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): A Randomized, Double-Blind, Phase 3 Clinical Trial

Abstract

Prognosis for locally advanced cervical cancer is poor, with 5-year progression-free survival (PFS) and overall survival ranging from 47% to 80%. For the past several decades, treatment has included external beam radiotherapy with concurrent chemotherapy followed by brachytherapy, and novel therapeutic options are needed. Pembrolizumab is an anti–programmed cell death protein 1 monoclonal antibody that has demonstrated some efficacy and safety in patients with persistent, recurrent, or metastatic cervical cancer.

The ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial sought to evaluate whether pembrolizumab, when administered in combination with and after chemotherapy, improves efficacy compared with chemoradiotherapy alone in newly diagnosed, high-risk, locally advanced cervical cancer. This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 176 medical centers in 30 countries. Adult patients with newly diagnosed, treatment-naive, high-risk stage, locally advanced, histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix were eligible for enrollment. Participants were randomized in a 1:1 ratio to either 5 cycles of pembrolizumab plus chemoradiotherapy followed by 15 cycles pembrolizumab (pembrolizumab-chemoradiotherapy group) or 5 cycles of placebo plus chemoradiotherapy followed by 15 cycles of placebo (placebo-chemoradiotherapy group). The 2 primary endpoints are PFS and overall survival, assessed in an intention-to-treat analysis and estimated using the nonparametric Kaplan-Meier method.

A total of 1060 participants were randomized between June 2020 and December 2022 to receive pembrolizumab-chemoradiotherapy (n = 529) or placebo-chemoradiotherapy (n = 531). Two participants, one in each group, did not receive study treatment. At the data cutoff, the median study follow-up was 17.9 months (interquartile range, 11.3–22.3 months) in both treatment groups, and 58% and 55% of participants in the pembrolizumab-chemoradiotherapy and placebo-chemoradiotherapy groups, respectively, remained on study treatment. A total of 115 participants (22%) in the pembrolizumab-chemoradiotherapy group and 154 (29%) in the placebo-chemoradiotherapy group had a PFS event (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.55–0.89; 1-sided P = 0.0020). Median PFS was not reached in either group, and the PFS rates at 24 months were 68% (95% CI, 62%–73%) in the pembrolizumab-chemoradiotherapy group and 57% (51%–63%) in the placebo-chemoradiotherapy group. The HR for disease progression or death was 0.72 (0.56–0.92) among participants with programmed cell death protein 1 ligand–positive tumors and 0.61 (0.18–2.07) among participants with programmed cell death protein 1 ligand–negative tumors. Overall survival at 24 months was 87% (82%–91%) in the pembrolizumab-chemoradiotherapy group and 81% (75–86) in the placebo-chemoradiotherapy group (HR for death 0.73; 95% CI, 0.49–1.07). Grade 3 or higher adverse events occurred in 75% of participants in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group.

The results of this phase 3, randomized, double-blind clinical trial suggest pembrolizumab plus chemoradiotherapy significantly improves PFS in patients with newly diagnosed, high-risk, locally advanced cervical cancer.