), 2018.

3. Grothey A, Tabernero J, Arnold D, et al: Fluoropyrimidine and bevacizumab plus or minus atezolizumab as first-line treatment for BRAF wild type metastatic colorectal cancer: Findings from the MODUL trial of biomarker-driven maintenance. ESMO 2018 Congress. Abstract LBA19. Presented October 22, 2018.

4. O’Neil B: Pembrolizumab (MK-3475) for patients with advanced colorectal carcinoma: Preliminary results from KEYNOTE-028. ESMO 2015 Congress. Abstract 502. Presented September 27, 2015.

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