Pembrolizumab/CCRT Yields Significant Efficacy in Advanced Cervical Cancer

"These data support pembrolizumab plus [chemoradiotherapy] as the new standard of care for patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer, and as an appropriate control arm in future clinical trials," according to study author Linda Rosenbaum Duska, MD, MPH.

A statistically significant and/or clinically meaningful improvement in efficacy was noted when pembrolizumab (Keytruda) plus chemoradiotherapy followed by pembrolizumab was used to treat patients with newly diagnosed, previously untreated, high-risk, stage IB to IIB with node-positive disease or stage III to IVA disease regardless of nodal status in locally advanced cervical cancer, according to the second interim analysis findings from the phase 3 KEYNOTE-A18 trial (NCT04221945) presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO).¹

The progression-free survival (PFS) data at the second interim analysis showed that 29.3% of patients had an event in the pembrolizumab arm vs 39.5% in the placebo arm. The median PFS was not reached (NR) in either arm (HR, 0.68; 95% CI, 0.56-0.84). The 36-month rate was 62.7% (95% CI, 56.4%-68.4%) vs 54.5% (95% CI, 49.3%-59.3%).

For comparison, at the first interim analysis, PFS events were noted in 21.7% of the pembrolizumab arm vs 29.9% of the placebo arm with a median PFS of NR in both arms (HR, 0.70; 95% CI, 0.55-0.89; P = .0020). The 24-month rates were 67.8% (95% CI, 61.8%-73.0%) vs 57.3% (95% CI, 51.2%-62.9%).

At the second interim analysis, the median overall survival (OS) was NR in both arms with 14.2% of patients in the pembrolizumab arm having an event vs 20.5% in the placebo arm (HR, 0.67; 95% CI, 0.50-0.90; P = .0040). The 36-month rates were 82.6% (95% CI, 78.4%-86.1%) vs 74.8% (95% CI, 70.1%-78.8%), respectively.

The median time from randomization to subsequent disease progression after beginning a new therapy or death by any cause (PFS2) was NR in both arms, with events occurring in 15.3% of the pembrolizumab arm vs 24.3% in the placebo arm (HR, 0.60; 95% CI, 0.46-0.80).

“These data support pembrolizumab plus [chemoradiotherapy] as the new standard of care for patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer, and as an appropriate control arm in future clinical trials,” Linda Rosenbaum Duska, MD, MPH, a gynecologic oncologist at the University of Virginia Health, stated during the presentation.

A total of 1060 patients were randomly assigned 1:1 to receive either 40 mg/m² of cisplatin weekly for 5 cycles and external beam radiation therapy (EBRT) followed by brachytherapy plus 200 mg of pembrolizumab every 3 weeks for 5 cycles followed by 400 mg of pembrolizumab every 6 weeks for 15 cycles, or 40 mg/m² of cisplatin weekly for 5 cycles and EBRT followed by brachytherapy plus placebo every 3 weeks for 5 cycles followed by placebo every 6 weeks for 15 cycles.

The primary end points were PFS by investigator or histopathologic confirmation and OS, and the secondary end point was PFS2.

The median age was 49 years old in the pembrolizumab arm vs 50 years old in the placebo arm, 48.0% vs 49.7% were White, 29.5% vs 27.9% were Asian, and 14.7% vs 16.2% were multiple races. A PD-L1 combined positive score (CPS) of less than 1 was noted in 4.2% vs 5.3%, 94.9% vs 93.8% had a CPS of 1 or more, and 0.9% vs 0.9% had missing CPS.

Stages at screening included 44.0% vs 42.6% having IB2 to IIB and 56.0% vs 57.4% having III to IVA. Additionally, 62.2% vs 61.0% had positive pelvic only lymph node involvement, 2.6% vs 1.9% had positive para-aortic only involvement, 19.7% vs 19.6% had positive pelvic and para-aortic involvement, and 15.9% vs 17.5% did not have positive involvement at either site.

Intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) was noted in 88.7% of patients in the pembrolizumab arm and 88.5% in the placebo arm, with 11.3% vs 11.5% not having IMRT or VMAT. The planned total radiation dose was less than 70 Gy for 8.9% of patients in the pembrolizumab arm vs 8.7% in the placebo arm, and 70 Gy or more was reported in 91.1% vs 91.3%.

The median number of cycles of pembrolizumab or placebo was 17 vs 16, respectively, with 5 cycles vs 5 cycles for cisplatin in each arm. The overall median treatment time was 52 days for radiation therapy in the pembrolizumab arm vs 52 days in the placebo arm. The median duration of EBRT was 37 days vs 37 days, and the median duration of brachytherapy was 12 days vs 12 days.

Grade 3 or higher adverse effects (AEs) occurred in 78.2% of the pembrolizumab arm vs 70.0% of the placebo arm, treatment-related AEs (TRAEs) in 69.1% vs 61.3%, and immune-mediated AEs in 4.7% vs 1.3%. Serious AEs were noted in 32.6% vs 28.5% for all-cause toxicity, 19.3% vs 13.4% for TRAEs, and 3.8% vs 1.1% for immune-mediated AEs.

The most common TRAEs included anemia (60.0%), nausea (57.6%), diarrhea (50.8%), and white blood cell count decreases (32.8%) in the pembrolizumab arm. Immune-mediated AEs were hypothyroidism (22.5%), hyperthyroidism (12.1%), gastritis (4.2%), and colitis (3.0%).

Duska also noted that based on previous results from the KEYNOTE-A18 trial, the FDA and European Commission had approved this treatment regimen for the aforementioned patient population.^2,3

References

1. Duska LR, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: overall survival and progression-free survival 2 results from the randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO). Seattle, WA; March 14-17, 2025.
2. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 Stage III-IVA cervical cancer. News release. FDA. January 12, 2024. Accessed March 15, 2025. https://tinyurl.com/25fvb223
3. Merck’s KEYTRUDA® (pembrolizumab) receives 30th approval from European Commission with two new indications in gynecologic cancers. News release. Merck. October 24, 2024. Accessed March 15, 2025. https://tinyurl.com/4z5s2f49