Presenter: Bhavana Pothuri, Department of Obstetrics and Gynecology, New York University
Co-Authors: Lucy Gilbert, MD, McGill University Health Centre-RI; Anna V. Tinker, MD, BC Cancer; Renaud Sabatier, MD, Department of Medical Oncology, Institut Paoli Calmettes, Aix-Marseille University; Valentina Boni, MD, Centro Integral Oncológico Clara Campal, Hospital Universitario HM Sanchinarro; David M. O’Malley, MD, The Ohio State University–James CCC; Sharad Ghamande, MD, Georgia Cancer Center, Augusta University; Linda Duska, MD, Emily Couric Clinical Cancer Center, University of Virginia; Prafull Ghatage, MD, Department of Gynecological Oncology, University of Calgary; Wei Guo, GlaxoSmithKline; Ellie Im, GlaxoSmithKline; Ana Oaknin, MD, PhD, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology
Background: Dostarlimab (TSR-042) is a humanized programmed death (PD)-1 receptor monoclonal antibody that blocks interaction with the PD-1 ligands. GARNET (NCT02715284) is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in patients with solid tumors.1
Objective: To explore the impact of mismatch repair status at the response to dostarlimab therapy in patients with recurrent or advanced endometrial cancer that progressed during or after a platinum-based chemotherapy regimen.
Methods: This multicenter, open-label, single-arm study included dose-escalation and expansion parts. We report on 2 independent expansion cohorts of patients with recurrent or advanced endometrial cancer associated with (1) mismatch repair-deficient (dMMR) or (2) mismatch repair-proficient (pMMR), as determined by immunohistochemistry (IHC), that progressed during or after a platinum-based chemotherapy regimen. Patients received 500 mg dostarlimab intravenously every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. The primary end points were the objective response rate (ORR) and duration of response (DOR), by blinded independent central review using RECIST v1.1.
Results: In total, 126 patients with dMMR and 145 with pMMR endometrial cancer identified by IHC were enrolled in the study and received dostarlimab. Of these, 103 and 142 patients, respectively, had sufficient follow-up time (24 weeks) for efficacy analyses. The mean follow-up was 16.3 months for patients with dMMR disease and 11.5 months for patients with pMMR disease. The ORR was 44.7% for patients with dMMR and 13.4% for patients with pMMR disease, with complete response seen in 10.7% and 2.1% of patients, respectively. Partial response was recorded in 34.0% of patients with dMMR disease and 11.3% of patients with pMMR disease; stable disease was recorded in 12.6% and 21.8% of patients, respectively. The disease control rate was 57.3% and 35.2%, respectively. Ongoing response was identified in 89.1% of patients with dMMR disease and 63.2% of patients with pMMR. The median DOR and overall survival were not reached. The 18-month DOR was 79.2% and 61.3%, respectively. The most common grade ≥3 treatment-emergent adverse events (AEs; N = 271) were anemia (12.2%), abdominal pain (4.8%), and dyspnea (4.1%). The most common grade ≥3 immune-related AEs were diarrhea, aspartate aminotransferase increased, and alanine aminotransferase increased (1.8% each). No treatment-related deaths occurred.
Conclusion: Dostarlimab demonstrated durable antitumor activity in patients with advanced or recurrent dMMR or pMMR endometrial cancer. dMMR status by IHC was associated with a higher response rate. No new safety signals were detected. These cohorts represent the largest prospective evaluation of a PD-1 (or PD-L1) therapy in endometrial cancer to date.
- Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti-programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: a nonrandomized phase 1 clinical trial. JAMA Oncol. 2020;6:1-7.