Overview
Overview: A single-arm phase 2 clinical trial (NCT03241745) at MSK evaluating the PD-1 inhibitor nivolumab in dMMR uterine and ovarian cancers, with an emphasis on identifying biomarkers of response.
Trial design & outcomes:
- 35 patients with dMMR uterine or ovarian cancers were enrolled, with co-primary endpoints of objective response rate (ORR) and progression-free survival at 24 weeks (PFS24).
- The ORR was 58.8% and the PFS24 rate was 64.7%, meeting both pre-specified endpoints. The disease control rate was 73.5%, and at a median follow-up of 42.1 months, median overall survival was not reached.
- 91% of patients experienced a treatment-related adverse event, most grade 1–2; 29% had grade 3–4 events, and no grade 5 events occurred.
Data generated/used for biomarker analyses:
- Tumor immune profiling examining dysfunctional T cell populations (CD8+PD-1+ and CD8+PD-1+TOX+) and their interaction with PD-L1+ cells, which were independently associated with PFS24.
- Somatic mutation analysis, identifying that the presence of MEGF8 or SETD1B mutations was associated with PFS24 response.
- Clinical outcomes data including ORR, PFS, OS, duration of response, and safety.
Key takeaway: The trial met its co-primary endpoints early, and the exploratory analyses highlight several genetic and tumor microenvironment parameters — including T cell dysfunction states and specific somatic mutations — associated with response to PD-1 blockade in dMMR gynecologic cancers, with the authors calling for validation in larger cohorts.