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Expert Point of View: Michael Overman, MD


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At the 2021 Gastrointestinal Cancers Symposium, the KEYNOTE-177 investigators updated their previously reported findings by showing further data relating to subsequent lines of therapy after disease progression. Their conclusion was that patients who received pembrolizumab initially still achieved better outcomes. Additionally, pembrolizu-mab-treated patients enjoyed clear benefits in terms of quality of life across all domains.

The study’s invited discussant, Michael Overman, MD, Professor in the Department of Gastrointestinal Oncology at The University of Texas MD Anderson Cancer Center, said the current analysis of second progression-free survival “reaffirms that pembrolizumab is the standard of care for front-line MSI-H or mismatch repair–deficient (dMMR) metastatic colorectal cancer, showing clear superiority related to efficacy, toxicity, and quality of life.”

Michael Overman, MD

Michael Overman, MD

After standard-of-care chemotherapy, the crossover rate was high, with 59% of patients ultimately receiving pembrolizumab or other PD-1–based therapies. Second progression-free survival—disease progression from the time of randomization to subsequent therapy—followed a similar track as the first progression-free survival curve, showing the superiority of pembrolizumab, he noted.

“I think a more interesting analysis, however, would be the subsequent therapy progression-free survival curves from the time of first disease progression. This would help evaluate certain subpopulations of interest within this trial,” Dr. Overman suggested.

“In particular, how do the 30% of patients whose disease progressed at first restaging on pembrolizumab respond to chemotherapy? How did the patients whose disease progressed on standard-of-care chemotherapy and then got subsequent PD-1–based therapy compare with those who received pembrolizumab as their initial line of care?” he explained. “I look forward to further presentations to help answer these additional questions.”

Because of the high crossover rate, the co-primary endpoint of overall survival may not be met, he predicted. “In essence, this will be assessing an initial anti–PD-1-based approach vs subsequent anti–PD-1 therapy. The statistical power to detect the planned difference in overall survival will likely be limited. These data are eagerly awaited,” he commented.

“In order to provide these [pembrolizumab’s] benefits to patients, it is critical that we test all patients with colorectal cancer for MSI or MMR status, both for the potential immunotherapy application and also for the benefit of identifying patients with Lynch syndrome,” he added. 

DISCLOSURE: Dr. Overman has served as a consultant or advisor to Array BioPharma, Bristol Myers Squibb, Gritstone Oncology, Janssen, MedImmune, Novartis, Pfizer, Promega, Roche/Genentech, and Spectrum Pharmaceuticals and has received research funding from Bristol Myers Squibb, MedImmune, Merck, and Roche.


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