FDA Approves Pembrolizumab Monotherapy Based on Biomarker Indication

June 17, 2020

The FDA approved pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high solid tumors.

The FDA has approved the anti-PD-1 therapy pembrolizumab (Keytruda) as a 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, according to Merck, the developer of the therapy.

The indication was approved under accelerated approval based on tumor response rate and durability of response; however, continued approval for this indication may be dependent upon verification and description of clinical benefit in the confirmatory trials.

“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 and professor of pharmacology at Yale School of Medicine, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, and associate cancer center director for translational research at Yale Cancer Center, said in the 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 accelerated approval was based on data from 10 cohorts of patients with various previously treated unresectable or metastatic tumors with TMB-H who were enrolled in the multicenter, non-randomized, open-label KEYNOTE-158 trial. The trial is designed to evaluate 200 mg of pembrolizumab every 3 weeks in the study participants.

The dual primary outcome measures were objective response rate (ORR) and duration of response (DOR) in the patients who received at least 1 dose of pembrolizumab, as assessed by blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Overall, 1050 individuals were included in the efficacy analysis. TMB was analyzed in a subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H.

Of the 102 participants whose tumors were TMB-H, pembrolizumab demonstrated an ORR of 29% (95% CI, 21-39), with a complete response (CR) rate of 4% and a partial response (PR) rate of 25%. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months). Importantly, among the 30 responding patients, 57% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer.

Moreover, in a pre-specified analysis of patients with TMB ≥13 mut/Mb (n=70), pembrolizumab demonstrated an ORR of 37% (95% CI, 26-50), with a CR rate of 3% and a PR rate of 34%. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months). Of the 26 responding patients, 58% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer. Even further, in an exploratory analysis in 32 patients whose cancer had TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was 13% (95% CI, 4-29), including 2 CRs and 2 PRs.

The median duration of exposure to pembrolizumab was 4.9 months (range, 0.03 to 35.2 months). The most common adverse reactions observed with pembrolizumab (reported in ≥20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain and abdominal pain.

The safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have yet to be established.

In addition to the approval of pembrolizumab, the FDA also approved the FoundationOne CDx test as the companion diagnostic to identify patients with solid tumors that are TMB-H who might benefit from immunotherapy treatment with pembrolizumab.

“These approvals stem from years of research into how TMB levels may influence a patient’s response to immunotherapy,” Brian Alexander, MD, MPH, chief medical officer at Foundation Medicine, said in the release. “It’s critical that healthcare professionals have access to a validated genomic test to measure TMB in clinical tumor assessments and pinpoint those who are more likely to respond. We’re proud to be collaborating with Merck to help match appropriate patients to this important treatment.”

Reference:

FDA Approves Second Biomarker-Based Indication for Merck’s KEYTRUDA® (pembrolizumab), Regardless of Tumor Type [news release]. Kenilworth, NJ. Published June 17, 2020. mrknewsroom.com/newsroom/news-releases/news-details/2020/FDA-Approves-Second-Biomarker-Based-Indication-for-Mercks-KEYTRUDA-pembrolizumab-Regardless-of-Tumor-Type/default.aspx. Accessed June 17, 2020.