The Food and Drug Administration (FDA) has granted accelerated approval to Keytruda® (pembrolizumab; Merck) as 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, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. Continued approval for this indication may be contingent upon verification of benefit in a confirmatory trial.

The accelerated approval was based on data from a prospectively-planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic solid tumors with TMB-H who were enrolled in the open-label phase 2 KEYNOTE-158 trial. Patients received pembrolizumab 200mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. 

The main efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) in patients who had received at least 1 dose of pembrolizumab as 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.

Among the 102 patients who had tumors identified as TMB-H, the ORR was 29% (95% CI, 21-39); 4% of patients achieved a complete response while 25% had a partial response. Findings showed that the median DoR had not been reached after a follow-up of 11.1 months. Among the 30 responders, 57% had response durations ≥12 months and 50% had response durations ≥24 months. Moreover, among 32 patients with TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was found to be 13% (95% CI, 4-29), with 2 complete responses and 2 partial responses.


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The safety profile of pembrolizumab in patients with TMB-H was found to be similar to that seen in other pembrolizumab trials involving solid tumors. The most common adverse reactions (≥20%) included fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. 

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The safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.

“It’s great to see the use of innovative biomarkers and immunotherapy come together with this approval and encouraging that we now have an option for patients with TMB-H tumors across cancer types, including rare cancers,” said Roy S. Herbst, MD, PhD, ensign professor of medicine (medical oncology) and professor of pharmacology, Yale School of Medicine; chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital; and associate cancer center director for translational research, Yale Cancer Center.

Additionally, the FDA approved the FoundationOne® CDx (Foundation Medicine) test as the companion diagnostic for Keytruda to identify patients with solid tumors that are TMB-H (≥10 mutations/ megabase).

For more information visit keytruda.com.

This article originally appeared on MPR