Platinum-based chemotherapy plus bevacizumab and paclitaxel is the standard first-line therapy for persistent, recurrent, or metastatic cervical cancer. The phase 2 KEYNOTE-158 trial found evidence of a response to pembrolizumab among patients with programmed death ligand-1 (PD-L1) positive cervical cancer.This double-blind phase 3 trial (KEYNOTE-826) evaluated the efficacy and safety of pembrolizumab or placebo in addition to platinum-based chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Patients older than 18 years who had not been treated with systemic chemotherapy and had not received radiotherapy within the 2 weeks before randomization were eligible. PD-L1 expression was measured according to combined positive score, defined as the number of PD-L1-staining cells in a tumor sample divided by the total number of viable tumor cells, multiplied by 100. Patients were enrolled at 151 sites in 19 countries and randomized in a 1:1 ratio to pembrolizumab (200 mg) or placebo every 3 weeks for up to 35 cycles. All patients received paclitaxel and the investigators' choice of cisplatin or carboplatin every 3 weeks, whereas bevacizumab was given according to local practice at the investigator's discretion. The primary outcomes were overall survival and progression-free survival. Superiority of pembrolizumab to placebo was tested in all patients with PD-L1 combined positive score of 1 or more, combined positive score of 10 or more, and in the intention-to-treat population.A total of 617 patients were randomized between November 2018 and January 2020, with 308 in the pembrolizumab group and 309 in the placebo group. A total of 548 patients had a PD-L1 combined positive score of 1 or more (273 in pembrolizumab group, 275 in placebo group) and 317 patients with a score of 10 or more (158 in pembrolizumab group, 159 in placebo group). The median follow-up time at first interim analysis was 22.0 months (15.1 to 29.4). The median treatment duration was 10.0 months in the pembrolizumab group and 7.7 months in the placebo group. Progression-free survival was significantly prolonged in the pembrolizumab group compared with the placebo group in patients with a PD-L1 score of 1 or more (median, 10.4 months [95% confidence interval (CI), 9.7-12.3] vs 8.2 months [95% CI, 6.3-8.5 months]), in patients with a PD-L1 score of 10 or more (median, 10.4 months [95% CI, 8.9-15.1] vs 8.1 months [95% CI, 6.2-8.8]), and in the intention-to-treat population (median, 10.4 months [95% CI, 9.1-12.1] vs 8.2 months [95% CI,). Overall survival was likewise significantly longer in the pembrolizumab group compared with the placebo group among patients with a PD-L1 score of 1 or more (24-month estimate of patients alive, 53.0%; 95% CI, 34.9-48.2), a score of 10 or more (24-month estimate, 54.4%; 95% CI, 45.5-62.4), and in the intention-to-treat population (24-month estimate, 50.4%; 95% CI, 43.8-56.6). Serious adverse events occurred in 49.8% of the patients in the pembrolizumab group and 42.4...

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 MEASURESThe 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. RESULTSAs 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 RELEVANCEIn 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.

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BackgroundDostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab.MethodsGARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review.ResultsScreening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5–22.1) for cohort A1 and 11.5 months (IQR 11.0–25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1–2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab.ConclusionDostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile.Trial registration numberNCT02715284.

Contributors: All the authors were involved in initial conception of the paper, interpreted the evidence involved in the review, drafted and critically revised the manuscript, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.