FDA Grants Full Approval to Pembrolizumab for Unresectable/Metastatic TMB-H Solid Tumors

The FDA has granted traditional approval to pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex; subcutaneous pembrolizumab) for adult and pediatric patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors, as determined by an FDA-authorized test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

In the updated indication, TMB-H is defined as 13 mutations per megabase. Previously, in June 2020, when the FDA granted accelerated approval to pembrolizumab for patients with unresectable or metastatic TMB-H solid tumors, TMB-H was defined as at least 10 mutations per megabase.^1,2

The full approval was backed by data from the phase 2 KEYNOTE-158 trial (NCT02628067).¹ Findings showed that among patients (n = 220) with TMB-H tumors with at least 13 mutations per megabase (cohort M, n = 145; cohorts A to J, n = 75), the overall response rate (ORR) was 36% (95% CI, 30%-43%). Additionally, 58% of patients experienced a duration of response (DOR) persisting for at least 12 months.

How was the KEYNOTE-158 trial conducted?

KEYNOTE-158 was an open-label, nonrandomized study that enrolled patients at least 18 years of age with histologically or cytologically confirmed advanced solid tumors. Notably, melanoma and non–small cell lung cancer were not among the list of eligible tumor types. Eligible patients needed disease progression following at least 1 prior line of standard-of-care systemic therapy, with the exception of patients with colorectal cancer, who needed at least 2 prior lines of standard therapy.

Other key inclusion criteria for all patients comprised radiologically measurable disease, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and adequate organ function.

Within the study, cohorts A through J included patients with various, previously treated advanced solid tumors.1 Cohort M featured patients with tumors that were TMB-H and non–microsatellite instability-high.

In cohorts A to J, pembrolizumab was administered at 200 mg every 3 weeks; patients in cohort M received the agent at 400 mg intravenously every 6 weeks. Treatment continued until unacceptable toxicity or documented disease progression.

ORR served as the trial’s primary end point.³ Secondary end points included DOR, progression-free survival, overall survival, and safety.

What is the safety profile of pembrolizumab for patients with TMB-H solid tumors?

Safety data from KEYNOTE-158 were consistent with the known safety profile of pembrolizumab monotherapy.¹

Per the agent’s prescribing information, the most common adverse effects reported in at least 20% of patients treated with pembrolizumab monotherapy include fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism.⁴

What is the recommended dose for pembrolizumab for TMB-H solid tumors?

In the updated indication, pembrolizumab is recommended at 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.¹ For pediatric patients, the agent is recommended at 2 mg/kg every 3 weeks, up to a maximum of 200 mg, until disease progression, unacceptable toxicity, or up to 24 months.

References

1. FDA grants traditional approval for pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph for unresectable or metastatic TMB-H solid tumors with updated indication. FDA. October 22, 2026. Accessed October 22, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph
2. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 16, 2020. Accessed October 22, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors
3. Study of pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-158/​KEYNOTE-158). ClinicalTrials.gov. Updated September 22, 2025. Accessed October 22, 2026. https://clinicaltrials.gov/study/NCT02628067
4. Keytruda. Prescribing information. Updated October 2026. Accessed October 22, 2026. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf