The PD-1 inhibitor pembrolizumab received accelerated approval for adult and pediatric patients with solid tumors that are mismatch repair–deficient or microsatellite instability–high. This is the first time the FDA has greenlighted a drug based not on tumor type, but on a common biomarker.

The FDA recently greenlighted its first-ever drug based not on tumor type, but on a common biomarker. Pembrolizumab (Keytruda; Merck) received accelerated approval for adult and pediatric patients with inoperable or metastatic solid tumors that are mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H).

MMR deficiency is a genotype that can be hereditary—as in Lynch syndrome—or sporadic, arising from defects in one or more mismatch repair proteins. As a result, tumors acquire the phenotype of MSI and accumulate hundreds—or even thousands—of somatic mutations, any of which could produce neoantigens capable of triggering a potent antitumor response in the presence of immunotherapy.

To Suzanne Topalian, MD, of the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy in Baltimore, MD, this tissue-agnostic indication for pembrolizumab “is extremely exciting, given that it arose from the germ of an idea here.” She and a team of Hopkins researchers, including Drew Pardoll, MD, PhD, led the first clinical trials of anti–PD-1 therapy several years ago, during which they reported that only one of 33 patients with advanced colorectal cancer experienced complete, durable disease regression (Clin Cancer Res 2013;19:462–8). Intrigued, Topalian and Pardoll discussed this exceptional responder with Luis Diaz, MD, and Bert Vogelstein, MD, two fellow researchers specializing in colorectal cancer genetics.

“They asked if the patient's tumor was MSI-high,” Topalian recalls. “It wasn't something we'd thought about, but a retrospective analysis proved their hunch right.” This “meeting of the minds” between cancer geneticists and immunologists prompted a seminal study of PD-1 blockade in dMMR tumors, led by Diaz and Dung Le, MD, followed by a series of trials on which the FDA based its decision (N Engl J Med 2015;372:2509–20).

Across five single-arm studies that enrolled 149 patients—90 with colorectal cancer, the rest with one of 14 other tumor types—the objective response rate to pembrolizumab was 39.6%, including 11 complete responses. At the time of data analysis, the median duration of response had not been reached. Most patients had their tumor status prospectively evaluated using local laboratory-developed tests: IHC for dMMR; PCR for MSI-H.

“It will be important to engage pathologists to incorporate this clinically relevant biomarker into standard practice,” says Lillian Siu, MD, of the Princess Margaret Cancer Centre in Toronto, Canada.

Equally key, notes David Rimm, MD, PhD, director of Yale Pathology Tissue Services in New Haven, CT, will be having “someone, or some company, produce a comprehensive set of controls to standardize test results, especially that of IHC, between labs.” He would also like the College of American Pathologists and the American Society of Clinical Oncology to set dMMR/MSI-H testing guidelines.

Jedd Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, sees “no reason why other anti–PD-1 therapies shouldn't work as well against hypermutated tumors,” and anticipates that more agents in this class will receive tissue-agnostic approvals. Besides dMMR/MSI-H, having other biomarkers achieve similar clinical utility in the future would be welcome, he adds, “as long as the data are rock-solid, because decisions about access to treatment would be on the line.”

Overall, this milestone on the FDA's part “should incentivize the conduct of more biomarker-driven basket studies,” Siu says, “because it sets precedence for a regulatory pathway that was previously uncertain.” –Alissa Poh

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