Sharing his perspective on KEYNOTE-177 with The ASCO Post was Axel Grothey, MD, Director of GI Cancer Research at the West Cancer Center, OneOncology, Memphis. “This is a very important, highly anticipated study,” he said.
Axel Grothey, MD
“It’s the first randomized trial of any checkpoint inhibitor in [microsatellite instability-high (MSI-H)] colorectal cancer, a subtype where we know immunotherapy works, from later-line studies. Regulatory bodies have wanted to see a randomized trial comparing immunotherapy to standard-of-care treatment before approving these agents in the first-line setting,” he noted.
The findings are not unexpected, based on previous studies in later treatment lines, and they are indeed “very positive,” showing a “dramatic” 40% reduction in the risk of disease progression and good separation of the Kaplan-Meier curves, he commented. “This is clinically meaningful—no question about that.”
Dr. Grothey did, however, have some questions about the study and its findings. For one, he found the use of the co-primary endpoints unusual in light of the potential for crossover. In fact, 59% of patients in the control arm did ultimately receive pembrolizumab, which could mean the overall survival endpoint will be hard to attain, he pointed out.
“It’s not ‘now or never’ access to the drug. It’s ‘now or later’ access because it also works in later lines of treatment…. We have to base our appreciation of these data on the progression-free survival, and I hope the regulatory agencies acknowledge this,” he said.
Further Considerations
Dr. Grothey also commented on the breakdown of best response, noting that this was progressive disease for 29.4% of the pembrolizumab arm, compared with only 12.3% of the chemotherapy arm. “There were two-and-a-half times more patients with progression of disease. I don’t think it’s pseudoprogression. I think it’s patients just not responding,” he said.
In line with this, for the first 6 months of the treatment period, the chemotherapy arm was favored, with the curves diverging in favor of pembrolizumab thereafter. “We can’t ignore that. There is a patient population with MSI-H tumors who just don’t benefit…. You can say you don’t care about this initial drop or progressive disease in more than twice as many patients, but I believe we owe it to our patients to figure out why this is so,” he remarked.
For these 30% of patients, pairing a PD-1 inhibitor with chemotherapy, as is done in lung cancer, could be the answer, he proposed. Atezolizumab plus chemotherapy is currently being evaluated in a U.S. cooperative group study whose results “will be even more interesting now” because of the KEYNOTE-177 findings, he added.
Finally, Dr. Grothey hopes that translational analyses from all these studies will indicate which patients—those with high PD‑L1 expression or high tumor mutational burden, perhaps—will benefit most from immunotherapy.
DISCLOSURE: Dr. Grothey has received honoraria from Aptitude Health, Elsevier, and Imedex; has served as a consultant/advisor for Genentech/Roche; has served in an institutional consulting or advisory role for Amgen, Array BioPharma, Bayer, Bristol-Myers Squibb, Boston Biomedical, Daiichi Sankyo, and Lilly; has received institutional research funding from Array BioPharma, Bayer, Boston Biomedical, Daiichi Sankyo, Eisai, Genentech/Roche, Lilly, and Pfizer; and has been reimbursed for travel or other expenses by Amgen, Array BioPharma, Bayer, Boston Biomedical, Bristol-Myers Squibb, and Genentech/Roche.
