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FDA Approves Merck's Keytruda, Foundation Medicine CDx for TMB-High Solid Tumors

NEW YORK – The US Food and Drug Administration has approved another tissue-agnostic indication for pembrolizumab (Merck's Keytruda), this time using tumor mutational burden as a biomarker to guide which refractory solid tumor patients can receive the immunotherapy.

The agency granted accelerated approval for pembrolizumab as a treatment for adult and pediatric patients with unresectable or metastatic solid tumors whose disease has progressed on other treatments and are out of alternative therapy options. Their tumors must also display a high mutational burden defined as having at least 10 mutations/Mb and assessed by an FDA-approved companion diagnostic.

Alongside the new drug indication approval, the FDA also approved Foundation Medicine's FoundationOne CDx as a test that doctors can use to identify cancer patients with TMB-high status who may be eligible for pembrolizumab.

"For the second time, Keytruda monotherapy is now approved based on a biomarker rather than the location in the body where the tumor originated," Scot Ebbinghaus, VP of clinical research at Merck Research Laboratories, said in a statement. In 2017, the FDA approved pembrolizumab for patients with unresectable or metastatic solid tumors with microstatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). 

The FDA granted accelerated approval for the latest indication based on pembrolizumab's impact on response rate and durability of response in the biomarker-defined population. The agency reviewed data from 10 cohorts in KEYNOTE-158, where TMB status was retrospectively established in patients with advanced solid tumors using FoundationOne CDx, using the prespecified cutpoints of at least 10 mutations/Mb and at least 13 mutations/Mb. Approximately 1,000 patients were included in the efficacy analysis and 790 patients had sufficient tissue for TMB analysis.

Of those evaluable for TMB, 102 patients, or 13 percent, had TMB of at least 10 mutations/Mb. The objective response rate in this group was 29 percent with 4 percent seeing their tumors completely disappear and 25 percent experiencing partial shrinking of their tumors. After a median follow-up of 11 months, the median duration of response had not been reached. Of the 30 patients still responding, 57 percent had ongoing responses to pembrolizumab for a year or longer, and half were responding for two years or longer.

In comparison, the objective response rate in patients with TMB of less than 10 mut/Mb was 6 percent.

Researchers also explored the efficacy of pembrolizumab using a higher TMB cut off (13 mutations/Mb) in 70 patients. Among these patients, 37 percent saw their tumors shrink, with 3 percent seeing a complete response and 34 percent having a partial response. Median duration of response had not been reached at 11.1 months. Of the 26 still-responding patients, 58 percent were responding for a year or more and half were responding for two or more years.

In a further exploratory analysis, researchers also considered the outcomes of 32 patients who had TMB of at least 10 mutations/Mb but less than 13 mutations/Mb. The objective response rate in this group was 13 percent with two complete and two partial responses.

Common adverse events with pembrolizumab were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, and rash. Pembrolizumab carries the risk of immune-mediated adverse reactions, such as pneumonitis, severe skin reactions, and solid organ transplant rejection, which can be severe or fatal. The safety and efficacy of pembrolizumab is not established in pediatric patients with central nervous system tumors who are TMB-high.

Since FDA has granted accelerated approval for this indication, Merck may need to conduct confirmatory trials to verify the benefit seen with pembrolizumab in KEYNOTE-158 in order to maintain approval.