GARNET

Background

GARNET is a phase I, open-label, single-arm basket trial evaluating dostarlimab monotherapy across multiple advanced solid tumor types. The endometrial cancer cohorts — cohort A1 (dMMR/MSI-H) and cohort A2 (MMRp/MSS) — enrolled heavily pretreated patients with advanced or recurrent endometrial carcinoma who had received ≥1 prior platinum-based regimen. GARNET was the pivotal study supporting FDA accelerated approval of dostarlimab for dMMR/MSI-H recurrent endometrial cancer in April 2021.

Interventions and follow up

Regimen: Dostarlimab 500 mg IV q3w × 4 doses then 1000 mg q6w until progression
Cohorts: A1 (dMMR/MSI-H endometrial), A2 (MMRp/MSS endometrial)
Primary endpoint: Objective response rate (ORR) by central blinded independent review
Key secondary: duration of response (DOR)
mFollow-up: 27.6 months (cohort A1)

Results

dMMR/MSI-H (cohort A1): ORR 43.5% (11 CR + 36 PR, n=129; 95% CI 34.8–52.5); median DOR not reached; DCR 58.9%
MMRp/MSS (cohort A2): ORR 14.1% (3 CR + 19 PR, n=161; 95% CI 9.0–20.8); median DOR 19.4 months

Adverse events

Overall: Grade 1–2 TRAEs 75.5%; Grade ≥3 TRAEs 16.6%; discontinuation due to TRAEs 5.5%
Most common any-grade: fatigue (17.6%), diarrhea (13.8%), nausea (13.8%)
Immune-mediated: predominant Grade ≥3 events — hepatitis, adrenal insufficiency, hypothyroidism

Conclusions

Dostarlimab monotherapy achieved a 43.5% ORR with durable responses (median DOR not reached) in heavily pretreated dMMR/MSI-H endometrial carcinoma, supporting the clinical benefit of PD-1 blockade in MMR-deficient tumors and the FDA accelerated approval of dostarlimab for this indication.

Key Limitations

Single-arm design — no randomized comparator; phase I dose-expansion cohort (not a registrational phase II trial); single-arm ORR as basis for accelerated approval requires confirmatory trial (confirmed by RUBY OS update); cohort A1 sample size (n=129) modest; MMRp cohort ORR 14.1% — clinically meaningful signal raising the question of a mechanism beyond MMR status; central MMR testing required; no OS as primary endpoint; OS follow-up too short for mature estimates.

Clinical Context

GARNET led to FDA accelerated approval (April 2021), then conversion to regular approval, of dostarlimab (Jemperli) for dMMR/MSI-H recurrent endometrial cancer. This is the tissue-restricted dMMR endometrial-specific approval, distinct from RUBY's first-line combination approval. The GARNET dMMR ORR (43.5%) is consistent with pembrolizumab in the KEYNOTE-158 endometrial cohort (57.1%) and positions dostarlimab as a second-line option for dMMR patients not receiving dostarlimab first-line.

References