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Ref Type Journal Article
PMID (36972026)
Authors Mirza MR, Chase DM, Slomovitz BM, dePont Christensen R, Novák Z, Black D, Gilbert L, Sharma S, Valabrega G, Landrum LM, Hanker LC, Stuckey A, Boere I, Gold MA, Auranen A, Pothuri B, Cibula D, McCourt C, Raspagliesi F, Shahin MS, Gill SE, Monk BJ, Buscema J, Herzog TJ, Copeland LJ, Tian M, He Z, Stevens S, Zografos E, Coleman RL, Powell MA, RUBY Investigators
Title Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.
Journal Vol Issue Date Pages Journal Short Title
The New England journal of medicine 2023 Mar 27 2145-2158 N Engl J Med
URL
Abstract Text Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer.We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed.Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group.Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MLH1 negative endometrial cancer sensitive Carboplatin + Dostarlimab-gxly + Paclitaxel Phase III Actionable In a Phase III trial (RUBY), Jemperli (dostarlimab-gxly) plus carboplatin and paclitaxel followed by Jemperli (dostarlimab-gxly) improved 24-month progression-free survival (61.4% vs 15.7%, HR 0.28, p<0.001) compared to placebo in patients with advanced or recurrent mismatch repair-deficient (dMMR, as indicated by a loss of MLH1, PMS2, MSH2, or MSH6 expression in an FDA-approved IHC test) or microsatellite instability-high (MSI-H) endometrial cancer (PMID: 36972026; NCT03981796). 36972026
MSH6 negative endometrial cancer sensitive Carboplatin + Dostarlimab-gxly + Paclitaxel Phase III Actionable In a Phase III trial (RUBY), Jemperli (dostarlimab-gxly) plus carboplatin and paclitaxel followed by Jemperli (dostarlimab-gxly) improved 24-month progression-free survival (61.4% vs 15.7%, HR 0.28, p<0.001) compared to placebo in patients with advanced or recurrent mismatch repair-deficient (dMMR, as indicated by a loss of MLH1, PMS2, MSH2, or MSH6 expression in an FDA-approved IHC test) or microsatellite instability-high (MSI-H) endometrial cancer (PMID: 36972026; NCT03981796). 36972026