FDA Grants Accelerated Approval to Pembrolizumab for Patients With TMB-H Solid Tumors


Pembrolizumab (Keytruda, Merck) monotherapy approved for adult and pediatric patients with unresectable or metastatic tumor mutational burden-high solid tumors.

The FDA today granted accelerated approval to pembrolizumab (Keytruda, Merck) monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, who have progressed following prior treatment and who have no satisfactory alternative treatment options.

The FDA also approved the FoundationOne CDx companion diagnostic test, which identifies patients with solid tumors that are TMB-H (≥10 mutations/ megabase) who may benefit from treatment with pembrolizumab.

Pembrolizumab is an anti-programmed cell death protein (PD)-1 therapy that increases the ability of the body’s immune system to detect and fight cancerous cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

The most recent approval for this indication was based on tumor response rate and durability of response, with continued approval possibly contingent upon verification and description of clinical benefit in confirmatory trials. Pembrolizumab’s safety and efficacy have not been established in pediatric patients with TMB-H central nervous system cancers, according to a press release.

“For the second time, Keytruda monotherapy is now approved based on a biomarker rather than the location in the body where the tumor originated,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in the press release. “TMB-H, defined as 10 mutations per megabase or more, can help identify patients most likely to benefit from Keytruda. We’re pleased that our collaborative efforts to advance biomarker research have resulted in our ability to provide a new treatment option that addresses a high unmet medical need for these patients with cancer.”

Immune-mediated adverse events (AEs) that can occur with pembrolizumab include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation.

The accelerated approval was based on data from an analysis of 1050 patients with previously treated unresectable or metastatic solid tumors with TMB-H, who were enrolled in KEYNOTE-158 (NCT02628067). The multicenter, non-randomized, open-label trial evaluated pembrolizumab in a 200 mg dose administered every 3 weeks. A subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements identifed 102 (13%) patients with tumors identified as TMB-H, which was defined as TMB ≥10 mut/Mb.

Patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease or a medical condition that required immunosuppression, were excluded.

The trial’s major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) in patients who were administered at least 1 dose of pembrolizumab as assessed by blinded independent central review, according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Of 102 patients whose tumors were TMB-H, pembrolizumab showed an ORR of 29% (95% CI, 21-39), with a complete response rate of 4% and a partial response rate of 25%. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months). Among 30 responding patients, the trial showed that 57% had ongoing responses of a year or more and 50% had ongoing responses of 24 months or longer, according to the press release.

The most common AEs were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain and abdominal pain.

“These approvals stem from years of research into how TMB levels may influence a patient’s response to immunotherapy,” said Brian Alexander, MD, MPH, chief medical officer, Foundation Medicine, in a press release. “It’s critical that health care professionals have access to a validated genomic test to measure TMB in clinical tumor assessments and pinpoint those who are more likely to respond. We’re proud to be collaborating with Merck to help match appropriate patients to this important treatment.”


FDA Approves Second Biomarker-Based Indication for Merck’s KEYTRUDA® (pembrolizumab), Regardless of Tumor Type. Merck; June 17, 2020. Accessed June 17, 2020.


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