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

Abstract

Importance: Deficient mismatch mutation repair mechanisms may sensitize endometrial cancers to anti-programmed death 1 (PD-1) therapies. Dostarlimab (TSR-042) is an investigational anti-PD-1 antibody that binds with high affinity to the PD-1 receptor.

Objective: To assess the antitumor activity and safety of dostarlimab for patients with deficient mismatch repair endometrial cancer.

Design, setting, and participants: This ongoing, open-label, single-group, multicenter study began part 1 on March 7, 2016, and began enrolling patients with deficient mismatch mutation repair endometrial cancer on May 8, 2017. Median follow-up was 11.2 months (range, 0.03 [ongoing] to 22.11 [ongoing] months; based on radiological assessments). Statistical analysis was performed July 8 to August 9, 2019.

Interventions: Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, treatment discontinuation, or withdrawal.

Main outcomes and measures: The primary end point was objective response rate and duration of response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.

Results: As of the data cutoff, 104 women (median age, 64.0 years [range, 38-80 years]) with deficient mismatch mutation repair endometrial cancers were enrolled and treated with dostarlimab. Of these, 71 had measurable disease at baseline and at 6 months or more of follow-up and were included in the analysis. There was a confirmed response in 30 patients (objective response rate, 42.3%; 95% CI, 30.6%-54.6%); 9 patients (12.7%) had a confirmed complete response, and 21 patients (29.6%) had a confirmed partial response. Responses were durable; the median duration of response was not reached (median follow-up was 11.2 months). The estimated likelihood of maintaining a response was 96.4% at 6 months and 76.8% at 12 months. Anemia (3 of 104 [2.9%]), colitis (2 of 104 [1.9%]), and diarrhea (2 of 104 [1.9%]) were the most common grade 3 or higher treatment-related adverse events.

Conclusions and relevance: In this nonrandomized trial, dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch mutation repair endometrial cancers after prior platinum-based chemotherapy.

Trial registration: ClinicalTrials.gov identifier: NCT02715284.

Figure 1.. Enrollment and Outcomes

Figure 2.. Tumor Best Percentage Change in Lesion Size From Baseline in the Efficacy-Evaluable Population (n = 71) and Duration of Treatment in Responders (n = 30)

A, Waterfall plot shows the maximum percentage change in target lesions from baseline, indicated by bar length; best overall response is indicated by color coding of bars and includes assessment of target, nontarget, and new lesions. B, Swimmer lane of duration of treatment for patients with an objective response. Patients were permitted to remain receiving treatment after progression if they were considered to be benefiting from treatment. (Two examples of this can be seen in lanes 2 and 5; in both cases, patients had progressive disease [PD] based on Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1] but were considered to be still responding per immune-related RECIST and continued receiving dostarlimab. The patient represented in lane 5 had progression based on immune-related RECIST on May 15, 2019.) Computed tomography scans after treatment discontinuation were used to monitor disease for follow-up. All assessments are based on blinded independent centralized review per RECIST v1.1. Ongoing indicates that patients were continuing to receive treatment at time of the data cutoff. CR indicates complete response; NE, not evaluable; PR, partial response; and SD, stable disease.