Pembrolizumab Plus Chemotherapy in Advanced Endometrial Cancer

Endometrial cancer is one of the only cancer types for which both incidence and mortality are rising, and survival has not improved during the past 4 decades. First-line treatment for advanced or recurrent endometrial cancer typically involves paclitaxel plus carboplatin. Immune checkpoint inhibitors such as pembrolizumab have shown promising results when administered alongside cytotoxic chemotherapy inmultiple types of solid tumors and have shown efficacy as a monotherapy as second-line treatment for mismatch repair-deficient (dMMR) endometrial cancer with high microsatellite instability. This phase 3, international, double-blind, randomized controlled trial aimed to evaluate standard-of-care treatment with paclitaxel plus carboplatin plus either pembrolizumab or placebo in patients with advanced or recurrent endometrial cancer. Two independent cohorts were evaluated: patients with dMMR disease and those with mismatch repair-proficient (pMMR) disease. A total of 395 sites in 4 countries recruited adult women with confirmed advanced-stage, metastatic, or recurrent endometrial cancer of any histologic subtype other than carcinosarcoma and a chemotherapy-free interval of 12months. Patientswere randomly assigned in a 1:1 ratio to paclitaxel plus carboplatin along with either pembrolizumab (200 mg intravenously every 3 weeks) or placebo for 6 cycles, followed by pembrolizumab or placebo maintenance every 6 weeks for up to 14 cycles. The primary study outcome was progression-free survival according to RECIST criteria. Secondary outcomes included safety, overall survival, and quality of life assessed using validated questionnaires. Between July 2019 andDecember 2022, a total of 816 patientswere recruited. The dMMRcohort included 225 women, whereas the pMMR cohort included 591. A total of 588 patients were available for evaluation of efficacy. The median follow-up was 12 months in the dMMR cohort and 7.9 months in the pMMR cohort, and at the time of follow-up, either pembrolizumab or placebo was discontinued in 57% of patients largely due to disease progression. Among dMMR patients at 12 months, the risk of disease progression or death was 70% lower with pembrolizumab than with placebo (hazard ratio, 0.30; 95% confidence interval, 0.19-0.48; P < 0.001). Among pMMR patients, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio 0.54; 95% confidence interval, 0.41-0.71; P < 0.001). No significant difference in quality-of-life metrics was reported at 6 weeks following randomization. Adverse events were recorded in more than 90% of all patients, and grade 3 or higher adverse events were recorded in 63.3% and 47.2% of patients in the dMMR pembrolizumab and placebo groups, respectively. Adverse events of grade 3 or greater were recorded in 55.1% and 45.3% of pMMR pembrolizumab and placebo groups, respectively. The results of this phase 3 trial found that the addition of pembrolizumab to carboplatin plus paclitaxel followed by pembrolizumab maintenance resulted in a 70% lower risk of disease progression or death in patients in with dMMR and 46% in patients with pMMR endometrial cancer compared with placebo.

Automated summary

Endometrial cancer is a type of cancer with increasing incidence and mortality rates, but with no improvement in survival over the past 40 years. Standard first-line treatment involves paclitaxel plus carboplatin. Immune checkpoint inhibitors like pembrolizumab have shown promise in combination with chemotherapy for various solid tumors, and as a second-line monotherapy for dMMR endometrial cancer. This phase 3 trial aimed to evaluate the efficacy of paclitaxel plus carboplatin with pembrolizumab or placebo in patients with advanced or recurrent endometrial cancer.