Endometrial and Gynecologic Cancers, Nivolumab Trial (MSK, 2024)

Overview

Single-center phase 2 clinical trial cohort (NCT03241745) of 35 patients with recurrent or advanced dMMR/MSI-H or hypermutated endometrial carcinoma (UCEC) and ovarian/fallopian tube/peritoneal cancers (OVT) treated with nivolumab at Memorial Sloan Kettering Cancer Center. Dataset designed to identify predictive biomarkers for response to PD-1 blockade beyond dMMR status. Data deposited in cBioPortal as ucec_msk_2024. PMID:38653864

Composition

  • 35 patients enrolled; 34 evaluable for response.
  • 83% endometrioid histology; median age 64 years (range 36–87); 77% White, 11% Black, 6% Asian.
  • Median follow-up: 42.1 months.
  • Cancer types: endometrial carcinoma (UCEC, primary) and ovarian/fallopian tube/peritoneal cancer (OVT).
  • All with dMMR (by IHC loss), MSI-H (by MSK-IMPACT), or hypermutation (≥20 somatic mutations on MSK-IMPACT). PMID:38653864

Assays / panels (linked)

  • MSK-IMPACT — MSI and TMB assessment, somatic profiling.
  • Whole-exome sequencing — 33 of 34 evaluable tumors.
  • Multiplexed immunofluorescence (Vectra system) — 25 patients; 7-marker panel (CD8, PD-1, TOX, PD-L1, PAX8, FoxP3, DAPI) for tumor microenvironment analysis.

Papers using this cohort

  • PMID:38653864 — Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses.

Notable findings derived from this cohort

  • ORR 58.8% (7 CR, 13 PR); PFS24 64.7% (97.5% one-sided CI: 46.5–100%); median PFS 21.6 months. PMID:38653864
  • TMB and PD-L1 expression were not predictive of response within the dMMR-selected population. PMID:38653864
  • Dysfunctional CD8+PD-1+ T cells (P = 0.006) and terminally dysfunctional CD8+PD-1+TOX+ T cells (P = 0.001) were strongly associated with PFS24; a multivariate model combining CD8+PD-1+TOX+ percentage and PD-L1+ cell proximity achieved AUC = 0.897 (P = 0.0007). PMID:38653864
  • MEGF8 mutations enriched in responders (32% vs. 0%; P = 0.027); SETD1B mutations enriched in responders (58% vs. 14%; P = 0.015). PMID:38653864
  • Mechanism of dMMR (genetic vs. epigenetic/MLH1 hypermethylation) did not predict differential nivolumab response (P = 0.43). PMID:38653864

Sources

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