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Pembrolizumab Demonstrates Robust and Durable Antitumour Activity in Patients with Previously Treated Advanced MSI-H/dMMR Endometrial Cancer

Pembrolizumab demonstrated durable antitumour activity with manageable toxicity in patients with advanced microsatellite instability–high (MSI-H) or mismatch repair–deficient endometrial cancer (dMMR). Findings from the KEYNOTE-158 study support the use of pembrolizumab as a treatment option for patients with advanced MSI-H/dMMR endometrial cancer with treatment failure on prior therapy. Efficacy and safety data in a larger number of patients and longer follow-up from the study are published by Dr. David M. O’Malley of the Division of Gynecologic Oncology, The Ohio State University Wexner Medical Center and The James Comprehensive Cancer Center in Columbus, OH, US and colleagues on 6 January 2022 in the Journal of Clinical Oncology.

Approximately 25% to 31% of patients with endometrial cancer have MSI-H/dMMR tumours. MSI-H/dMMR endometrial cancer is associated with a higher neoantigen load and increased CD3-positive, CD8-positive, and PD-1–expressing tumour infiltrating lymphocytes and PD-L1–expressing intraepithelial and peritumoural immune cells compared with microsatellite stable endometrial cancers.

Pembrolizumab first demonstrated antitumour activity in patients with endometrial cancer in the phase Ib KEYNOTE-028 study, in which an objective response rate (ORR) of 13% was observed in a population of patients with PD-L1–positive disease. In a prospective analysis from the KEYNOTE-016 study, pembrolizumab resulted in an OR in 53% of patients with dMMR endometrial cancer.

In the non-randomised, open-label, multicohort, phase II KEYNOTE-158 study of pembrolizumab in multiple types of advanced rare cancers, pembrolizumab demonstrated an ORR of 34.3% among 233 patients with previously treated unresectable or metastatic MSI-H/dMMR non-colorectal cancers. In an initial analysis of outcomes among the first 49 patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158, the ORR was 57%.

In the latest article published in the Journal of Clinical Oncology, the study team reports efficacy and safety data in a larger number of patients with longer follow-up among patients with previously treated advanced MSI-H/dMMR endometrial cancer from KEYNOTE-158 study. Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumour, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles.

The primary endpoint was ORR per RECIST v1.1 by independent central radiologic review. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.

As of 5th October 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population comprising patients who received at least 1 dose of pembrolizumab and had ≥26 weeks of follow-up (N = 79), the median time from first dose to data cut-off was 42.6 months. The ORR was 48% (95% confidence interval [CI] 37 to 60).

Median DoR was not reached (2.9-49.7+ months). Median PFS was 13.1 (95% CI, 4.3 to 34.4) months, and median OS was not reached (95% CI, 27.2 months to not reached).

Among all treated patients, 76% had at least 1 treatment-related adverse event and 12% had grades 3-4. There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients with 7% having grades 3-4, but there were no fatal events.

The authors commented that treatment options after failure of first-line therapy are limited. The current results confirm and extend initial findings from patients with MSI-H/dMMR advanced endometrial cancer enrolled in the KEYNOTE-158 study. The findings support the use of pembrolizumab as a treatment option in this setting.

The study limitation was its single-arm design. Furthermore, too few patients were assessed for PD-L1 status to allow for a meaningful evaluation of outcomes by PD-L1 expression.

The results were presented previously at the ESMO 2021 Congress.

The study was supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Reference

O’Malley DM, Mendonca Bariani G, Cassier PA, et al. Pembrolizumab in Patients With Microsatellite Instability–High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. Journal of Clinical Oncology; Published online 6 January 2022. DOI: 10.1200/JCO.21.01874

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