The FDA has approved pembrolizumab (Keytruda®, Merck) as a monotherapy for patients with advanced endometrial carcinoma that is microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) who have disease progression subsequent to systemic therapy and are not eligible for curative therapy or radiation. In addition, the FDA also approved the VENTANA MMR RxDx Panel (Ventana Medical Systems, Roche Tissue Diagnostics) to be used as a companion diagnostic device for selecting eligible patients with dMMR in solid tumors for treatment using pembrolizumab.
"Approximately 25% to 31% of patients with endometrial cancer have tumors with high levels of MSI-H and dMMR," wrote David M. O'Malley, MD, Professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine, and colleagues, in their published results of the KEYNOTE-158 clinical trial (NCT02628067), on which the approval was based. "The humanized monoclonal anti–programmed cell death protein 1 (PD-1) antibody pembrolizumab has demonstrated antitumor activity in patients with MSI-H/dMMR tumors and in patients with endometrial cancer."
The phase 2, open-label, non-randomized, multicohort trial enrolled 90 patients with unresectable or metastatic MSI-H/dMMR endometrial carcinoma. The patients were put into either Cohort D (11 patients), where their MSI-H/dMMR status would be evaluated retrospectively via polymerase chain reaction (PCR) at a central laboratory, or Cohort K (79 patients), where their status would be evaluated prospectively via PCR and/or immunohistochemistry (IHC) at a local laboratory. Patients received 200 mg of pembrolizumab intravenously on Day 1 of every three-week cycle until unacceptable toxicity or documented disease progression. The primary end point was objective response rate, with secondary end points being duration of response, progression-free survival, and overall survival.
At a median follow-up of 42.6 months, pembrolizumab produced significant antitumor activity, with an objective response rate of 48%. The median duration of response was not met, with approximately two-thirds of patients estimated by the Kaplan-Meier curve to have a response duration of ≥3 years. The median progression-free survival was 13.1 months, and the median overall survival was not reached. The three-year rate of overall survival estimated by Kaplan-Meier was 60%. Following data cutoff, 21 of 38 patients with a confirmed response had an ongoing response.
Adverse reactions experienced by ≥20% of patients who received pembrolizumab as a single dose were fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritis, dyspnea, constipation, pain, abdominal pain, nausea, and hypothyroidism. Immune-mediated adverse reactions are also noted on the label as a precaution, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.
"Pembrolizumab demonstrated robust and durable antitumor activity with manageable toxicity in patients with advanced MSI-H/dMMR endometrial cancer," concluded Dr. O'Malley and colleagues in their report. "These findings support the use of pembrolizumab as a treatment option for patients with advanced MSI-H/dMMR endometrial cancer with treatment failure on prior therapy."
The recommended dose of pembrolizumab is 200 mg every three weeks or 400 mg every six weeks until disease progression, unacceptable toxicity, or up to 24 months.
For More Information
O'Malley DM, Bariani GM, Cassier PA, et al (2022). Pembrolizumab in patients with microsatellite instability–high advanced endometrial cancer: results from the KEYNOTE-158 study. J Clin Oncol, 752-762. DOI:10.1200/JCO.21.01874.
Clinicaltrials.gov (2022). Study of pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-158/KEYNOTE-158). NLM identifier: NCT02628067.
Keytruda® (pembrolizumab) prescribing information (2022). Merck. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125514s110lbl.pdf
US Food and Drug Administration (2022). FDA approves pembrolizumab for advanced endometrial carcinoma. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-endometrial-carcinoma
Image Credit: Nephron. Licensed under CC BY-SA 3.0
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