Pembrolizumab or Placebo With Chemoradiotherapy Followed by Pembrolizumab or Placebo for Newly Diagnosed, High-Risk, Locally Advanced Cervical Cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): Overall Survival Results From a Randomized, Double-blind, Placebo-Controlled, Phase 3 Trial

An estimated 660,000 new cases of cervical cancer were reported globally in 2022, with 350,000 deaths attributable to the disease. Eternal beam radiotherapy with concurrent chemotherapy and subsequent brachytherapy is the current standard of care, and few advances have been made in recent years to increase the effectiveness of treatments for cervical cancer. Those with high-risk, locally advanced cervical cancer often face poor outcomes even with treatment, which shows an additional need to advance treatment options for this population. This study was designed to report the overall survival results from the second analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial evaluating the effectiveness of pembrolizumab in combination with or after chemoradiotherapy compared with chemoradiotherapy alone. The first analysis of this study showed a statistically significant and clinically meaningful improvement in progression-free survival of advanced cervical cancer. This is an ongoing, randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 176 sites in 30 countries in Asia, Australia, Europe, and North and SouthAmerica, with methodology previously published. Inclusion criteria were 18 years or older, newly diagnosed with cervical cancer, high-risk (FIGO [International Federation of Gynaecology and Obstetrics] 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix, adequate organ function, and provision of a tumor sample collected froma core, incisional, or excisional biopsy. Exclusion criteria were other histological cervical cancer subtypes, FIGO 2014 stage IVB disease, previous hysterectomy, and previous systemic therapy, immunotherapy, definitive surgery, or radiation. The primary outcomes of the study are progression-free survival assessed via RECIST version 1.1 or histopathological confirmation of suspected progression, as well as overall survival defined as time from randomization to time of death from any cause. Between June 9, 2020, and December 15, 2022, there were 1060 individuals who underwent randomization, with 529 in the pembrolizumab group and 531 in the control group. All but 2 patients, one from each group, began study treatment, 428 completed study treatment, and 459 discontinued study treatment before the second interim analysis. Of those who discontinued study treatment, many attributed this to radiographic progression or adverse events; at the time of second analysis, 171 individuals were still participating in study treatment. At the second interim cutoff date of January 8, 2024, 75 individuals in the pembrolizumab group and 109 individuals in the control group had died (hazard ratio [HR], 0.67; 95% confidence interval, 0.50-0.90; P = 0.0040). This showed a statistically significant improvement in overall survival, although median overall survival was not reached for either group. At the cutoff date, 155 individuals in the pembrolizumab group and 210 individuals in the control group had a progression-free survival event, with an HR reported at 0.68 (95% confidence interval, 0.56-0.84). All previously specified subgroups showed an HR less than 1 for disease progression or death comparing the pembrolizumab group to the control. Adverse events associated with treatment occurred in all patients in the pembrolizumab group and in 99% of patients in the control group. These results indicate a continued statistically significant and clinically meaningful improvement in overall survival rate in individuals treated with pembrolizumab in conjunction with chemoradiotherapy when compared with chemoradiotherapy alone. The addition of pembrolizumab decreased the likelihood of both death and disease progression. Future studies should focus on updating the FIGO staging to the 2018 guidelines, which are current, as well as more statistical power devoted to reproducing and validating the results of subgroup analyses.