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Expert Point of View: Howard (Jack) West, MD, and William R. Sellers, MD


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Howard (Jack) West, MD

Howard (Jack) West, MD

Howard (Jack) West, MD, Associate Clinical Professor in Medical Oncology at City of Hope Comprehensive Cancer Center, Duarte, California, was impressed with the data from the KRYSTAL-1 trial.

“It’s great to see new data on another entrant into the space for patients with KRAS G12C mutation–positive non–small cell lung cancer, which comprises about 12% to 13% of the population. Sotorasib was the first agent to break the impasse and show promising activity, though the response rate of approximately 35% and relatively limited duration of benefit with sotorasib illustrate that it falls short of what we have come to hope for in our most effective targeted therapies for a driver mutation,” Dr. West said.

“The response rate with adagrasib of 45% is encouraging, particularly as the are all confirmed responses, and the benefit of adagrasib was seen even in patients with coincident STK11 and/or KEAP1 mutations, which are generally associated with worse outcomes. Notably, these findings are still very early with adagrasib, but the early results appear quite promising, with four of six patients in the initial cohort who responded, demonstrating ongoing responses approaching 1 year in duration,” he commented.

William R. Sellers, MD

William R. Sellers, MD

William R. Sellers, MD, Professor of Medicine at Harvard Medical School and Dana-Farber Cancer Institute and Co-Chair of the EORTC-NCI-AACR Symposium, commented that an important goal in cancer drug discovery for years has been finding drugs that successfully and selectively inhibit the action of mutant versions of the KRAS gene. Mutations in KRAS are common in a number of major cancers that are often hard to treat, he said.

“Although preliminary, the results of the KRYSTAL-1 trial so far look very promising. Certainly, I look forward to the peer review of these data and to the longer-term follow-up of treated patients so we can evaluate the durability of the benefit,” Dr. Sellers said. “It will also be interesting to see how adagrasib performs in combination with other existing therapies. These data also suggest that targeting other forms of mutant KRAS will be clinically important.” 

DISCLOSURE: Dr. West has received honoraria from AstraZeneca, Genentech/Roche, Merck, and Takeda; has served as a consultant or advisor to AstraZeneca, Genentech/Roche, Merck, and Takeda; and has participated in speakers bureaus for AstraZeneca, Merck, and Takeda. Dr. Sellers has served in a leadership role for Bluebird Bio, Civetta Therapeutics, Novartis, and Peloton Therapeutics; holds stock or other ownership interests in Bluebird Bio, Civetta Therapeutics, Ideaya Biosciences, Novartis, and Peloton Therapeutics; has received honoraria from Genentech; has served as a consultant or advisor to Array BioPharma, Astex Pharmaceuticals, Civetta Therapeutics, Dynamo Therapeutics, Epidarex Capital, Ibsen Pharmaceuticals, Ideaya Biosciences, Pearl River Therapeutics, Peloton Therapeutics, Servier Pharmaceuticals, Syndax Therapeutics, and Vida Ventures; has received research funding from Deerfield Management, Merck, Pfizer, and Ridgeline Discovery; holds intellectual property in EGFR mutations patents; and has been reimbursed for travel, accommodations, or other expenses by Astex Pharmaceuticals, Bluebird Bio, Ideaya Biosciences, Merck, Peloton Therapeutics, and Servier.


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Another novel oral KRAS inhibitor—adagrasib (MRTX849)—has shown promise in early clinical trials, according to investigators of the KRYSTAL-1 study who reported findings at the virtual 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.1,2 The conference is jointly provided...

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