On June 16, 2020, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda®) 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, as determined by an FDA-approved test, that have progressed following prior treatment and have no satisfactory alternative treatment options.

FDA Approves Pembrolizumab for Patients With TMB-H Solid Tumors

FDA also approved the FoundationOne®CDx assay as a companion diagnostic for pembrolizumab.

Efficacy was investigated in a prospectively planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in a multicenter, non-randomized, open-label trial (KEYNOTE-158; NCT02628067). Patients received 200 mg of pembrolizumab via IV infusion every three weeks until they experienced unacceptable toxicity or documented disease progression.

The main efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) in patients who received at least one dose of pembrolizumab as assessed by blinded independent central review according to response evaluation criteria in solid tumors 1.1, modified to follow a maximum of 10 target lesions (maximum of five target lesions per organ).

A total of 102 patients (13%) had tumors identified as TMB-H, defined as TMB ≥ 10 mut/Mb. ORR for those patients was 29% (95% CI = 21, 39), with a 4% complete response rate and 25% partial response rate. Median DoR was not reached, with 57% of patients having response durations of at least 12 months and 50% of patients having response durations of at least 24 months.

Adverse reactions occurring in patients with TMB‑H tumors enrolled in the trial were similar to those occurring in patients with other solid tumors who received pembrolizumab as a single agent. The most common were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is also associated with immune-mediated adverse effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and adverse skin reactions.

The prescribing information for pembrolizumab includes a limitation of use stating that the safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.

The recommended pembrolizumab dosage regimen for TMB-H solid tumors is 200 mg every three weeks or 400 mg every six weeks for adults and 2 mg/kg (up to a maximum of 200 mg) every three weeks for pediatric patients.

View full prescribing information for pembrolizumab.

The review used Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment.

FDA granted the application priority review. A description of FDA expedited programs is in the Guidance for Industry—Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.   

For assistance with single-patient oncology investigational new drug applications, contact the Oncology Center of Excellence’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.