Adding pembrolizumab to cCRT ups PFS in high-risk locally advanced cervical cancer

In patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer, adding pembrolizumab to concurrent chemoradiotherapy (cCRT) significantly improves progression-free survival (PFS) vs cCRT alone, according to results of the phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study presented at European Society for Medical Oncology Congress 2023 (ESMO 2023).

“This is very exciting as it is the first positive study in locally advanced cervical cancer since 1999,” commented discussant Professor Bradley J. Monk of the University of Arizona College of Medicine, Creighton University School of Medicine, HonorHealth Research Institute, Phenox, Arizona, US.

“Our data support pembrolizumab plus cCRT as a new potential [first-line] standard of care for patients with high-risk locally advanced cervical cancer,” said investigator Dr Domenica Lorusso of Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of Sacred Heart, Rome, Italy. [Lorusso D, et al, ESMO 2023, abstract LBA38]

The trial included 1,060 patients with stage IB2–IIB node-positive or stage III–IVA disease based on the International Federation of Gynecology and Obstetrics (FIGO) 2014 criteria. The patients, recruited from 30 countries, were randomized 1:1 to receive 5 cycles of pembrolizumab 200 mg or placebo Q3W plus cCRT, followed by 15 cycles of pembrolizumab 400 mg or placebo Q6W. cCRT consisted of 5 cycles of cisplatin (40 mg/m² QW) plus external-beam radiotherapy (EBRT) followed by brachytherapy. Primary endpoints were PFS by investigator assessment and overall survival (OS).

At baseline, median age was 49 years in the pembrolizumab arm (n=529) and 50 years in the placebo arm (n=531). Asian patients accounted for 29.3 percent and 27.9 percent of the respective arms. PD-L1 combined positive score was ≥1 in 94.9 percent and 93.8 percent of the patients, respectively. Squamous cell carcinoma was the dominant histological type (81.9 percent and 84.9 percent, respectively), and lymph node involvement was present in 84.1 percent and 82.5 percent of the patients, respectively.

“High-quality radiotherapy was delivered, with >88 percent of patients in each arm receiving intensity-modulated radiotherapy or volumetric modulated arc therapy. A planned total radiotherapy dose of ≥70 Gy was delivered to about 91 percent of patients in each arm,” said Lorusso.

“Pembrolizumab showed a statistically significant and clinically meaningful improvement in PFS vs placebo at the first interim analysis, after a median follow-up of 17.9 months,” reported Lorusso. “PFS rate at 24 months was 67.8 percent in the pembrolizumab arm vs 57.3 percent in the placebo arm, with a hazard ratio [HR] of 0.70 [95 percent confidence interval (CI), 0.55–0.89; p=0.0020]. Median PFS was not reached in either arm.”

“The PFS benefit with pembrolizumab was consistent across all prespecified subgroups,” she added.

OS data, with only 42.9 percent maturity, showed a trend in favour of pembrolizumab vs placebo (24-month OS rate, 87.2 percent vs 80.8 percent; median, not reached in either arm; HR, 0.73; 95 percent CI, 0.49–1.07).

Objective response rate was 79.3 percent with pembrolizumab vs 75.9 percent with placebo (difference, 3.4 percent; 95 percent CI, -1.7 to 8.5), while 12-month duration of response rate was 81.4 percent vs 77.3 percent.

“The safety profile of pembrolizumab plus cCRT was manageable and as expected,” noted Lurosso.

Grade 3/4 treatment-related adverse events (AEs) were reported in 67.0 percent vs 60.6 percent of patients in the pembrolizumab vs placebo arm, while serious treatment-related AEs were reported in 17.2 percent vs 12.3 percent of patients. These AEs led to discontinuation of any treatment in 15.3 percent vs 23.6 percent of patients, and discontinuation of all treatment in none vs 0.2 percent of patients.

Grade 3/4 immune-mediated AEs were reported in 4.2 percent vs 1.1 percent of patients. However, <2 percent of pembrolizumab-treated patients experienced grade 3/4 thyroid dysfunction.

“The addition of pembrolizumab to cCRT showed no negative impact on patient-reported outcomes, including quality of life,” Lurosso added.