Mercks Keytruda Inches Toward Another Biomarker-based Approval

Merck & Co immuno-oncology competitors have tried, so far fruitlessly, to use the investigational biomarker tumor mutational burden to help them win approvals. But regulators apparently like what they’re seeing from Merck where TMB is concerned. The FDA has awarded the pharma giant a priority review for the use of solo Keytruda in previously treated patients with high tumor mutational burdens, no matter where those tumors are in the body. The move will shorten the regulatory timeline, bringing the deadline for the agency’s verdict up to June 16. Regulators based the decision on data from Merck’s phase 2 Keynote-158 trial—the same trial which helped it land the first-ever green light based on a biomarker, regardless of cancer type. It brought that approval, for patients with microsatellite instability-high or mismatch repair deficient solid tumors, home in 2017. Between then and now, though, there’s been a lot of hype around tumor mutational burden, or TMB—and so far, nothing to show for it when it comes to approvals. Most notoriously, Bristol-Myers Squibb based its initial 2018 regulatory filing for its Opdivo-Yervoy combo on the biomarker, seeking an approval in TMB-high patients—only to pull it early last year. As an October analysis of that trial data showed, the survival benefit in patients with high TMB and low TMB appeared “quite similar (based on hazard ratios compared to chemotherapy),” Credit Suisse analyst Vamil Divan noted in October 2018. More recently, AstraZeneca also came up short in the TMB arena, with its Imfinzi-tremelimumab combo failing to extend the lives of a group of previously untreated patients with stage 4 metastatic non-small cell lung and TMB-high tumors. RELATED: WCLC: Merck analyses throw doubt on new biomarker's utility Merck, sitting pretty in the lung cancer department, has meanwhile been busy touting its Keytruda-chemo combo’s ability to work across all patients, TMB or no TMB. Last September, it trumpeted an analysis showing that “there does not appear to be a role” for TMB in determining which patients are most likely to benefit from its market-leading dual regimen. None of those studies—all employing combinations—have said solo therapies can’t make a mark on TMB-high tumors, though. “We think TMB is an important area to study, and we are studying it,” Roy Baynes, M.D., Merck SVP and head of global clinical development, said in September.

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