FDA Grants Full Approval to Pembrolizumab for MSI-H and dMMR Solid Tumors


A full approval has been granted to pembrolizumab by the FDA for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient solid tumors.

The FDA has granted full approval to pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed after receiving previous treatment and for those who have no satisfactory alternative treatment options.

This is the first full approval for an immunotherapy based on a predictive biomarker, regardless of solid tumor type.

“This approval reinforces the important role of [pembrolizumab] in certain patients with MSI-H or dMMR solid tumors facing a variety of cancers,” said Luis A. Diaz, Jr., MD, head of the Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York City, in a press release. “These data also further underscore the need for biomarker testing to identify patients who may be eligible for this therapy.”

Previously in 2017, pembrolizumab was granted an accelerated approval for this indication. Now, the conversion to a full approval is based on results from the phase 2 KEYNOTE-158 (NCT02628067), KEYNOTE-164 (NCT02460198), and KEYNOTE-051 (NCT02332668) trials that evaluated data among 504 adult and pediatric patients across more than 30 types of cancer.

In the KEYNOTE-164 trial, 124 patients with advanced MSI-H/dMMR colorectal cancer that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan with or without anti-VEGF/EGFR mAb-based therapy were evaluated. KEYNOTE-158 enrolled 373 patients with advanced MSI-H/dMMR non-colorectal cancers who had disease progression following prior therapy. In cohort K of the study, patients were prospectively enrolled with MSI-H/dMMR tumors while those in cohorts A through J were retrospectively identified in 1 of 10 solid tumor cohorts. Lastly, KEYNOTE-051 enrolled 7 pediatric patients with MSI-H/dMMR cancers.

Each of the multicenter, non-randomized, open-label multi-cohort trials did not include patients with autoimmune disease or patients who had a medical condition that required immunosuppression. MSI or MMR tumor status was determined using polymerase chain reaction or immunohistochemistry, regardless of histology, respectively.

Adult patients received 200 mg pembrolizumab intravenously every 3 weeks, while pediatric patients received 2 mg/kg every 3 weeks until unacceptable toxicity, disease progression, or a maximum of 24 months. In KEYNOTE‑164 and KEYNOTE‑158, assessment of tumor status was performed every 9 weeks through the first year, then every 12 weeks following. The KEYNOTE‑051 study had assessment of tumor status performed every 8 weeks for 24 weeks, and then every 12 weeks thereafter.

Investigators evaluated the primary end points of objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review according to RECIST v1.1 in the KEYNOTE-158 trial, and as assessed by the investigator according to RECIST v1.1 in the KEYNOTE-051 trial.

Findings from a pooled analysis of the 3 trials revealed that treatment with pembrolizumab elicited an ORR of 33.3% among patients (95% CI, 29.2%-37.6%). This included a complete response rate of 10.3% and a partial response rate of 23.0% at a median follow-up time of 20.1 months (range, 0.1-71.4). Of the 168 patients who responded to treatment, 77% had responses lasting 12 months or longer, and 39% had responses lasting 36 months or longer. Further, the median DOR was 63.2 months (range, 1.9+ to 63.9+).

Pembrolizumab showed an ORR of 34% (95% CI, 26%-43%) with a DOR ranging from 4.4 to 58.5+ months among patients with MSI-H/dMMR colorectal cancer (n = 124). For patients with other MSI-H/dMMR non-colorectal solid tumors (n = 380), the ORR with pembrolizumab was 33% (95% CI, 28%-38%), and the DOR ranged from 1.9+ to 63.9+ months.

Data from the KEYNOTE-158 and KEYNOTE-164 trials revealed that the median duration of exposure to pembrolizumab treatment was 6.2 months (range, 1 day to 53.5 months). In KEYNOTE-051, the median duration of exposure was 2.1 months (range, 1 day to 25 months).

"Today’s approval builds on the 2017 accelerated approval of [pembrolizumab] as the first immunotherapy with a tumor agnostic indication and supports the role of [pembrolizumab as an effective immunotherapy option based on a pan-tumor predictive biomarker," said Scot Ebbinghaus, MD, vice president, global clinical development, Merck Research Laboratories, in the release. “This milestone reflects Merck’s longstanding commitment to biomarker research and personalizing treatment strategies for patients.”

FDA converts to full approval indication for KEYTRUDA® (pembrolizumab) for certain adult and pediatric patients with advanced microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. News release. Merck. March 29, 2023. Accessed March 29, 2023. https://bit.ly/3KixVkQ
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