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FDA approves pembrolizumab across TMB-high solid tumors


Pembrolizumab has been granted a second tumor-agnostic FDA indication, this one for patients with solid tumors with a high tumor mutational burden.

The FDA has granted an accelerated approval to the PD-1 inhibitor pembrolizumab (Keytruda) 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 that have progressed following prior treatment and who have no satisfactory alternative treatment options.1

The FDA action marks the second tumor-agnostic approval for pembrolizumab, which was previously approved for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high or mismatch repair deficient solid tumors.

The approval was based on findings from the phase 2 KEYNOTE-158 trial, in which pembrolizumab induced an objective response rate (ORR) of 29% (n = 30) in a cohort of 102 patients with various previously treated unresectable or metastatic TMB-H (≥10 mut/Mb) solid tumors. The ORR comprised a 4% complete response rate and a 25% partial response rate. The median duration of response had not been reached (range, 2.2+ to 34.8+ months) at a median follow-up of 11.1 months. Among the responders, 57% and 50% had responses ongoing at ≥12 months and ≥24 months, respectively.

To receive pembrolizumab for this indication, a patients’ TMB status must be determined by an FDA-approved test. The FDA simultaneously approved the FoundationOne CDx test as a companion diagnostic to assess TMB-H status in patients with solid tumors.

“As physicians, we are always looking to find new options for patients, especially in the second-line or higher treatment setting,” 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, stated in a press release. “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.”

The approval was specifically based on a prospectively planned retrospective analysis of 10 patient cohorts from the open-label, nonrandomized, multicenter KEYNOTE-158 trial (NCT02628067). The cohorts included patients with previously treated unresectable or metastatic solid tumors. Prior treatment with PD-1 inhibitors or other immune-modulating monoclonal antibodies was not allowed.

Overall, the efficacy analysis population included 1050 patients and TMB status was evaluated in a subset of 790 patients. Testing identified 102 of the 790 patients as having TMB-H tumors, defined as TMB ≥10 mut/Mb. The median age of these patients was 61 years (range, 27-80), with 34% being aged ≥65 years. Eighty-one percent were White, 41% had an ECOG performance status of 0, and 58% had an ECOG performance status of 1. Regarding prior lines of therapy, 56% of patients had received at least 2.

Patients received pembrolizumab at 200 mg every 3 weeks.

Beyond the analysis of patients with TMB ≥10 mut/Mb, the trial design also included an analysis of patients with TMB ≥13 mut/Mb. Among the 70 patients with this status, the ORR was 37% (n = 26), comprising a complete response rate of 3% and a partial response rate of 34%. The median duration of response had had not been reached (range, 2.2+ to 34.8+ months) at a median follow-up of 11.1 months. Among the responders, 58% and 50% of patients had ongoing responses at ≥12 months and ≥24 months respectively.

Investigators also conducted an exploratory analysis of patients with TMB status ≥10 mut/Mb and <13 mut/Mb. In the 32 patients who met these criteria the ORR was 13%, including 2 complete responses and 2 partial responses.

Patients were exposed to pembrolizumab for a median duration of 4.9 months (range, 0.03-35.2 months). Merck (MSD) the manufacturer of pembrolizumab noted in the press release that the most frequently reported (≥20% of patients) adverse events across all grades were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

The accelerated approval of pembrolizumab for this indication is contingent on the results of a confirmatory trial. Also of note, the label for this indication includes a “limitations of use” stipulation stating that, “The safety and effectiveness of Keytruda in pediatric patients with TMB-H central nervous system cancers have not been established.”2

In the Urology field, pembrolizumab also has approved indications for urothelial carcinoma and renal cell carcinoma.


1. FDA Approves Second Biomarker-Based Indication for Merck’s KEYTRUDA® (pembrolizumab), Regardless of Tumor Type. Published June 17, 2020. https://bit.ly/3enCh89. Accessed June 17, 2020.

2. Keytruda (pembrolizumab): Highlights Of Prescribing Information. https://bit.ly/2Ybohsh. Accessed June 17, 2020.

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