Overall survival benefit of pembrolizumab plus chemoradiotherapy for patients with high-risk locally advanced cervical cancer

Abstract

The addition of pembrolizumab to chemoradiotherapy for patients with high-risk locally advanced cervical cancer significantly improved overall survival (OS), according to the second interim analysis of the phase 3 KEYNOTE-A18 trial published in The Lancet.¹

The finding provides further support for adding pembrolizumab to chemoradiotherapy in this setting, and it builds on previously reported results showing a significant improvement in progression-free survival.² These latter findings resulted in the US Food and Drug Administration’s approval of this regimen for patients with high-risk, International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III–IVA cervical cancer.³

Domenica Lorusso, MD, PhD, director of the Gynecological Oncology Unit at Humanitas Hospital San Pio X in Milan, Italy, and lead author of the study, first presented the results at the 2024 annual meeting of the European Society for Medical Oncology.⁴

At a median follow-up of 29.9 months, the 36-month OS rate was 82.6% for patients treated with pembrolizumab and chemoradiotherapy and 74.8% for patients treated with chemoradiotherapy alone, with a hazard ratio (HR) for death of 0.67 (95% CI, 0.50–0.90; p = .004).

The trial included 1060 newly diagnosed patients with high-risk locally advanced cervical cancer randomized 1:1 to five cycles of pembrolizumab (200 mg) with concurrent chemoradiotherapy followed by 15 cycles of pembrolizumab (400 mg) (the investigational arm) or five cycles of a placebo with concurrent chemoradiotherapy followed by 15 cycles of a placebo (the control arm). Chemoradiotherapy included five cycles of cisplatin (40 mg/m²) once weekly plus external-beam radiotherapy followed by brachytherapy.

At the time of randomization, patients were stratified by the planned type of external-beam radiotherapy (intensity-modulated radiotherapy [IMRT] or volumetric modulated arc therapy [VMAT] vs. non-IMRT or non-VMAT), the stage of cervical cancer at screening, and the planned total radiotherapy dose (<70 vs. ≥70 Gy).

The benefit of adding pembrolizumab to chemoradiotherapy generally was consistent among prespecified subgroups. For example, the HR for death was 0.89 (95% CI, 0.55–1.44) for patients at FIGO stages IB2–IIB and 0.57 (95% CI, 0.39–0.83) for patients at FIGO stages III–IVA.

Grade 3 or higher treatment-related adverse events were seen in 78% and 70% of the patients in the investigational and placebo arms, respectively. The most common event was anemia, with decreases in both white blood cell counts and neutrophil counts. Potential immune-mediated adverse events occurred in 39% and 17% of the patients, respectively.

“In the context of modern and high-quality radiotherapy that is curative in 75% of patients, the addition of pembrolizumab further increases overall survival by 8%,” says Dr Lorusso. “This should be considered the next standard of care.”