Expert Point of View: Neil Howard Segal, MD, PhD


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Neil Howard Segal, MD, PhD

Early analysis demonstrates compelling efficacy of pembrolizumab in this rare, but immunologically important, subset of colorectal cancer characterized by microsatellite instability and hypermutation.

—Neil Howard Segal, MD, PhD

Neil Howard Segal, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, who discussed the study at the 2015 ASCO Annual Meeting, emphasized that pembrolizumab (Keytruda) exerted a “clear benefit in patients with mismatch repair deficiency,” based on the “very impressive response rate of 62% vs 0%,” the primary endpoint, as well as the encouraging progression-free survival.

“This endpoint will likely continue to be met once accrual has been completed and the statistical outcome has been determined,” he predicted. He added that although progression-free survival in the mismatch repair–proficient cohort seems “short,” it is similar to what some other studies have shown.

Referring to Dr. Le’s discussion of mutational burden and its role in mismatch repair and response, Dr. Segal commented that such tumors and their release of antigens constitute “essentially a gold mine” for the immune system and therapies that modulate it. He further noted that minimum thresholds for mutational burden, as they relate to response to anti–PD-1 agents, have been established for melanoma (> 100 mutations) and for non–small cell lung cancer (> 178).

“This study demonstrates that this principle may also apply in colorectal cancer: high mutational burden (at least in microsatellite-high tumors) correlates with improved response rate, progression-free survival, and overall survival,” he said.

“However, can we learn something from this about conventional, stable colorectal cancer?” he questioned. “Conventional” colorectal cancer accounts for at least 95% of colorectal tumors, he pointed out, and in this study, 0% of such tumors responded to pembrolizumab.

Dr. Segal believes there are “factors beyond mutational burden that impair colorectal cancer” and that “immune-promoting strategies need to be studied in addition to blockade of the PD-1 pathway,” such as immune agonists, antigen-release strategies, and  possibly vaccination with neo-epitopes.

Dr. Segal concluded, “Early analysis from the current study demonstrates compelling efficacy of pembrolizumab in this rare, but immunologically important, subset of colorectal cancer characterized by microsatellite instability and hypermutation. There is potential for change in clinical practice in the treatment of metastatic microsatellite-high colorectal cancer after progression on standard therapy.”

“These data support initiating a front-line randomized study in metastatic microsatellite-high disease,” he concluded, adding, “There is no further role for PD-1 blockade alone in conventional colorectal cancer: factors beyond mutational burden are important.” ■

Dislosure: Dr. Segal has received research funding from Merck.

 

 


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