FDA Approves Second Biomarker-Based Indication for Pembrolizumab

The FDA today granted accelerated approval to the second biomarker-based indication for Merck’s Keytruda (pembrolizumab), an anti-PD-1 therapy, regardless of tumor type. The treatment is now indicated for adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) (≥10 mutations/megabase) solid tumors (determined by an FDA-approved test) that progressed after previous treatment and for which there are no satisfactory alternative treatments.

Pembrolizumab increases the ability of the body’s immune system to help detect and fight tumor cells by blocking the interaction between programmed cell death protein 1 (PD-1) and its ligands, PD-L1 and PD-L2. This activates T lymphocytes which can affect both tumor and healthy cells. Due to the high number of mutations present in TMB-H tumors, they are easier for the immune system to identify, and thus may be more likely to respond to certain immunotherapies.

The accelerated approval is based on tumor response rate and durability of response evidenced in a prospectively-planned retrospective analysis of 10 cohorts of patients enrolled in the KEYNOTE-158 trial. The non-randomized, multicenter, open-label trail evaluated effects of 200 mg of pembrolizumab every 3 weeks in patients with various previously treated unresectable or metastatic solid tumors with TMB-H.

In 102 patients whose tumors were TMB-H, pembrolizumab exhibited an objective response rate of 29% (95% CI, 21-39), a complete response rate of 4% and a partial response rate of 25%. Researchers found, “among the 30 responding patients, 57% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer.”

A companion diagnostic to pembrolizumab, FoundationOne CDx was also today approved by the FDA as only approved companion diagnostic to measure TMB. The comprehensive genomic profiling assay (GPA) aids in identifying patients who meet requirements for treatment with pembrolizumab, and is available for prescription use only. Specifically, the diagnostic identifies TMB, a measure of the number of somatic mutations per coding region within a tumor’s genome. The KEYNOTE-158 trial included a clinical trial assay based on FoundationOne CDx to determine tumor tissue’s TMB status.

“Not only does this approval mean that clinicians will be able to identify more patients who could benefit from this treatment option, but it’s an important milestone in the shift toward making biomarker-driven, tumor agnostic therapies available to patients, which is possible through an FDA-approved companion diagnostic,” said Brian Alexander, MD, chief medical officer of Foundation Medicine. Currently, FoundationOne CDx is approved as a companion diagnostic test for more than 20 therapies for multiple types of cancer.

Continued approval for pembrolizumab’s indication may be contingent upon confirmatory trial results yielding data on verification and description of clinical benefits. In addition, “the safety and effectiveness of Keytruda in pediatric patients with TMB-H central nervous system cancers have not been established.”

Potentially severe or fatal immune-mediated adverse reactions may occur when taking pembrolizumab, such as pneumonitis, colitis, and hepatitis, among other conditions. Severe or life-threatening infusion-related reaction can also occur. The most common side effects reported by KEYNOTE-158 trial participants were fatigue, musculoskeletal pain, decreased appetite, among others.

“It’s great to see the use of innovative biomarkers and immunotherapy come together with this approval and encouraging that we now have an option for patients with TMB-H tumors across cancer types, including rare cancers,” said Roy S. Herbst, MD, PhD, professor of medicine (medical oncology) and professor of pharmacology at Yale School of Medicine.