A phase 2 trial of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability (NCT02899793): Updated survival and response analyses

Gynecol Oncol. 2025 Jun:197:110-115. doi: 10.1016/j.ygyno.2025.04.591. Epub 2025 May 6.

Abstract

Objective: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for response to immune checkpoint inhibitors. We report updated results including objective response rate, progression free survival, and overall survival data with 5-year follow-up in recurrent platinum-resistant, MSI-H, endometrial cancer (EC) patients fully sequenced using whole exome sequencing (WES) and treated within a prospective phase II study with pembrolizumab (NCT02899793).

Methods: Tumors from patients with measurable MSI-H/dMMR endometrial cancer confirmed by immunohistochemistry, polymerase chain reaction, and MLH-1 methylation assays were sequenced using whole exome sequencing and the FoundationOne platform for the identification of Lynch, Lynch-like, and MLH-1 methylated characteristics before receiving pembrolizumab 200 mg every 3 weeks for up to 24 months. The primary endpoint was objective response rate (ORR), and secondary endpoints were progression free survival (PFS), and overall survival (OS).

Results: After almost 97 person-years of follow-up, the Lynch-like subgroup (n = 6) of MSI-H/dMMR patients continues to exhibit better ORR than the methylated (n = 18) subgroup (100 % versus 44 %, Fisher's exact P = 0.024), as well as improved PFS (unreached for Lynch-like versus 14.6 months, Log-Rank P = 0.005) and improved OS (unreached for Lynch-like versus 32.6 months, Log-Rank P = 0.058). Toxicity was manageable in both groups of MSI-H patients.

Conclusion: Mature follow-up results continue to suggest the prognostic significance of Lynch-like versus methylated MSI-H/dMMR features in endometrial cancer patients treated with pembrolizumab in terms of ORR, PFS, and OS. Stratification for these translational aspects may be warranted in future clinical trials with immune checkpoint inhibitors in MSI-H/dMMR endometrial cancer patients.

Keywords: Anti-PD1 checkpoint blockade; Clinical trial results; Endometrial cancer; Immunotherapy; Lynch-like MSI-H tumors; Phase 2 clinical trial.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized* / administration & dosage
  • Antibodies, Monoclonal, Humanized* / adverse effects
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antineoplastic Agents, Immunological* / adverse effects
  • Antineoplastic Agents, Immunological* / therapeutic use
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / drug therapy
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
  • DNA Mismatch Repair
  • Endometrial Neoplasms* / drug therapy
  • Endometrial Neoplasms* / genetics
  • Endometrial Neoplasms* / mortality
  • Endometrial Neoplasms* / pathology
  • Female
  • Humans
  • Microsatellite Instability
  • Middle Aged
  • MutL Protein Homolog 1 / genetics
  • Neoplasm Recurrence, Local* / drug therapy
  • Neoplasm Recurrence, Local* / genetics
  • Progression-Free Survival
  • Prospective Studies

Substances

  • pembrolizumab
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents, Immunological
  • MutL Protein Homolog 1
  • MLH1 protein, human

Associated data

  • ClinicalTrials.gov/NCT02899793