First-line pembrolizumab versus carboplatin plus paclitaxel in participants with mismatch repair-deficient advanced or recurrent endometrial cancer (KEYNOTE-C93/GOG-3064/ENGOT-en15): interim analysis

A need exists for first-line chemotherapy-free options in advanced or recurrent endometrial cancer. We therefore assessed the efficacy, quality of life, and safety of first-line pembrolizumab versus carboplatin plus paclitaxel in mismatch repair-deficient (dMMR) advanced or recurrent endometrial cancer. The KEYNOTE-C93/GOG-3064/ENGOT-en15 multicentre, open-label, randomised, active-comparator controlled, phase 3 trial was conducted at 122 centres in 24 countries in the Americas, Asia, Europe, and Oceania. Adult participants (≥18 years) with inoperable, stage III or IV, persistent, advanced, or recurrent dMMR endometrial cancer were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles or intravenous carboplatin area under the curve 5 mg/mL or 6 mg/mL per min plus paclitaxel 175 mg/m 2 on day 1 of each 3-week cycle for six cycles. Randomisation was stratified by disease status, histology, and previous receipt of (neo)adjuvant chemotherapy. Primary endpoints were progression-free survival per RECIST version 1.1, by blinded independent central review, and overall survival. This trial is registered at ClinicalTrials.gov, NCT05173987, and is ongoing. Between Feb 22, 2022, and Dec 12, 2023, 299 participants were assigned to pembrolizumab (n=149) or carboplatin plus paclitaxel (n=150). At the cutoff for the prespecified interim analysis in the intention-to-treat population (April 24, 2026), median progression-free survival was 38·2 months (95% CI 17·9 months-not reached) in the pembrolizumab group versus 8·4 months (6·8-10·4) in the carboplatin plus paclitaxel group (hazard ratio [HR] 0·57, 95% CI 0·42-0·79; p=0·0002). Estimated progression-free survival was 75% (95% CI 67-81) versus 76% (68-82) at 6 months, 67% (59-74) versus 40% (32-48) at 12 months, and 53% (44-61) versus 30% (22-38) at 36 months. The prespecified statistical significance criterion for overall survival was not met at the interim analysis (medians not reached; HR 0·77, 95% CI 0·52-1·15; p=0·10). Grade 3 or higher treatment-related adverse events occurred in 27 (18%) of 149 participants in the pembrolizumab group and 73 (51%) of 144 in the carboplatin plus paclitaxel group. Treatment-related adverse events of any grade that occurred in at least 25% of participants in either group included alopecia (three [2%] of 149 in the pembrolizumab group, 72 [50%] of 144 in the carboplatin plus paclitaxel group), anaemia (seven [5%], 71 [49%]), nausea (seven [5%], 41 [28%]), decreased neutrophil count (five [3%], 40 [28%]), peripheral neuropathy (none, 38 [26%]), and fatigue (20 [13%], 37 [26%]). Treatment-related adverse events led to treatment discontinuation in 14 (9%) of 149 participants in the pembrolizumab group and 21 (15%) of 144 participants in the carboplatin plus paclitaxel group; they resulted in death in two participants in the pembrolizumab group (hepatic failure and bacterial meningitis [n=1 each]) and one participant in the carboplatin plus paclitaxel group (pulmonary embolism). First-line pembrolizumab showed a statistically significant and clinically meaningful improvement in progression-free survival, with lower frequency of overall and grade 3 or above treatment-related adverse events. The study did not compare pembrolizumab monotherapy with the current standard of care (immunotherapy plus chemotherapy). Merck Sharp & Dohme, a subsidiary of Merck & Co.