FDA Approves Pembrolizumab in Metastatic TMB-H Solid Tumors

The FDA approved intravenous pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) for pediatric or adult patients with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors harboring at least 13 mutations/megabase (mut/Mb) as determined by an FDA-authorized test and progression following prior treatment and those who have no satisfactory alternative treatment options, according to a news release from the agency.¹

This decision converts a previous accelerated approval for pembrolizumab in unresectable or metastatic TMB-H solid tumors to traditional approval. The new indication also encompasses TMB-H as having 13 mut/Mb, as efficacy to support traditional approval was not confirmed in patients with TMB of 10 to 12 mut/Mb.

Supporting data for the approval came from 2 groups of patients in the phase 2 KEYNOTE-158 trial (NCT02628067).² Cohort M of the trial included prospectively enrolled patients with tumors that were TMB-H and not microsatellite instability-high (MSI-H), while Cohorts A through J included a prospectively planned retrospective analysis of patients with TMB-H tumors identified within 10 cohorts of patients with various previously treated unresectable or metastatic solid tumors.

Among 220 patients with tumors with TMB ≥13 mut/Mb, including 145 in Cohort M and 75 in Cohorts A to J, the objective response rate (ORR) was 36% (95% CI, 30%-43%). Additionally, 58% of responders had a response sustained for at least 12 months.

The safety profile of pembrolizumab monotherapy for the updated indication was comparable with prior reports of pembrolizumab monotherapy. The agent’s prescribing information includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.

The trial’s primary end point was ORR. Secondary end points included duration of response, progression-free survival, overall survival, and adverse effects.

“The conversion of pembrolizumab from accelerated to traditional approval for TMB-H solid tumors provides further evidence supporting the role of TMB as a biomarker for immunotherapy across multiple tumor types. The updated threshold from [at least 10] to [at least] 13 mut/Mb, based on efficacy data from the KEYNOTE-158 trial, is particularly noteworthy, as it highlights the importance of refining biomarker cutoffs based on clinical efficacy data,” Chinmay Jani, MD, a medical oncologist at Sylvester Comprehensive Cancer Center of the University of Miami Miller School of Medicine, stated in a written correspondence to CancerNetwork^® regarding the approval.

The recommended dose for intravenous pembrolizumab monotherapy in the updated indication is 200 mg every 3 weeks or 400 mg every 6 weeks in the absence of disease progression, unacceptable toxicity, or up to 24 months. The recommended dose for pediatric patients is 2 mg/kg every 3 weeks to a maximum dose of 200 mg until disease progression, unacceptable toxicity, or up to 24 months.

“This approval highlights an important principle of biomarker-driven oncology: molecular biomarkers can help guide treatment decisions across different cancer types, but their predictive utility must be continuously evaluated and validated to better identify patients most likely to derive meaningful and durable benefit. Ultimately, this represents the continued convergence of precision medicine and immunotherapy, where molecular characterization increasingly informs patient selection and therapeutic decision-making,” Jani concluded.

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. News release. FDA. October 22, 2026. Accessed October 22, 2026. https://tinyurl.com/bdjc2jpv
2. 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://tinyurl.com/5cfv5m9v