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FDA Approval Summary: Pembrolizumab for the Treatment of Tumor Mutational Burden-High Solid Tumors
Leigh Marcus1, Lola A Fashoyin-Aje2, Martha Donoghue2
1Office of Oncologic Diseases, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. Leigh.Marcus@fda.hhs.gov.
Abstract:
The FDA approved pembrolizumab on June 16, 2020, 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. FDA granted the approval based on a clinically important overall response rate (29%; 95% confidence interval, 21-39) and duration of response (57% of responses lasting ≥ 12 months) in the subset of patients with TMB-H solid tumors (n = 102) spanning nine different tumor types enrolled in a multicenter single-arm trial (KEYNOTE-158). The efficacy of pembrolizumab was supported by the results of whole-exome sequencing (WES) analyses of TMB in additional patients enrolled across multiple pembrolizumab clinical trials, and a scientific understanding of the effects of PD-1 inhibition. Overall, the adverse event profile of pembrolizumab was similar to the adverse event profile observed in prior trials that supported the approval of pembrolizumab in other indications. This approval of pembrolizumab is the first time that the FDA has approved a cancer treatment for an indication based on TMB, and the fourth based on the presence of a biomarker rather than the primary site of origin.
Insights
The FDA approved pembrolizumab for unresectable or metastatic tumor mutational burden-high solid tumors. This landmark approval marks the first cancer treatment indication based on TMB, offering new hope for patients.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Pembrolizumab is an immunotherapy targeting PD-1.
- Tumor mutational burden (TMB) is an emerging predictive biomarker for immunotherapy response.
- Prior treatments may be insufficient for patients with TMB-high solid tumors.
Purpose of the Study:
- To evaluate the efficacy and safety of pembrolizumab in patients with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors.
- To establish TMB as a basis for FDA drug approval in oncology.
Main Methods:
- A multicenter, single-arm trial (KEYNOTE-158) enrolled patients with TMB-H solid tumors who progressed on prior therapy.
- Tumor mutational burden was assessed using FDA-approved tests and whole-exome sequencing (WES).
- Overall response rate (ORR) and duration of response (DOR) were key efficacy endpoints.
Main Results:
- Pembrolizumab demonstrated a 29% ORR in the TMB-H solid tumor subset (n=102).
- Of responders, 57% experienced a duration of response of at least 12 months.
- The adverse event profile was consistent with previous pembrolizumab trials.
Conclusions:
- Pembrolizumab is effective for adult and pediatric patients with TMB-H solid tumors progressing on prior treatment.
- This approval represents a significant advancement, being the first FDA cancer treatment indication based on TMB.
- Biomarker-based approvals, like this one for TMB, are increasingly important in personalized oncology.
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