As reported in The Lancet Oncology by Domenica Lorusso, MD, PhD, and colleagues, the phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial has shown that the addition of pembrolizumab to chemoradiotherapy improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer.

Data from the trial supported the January 2024 approval of pembrolizumab with chemoradiotherapy in patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III to IVA disease on the basis of significantly improved progression-free survival.

Domenica Lorusso, MD, PhD

Study Details

The double-blind trial included 1,060 patients with FIGO stage IB2 to IIB node-positive to stage III to IVA disease from sites in 30 countries. They were randomly assigned between June 2020 and December 2022 to receive 5 cycles of pembrolizumab at 200 mg (n = 529) or placebo (n = 531) every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab at 400 mg or placebo every 6 weeks. Chemoradiotherapy included five cycles of cisplatin at 40 mg/m² once weekly plus external-beam radiotherapy followed by brachytherapy. A total of 598 patients (56.4%) had stage III to IVA disease. The primary endpoints of the study were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.

Efficacy Outcomes

At data cutoff in January 2023, median follow-up was 17.9 months (interquartile range = 11.3–22.3 months) in both treatment groups. Median progression-free survival was not reached in either group. Estimated rates at 24 months were 68% (95% confidence interval [CI] = 62%–73%) in the pembrolizumab/chemoradiotherapy group vs 57% (95% CI = 51%–63%) in the placebo/chemoradiotherapy group (hazard ratio [HR] = 0.70, 95% CI = 0.55–0.89, P = .0020).

Among 294 vs 304 patients with stage III to IVA disease, the hazard ratio for the pembrolizumab/chemotherapy group vs the placebo/chemotherapy group for progression-free survival was 0.58 (95% CI = 0.42–0.80). Among 235 vs 227 patients with stage IB2 to IIB disease, the hazard ratio was 0.91 (95% CI = 0.63–1.31).

At time of analysis of overall survival (42.9% information fraction), estimated overall survival at 24 months among all patients was 87% (95% CI = 82%–91%) in the pembrolizumab/chemoradiotherapy group vs 81% (95% CI =75%–86%) in the placebo/chemoradiotherapy group (HR = 0.73, 95% CI = 0.49–1.07).

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 67% of patients in the pembrolizumab/chemoradiotherapy group vs 61% of those in the placebo/chemoradiotherapy group. The most common in the pembrolizumab/chemoradiotherapy group were anemia (19% vs 16% in control group), decreased white blood cells (19% vs 21%), and decreased neutrophils (15% vs 15%). Serious treatment-related adverse events occurred in 17% vs 12% of patients. Treatment-related adverse events led to discontinuation of any treatment component in 15% vs 13% of patients. Any grade immune-related adverse events in the pembrolizumab/chemoradiotherapy group included hypothyroidism in 19% and hyperthyroidism in 11%. Treatment-related adverse events led to death in two patients in the pembrolizumab/chemoradiotherapy group (due to immune-mediated gastritis and large intestine perforation) and in two in the placebo/chemoradiotherapy group (due to bone marrow failure and neutropenic colitis).

The investigators concluded, “Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer.”

Dr. Lorusso, of the Gynaecology Oncology Unit, Fondazione Policlinico Universitario A Gemelli IRCCS and Catholic University of Sacred Heart, Rome, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funding by Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit thelancet.com.