FDA Grants Traditional Approval to Pembrolizumab in TMB-H Solid Tumors

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

The October 16, 2026 decision comes with a narrower definition of eligibility: TMB-H is now defined as at least 13 mutations per megabase (mut/Mb), as determined by an FDA-authorized test, rather than the 10 mut/Mb threshold used since 2020.¹

What did the FDA change in the TMB-H indication?

Pembrolizumab first received accelerated approval in this tumor-agnostic setting in June 2020 for patients with TMB of at least 10 mut/Mb.^1,2 The new action converts that accelerated approval to traditional approval and amends the indication to TMB of at least 13 mut/Mb. According to the FDA, efficacy to support traditional approval was not confirmed in patients with TMB of 10 to less than 13 mut/Mb.¹

The change means that some patients whose tumors met the original cutoff will no longer fall within the labeled indication. Data reported at the time of the 2020 approval had already pointed to a difference between the 2 groups. In a prespecified analysis of 70 patients with TMB of at least 13 mut/Mb, the objective response rate (ORR) was 37% (95% CI, 26%-50%), and in an exploratory analysis of 32 patients with TMB of at least 10 and less than 13 mut/Mb, the ORR was 13% (95% CI, 4%-29%).²

What trial data supported the traditional approval?

Efficacy was evaluated in 2 groups of patients from the multicohort phase 2 KEYNOTE-158 trial (NCT02628067).¹ Cohort M prospectively enrolled patients whose tumors were TMB-H and not microsatellite instability–high (MSI-H). Cohorts A through J made up 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.¹

Patients in cohorts A through J received pembrolizumab 200 mg every 3 weeks, and patients in cohort M received pembrolizumab 400 mg intravenously every 6 weeks, until unacceptable toxicity or documented disease progression.¹

The major efficacy outcome measures were ORR and duration of response (DOR), assessed by blinded independent central review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.¹

How did patients with TMB of at least 13 mut/Mb respond?

The efficacy population included 220 patients with TMB of at least 13 mut/Mb who received at least 1 dose of pembrolizumab:¹

• Cohort M: 145 patients
• Cohorts A through J: 75 patients
• ORR across both groups: 36% (95% CI, 30%-43%)
• DOR of at least 12 months: 58% of patients
• Progression-free survival and overall survival for the updated population were not reported in the FDA announcement.¹

The original TMB-H analysis of KEYNOTE-158, published in The Lancet Oncology in 2020, enrolled patients with anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small cell lung, thyroid, and vulvar cancers. In that analysis, 102 of 790 patients (13%) evaluable for TMB had TMB of at least 10 mut/Mb, and objective responses occurred in 30 of those 102 patients (29%; 95% CI, 21%-39%) vs 43 of 688 patients (6%; 95% CI, 5%-8%) without TMB-H tumors.³

What safety findings should nurses know about?

The FDA reported that the safety profile of pembrolizumab monotherapy in the updated indication was consistent with the known safety profile of pembrolizumab monotherapy.¹

The prescribing information includes warnings and precautions for:¹

• Immune-mediated adverse reactions
• Infusion-related reactions
• Complications of allogeneic hematopoietic stem cell transplantation
• Embryo-fetal toxicity

In the 2020 TMB-H analysis, 11 of 105 patients (10%) had treatment-related serious adverse events.³ The most common adverse reactions to pembrolizumab reported at the time of the accelerated approval, occurring in at least 20% of patients, were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.²

What dosing applies to the updated indication?

For adults, the recommended dose of pembrolizumab monotherapy is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months. For pediatric patients, the recommended dose is 2 mg/kg every 3 weeks, up to a maximum of 200 mg, on the same schedule.¹

For pembrolizumab and berahyaluronidase alfa-pmph, the FDA directs clinicians to that product's prescribing information.¹ When the subcutaneous formulation was approved in September 2025, the recommended dose was either 395 mg of pembrolizumab and 4800 units of berahyaluronidase alfa-pmph every 3 weeks or 790 mg of pembrolizumab and 9600 units of berahyaluronidase alfa-pmph every 6 weeks.⁴ Its labeling lists hypersensitivity and administration-related reactions among its warnings.⁴

How does this approval fit with earlier pembrolizumab approvals?

TMB-H was the second biomarker-based, tumor-agnostic indication for pembrolizumab, following the 2017 accelerated approval for MSI-H or mismatch repair–deficient solid tumors.² Oncology Nursing News covered the original TMB-H accelerated approval in 2020, when the FoundationOne CDx assay was used to assess TMB in KEYNOTE-158.⁵

The subcutaneous formulation was approved in September 2025 for the solid tumor indications of IV pembrolizumab, with a median injection time of 2.0 minutes in the phase 3 3475A-D77 trial, as previously reported by Oncology Nursing News.⁶

The TMB-H data come from single-arm cohorts, and the efficacy population for the traditional approval combines a prospectively enrolled cohort with a retrospective analysis. Responses across individual tumor types were not broken out in the FDA announcement.¹ The review used the FDA's Assessment Aid, a voluntary submission from the applicant to facilitate the agency's assessment.¹

What are the key takeaways for oncology nurses?

• Recheck the number, not just the label: TMB-H now means at least 13 mut/Mb by an FDA-authorized test. Patients with prior reports of 10 to less than 13 mut/Mb fall outside the updated indication.¹
• Set realistic expectations: about 1 in 3 patients (36%) responded in the 220-patient efficacy population, which can inform shared decision-making conversations.¹
• Plan for durable treatment: 58% of patients had a DOR of 12 months or longer, and treatment may continue up to 24 months.¹
• Monitor for immune-mediated adverse reactions throughout treatment and educate patients and caregivers on which symptoms to report promptly.¹
• Confirm the formulation and schedule: IV dosing can be every 3 or 6 weeks for adults, pediatric dosing is weight based, and subcutaneous dosing follows its own prescribing information.^1,4

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://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph
2. FDA approves second biomarker-based indication for Merck's KEYTRUDA (pembrolizumab), regardless of tumor type. News release. Merck. June 17, 2020. Accessed October 22, 2026. https://www.merck.com/news/fda-approves-second-biomarker-based-indication-for-mercks-keytruda-pembrolizumab-regardless-of-tumor-type/
3. Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020;21(10):1353-1365. doi:10.1016/S1470-2045(20)30445-9
4. FDA approves pembrolizumab and berahyaluronidase alfa-pmph for subcutaneous injection. News release. FDA. September 19, 2025. Accessed October 22, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-and-berahyaluronidase-alfa-pmph-subcutaneous-injection
5. FDA approves pembrolizumab for TMB-high solid tumors. Oncology Nursing News. June 17, 2020. Accessed October 22, 2026. https://www.oncnursingnews.com/view/fda-approves-pembrolizumab-for-tmbhigh-solid-tumors
6. Hoyt B. Subcutaneous pembrolizumab is FDA approved, slashes chair time. Oncology Nursing News. September 19, 2025. Accessed October 22, 2026. https://www.oncnursingnews.com/view/subcutaneous-pembrolizumab-is-fda-approved-slashes-chair-time