Merck's Keytruda nabs 2nd biomarker-driven FDA nod, regardless of tumor type

The FDA has approved Merck's Keytruda in previously treated TMB-H tumors regardless of their locations. (Merck)

Three years ago, Merck & Co.’s Keytruda became the first drug to nab an FDA approval to treat any cancer bearing certain specific genetic features, regardless of where in the body it started. Now, it has added a second so-called tumor-agnostic indication.

Keytruda as a monotherapy has won an FDA go-ahead in previously treated tumors with high levels of the biomarker tumor mutational burden (TMB) in any part of the body if the patient has no alternative options, Merck said Wednesday.

The accelerated nod is based on tumor shrinkage data and durability of response observed in a retrospective analysis of a clinical trial covering many tumor types.

In the phase 2 Keynote-158 trial in patients with previously treated solid tumors, 102 patients were found to have TMB-high tumors, according to Merck. In this population, Keytruda shrank tumors in 29% of patients. Among the 30 patients who responded, half had ongoing responses of two years or longer. The median duration of response had not been reached after a median follow-up of 11.1 months.

Data from the Keynote-158 study previously helped Keytruda earn its initial tumor-agnostic label in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed after prior therapy.

TMB level is viewed as a possible predictor of a patient’s response to immuno-oncology agents. “TMB-H, defined as 10 mutations per megabase or more, can help identify patients most likely to benefit from Keytruda,” Scot Ebbinghaus, vice president of clinical research at Merck Research Laboratories, said in a statement.

RELATED: Merck's Keytruda inches toward another biomarker-based OK with latest priority review

But fellow PD-1/L1 players Bristol Myers Squibb and AstraZeneca haven’t had much luck with TMB as a biomarker. BMS previously pulled a front-line non-small cell lung cancer filing for its Opdivo-Yervoy combo based on that marker. While the company was seeking an approval in TMB-high patients, an analysis showed the survival benefit between high- and low-TMB patients appeared “quite similar,” Credit Suisse analyst Vamil Divan noted at the time. The company only recently secured that critical FDA green light after changing the trial protocol to instead focus on PD-L1 status.

In August, AstraZeneca found its Imfinzi-tremelimumab dual immunotherapy combo failed to extend the lives of previously untreated patients with stage 4 metastatic non-small cell lung cancer with TMB-H tumors when compared with chemo.

RELATED: ASCO: Merck's Keytruda doubles time to disease progression in certain colorectal cancer patients

Meanwhile, Keytruda recently reported positive data that could help it score another biomarker-based OK, pushing it to the front-line setting in MSI-H and dMMR colorectal cancer. In newly diagnosed patients, the PD-1 drug kept cancer at bay for 16.5 months, about twice as long as the 8.2 months posted by chemo, Merck unveiled at this year’s American Society of Clinical Oncology (ASCO) virtual event. That translated into a 40% reduction in the risk of disease progression or death.

As is the case with several other cancer indications, Keytruda is wrestling with Bristol’s rival PD-1 inhibitor Opdivo in MSI-H/dMMR cancer. Opdivo currently holds an FDA nod in previously treated MSI-H or dMMR colorectal cancer, and BMS is running the phase 3 CheckMate-8HW trial pitting Opdivo—with or without CTLA4 inhibitor Yervoy—against chemotherapy in MSI-H/dMMR colorectal cancer patients irrespective of prior treatment history.