Updated findings from the second planned interim analysis of the phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study solidify the PD-1 inhibitor pembrolizumab plus concurrent chemoradiotherapy, followed by pembrolizumab maintenance, as the upfront standard of care for high-risk, locally advanced cervical cancer. This late-breaking abstract was presented at the 2025 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer by Linda Duska, MD, MPH, FASCO, Professor of Obstetrics and Gynecology at the University of Virginia School of Medicine in Charlottesville.1
Dr. Duska presented data on overall survival, progression-free survival, and progression-free survival 2 (PFS2), defined as the time from initiation of new anticancer therapy to second disease progression or death from any cause. The previous analysis, which demonstrated improved overall survival, was reported at the European Society for Medical Oncology (ESMO) Congress 20242 and in The Lancet.3 The experimental regimen was approved in January 2024 for patients with FIGO (International Federation of Gynecology and Obstetrics) 2014 stage III–IVA cervical cancer after the first interim analysis reported a statistically significant progression-free survival.
“At the second interim analysis, overall survival at 36 months was significantly improved with pembrolizumab..., with a hazard ratio of 0.67.”— LINDA DUSKA, MD, MPH, FASCO
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Patients treated with pembrolizumab plus chemoradiotherapy, at 3 years, had a 32% reduced risk of disease progression, a 40% reduced risk of second disease progression (PFS2), and a 33% reduced risk of death. Benefit continued to be observed in all subsets of patients, she reported.
“The data support pembrolizumab plus concurrent chemoradiotherapy as a 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,” Dr. Duska said.
Phase III Trial Results
The randomized, double-blind, placebo-controlled phase III study enrolled high-risk patients with newly diagnosed, locally advanced squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. The 1,060 patients were randomly assigned to receive pembrolizumab plus chemoradiotherapy followed by pembrolizumab maintenance or placebo plus chemoradiotherapy followed by placebo maintenance. The primary endpoints were investigator-assessed progression-free survival and overall survival. PFS2 was a secondary endpoint.
In the first interim analysis, the study achieved its progression-free survival endpoint, with a hazard ratio of 0.7 favoring the experimental arm. Because this first interim analysis reached statistical significance, a formal statistical assessment was not conducted in the second interim analysis, but the descriptive statistics showed sustained benefit with pembrolizumab. At 36 months, 62.7% of the pembrolizumab arm were progression-free, compared with 54.5% of the control arm (hazard ratio [HR] = 0.68; 95% confidence interval [CI] = 0.56–0.84). Separation of the Kaplan-Meier curves was sustained after they began separating at 3 months. Consistent benefit of pembrolizumab was seen across all prespecified subgroups.
At the second interim analysis, overall survival at 36 months was significantly improved with pembrolizumab, with 82.6% of the experimental arm alive vs 74.8% of the control arm (HR = 0.67; P = .0040). Median overall survival was not reached in either group. The curves began separating at 10 months and remained separated over the follow-up period, stated Dr. Duska.
KEY POINTS
- The second planned interim analysis of the phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial in high-risk, locally advanced cervical cancer solidify the benefit shown previously for pembrolizumab plus concurrent chemoradiotherapy, establishing this regimen as a new standard of care.
- At 3 years, patients treated with pembrolizumab plus chemoradiotherapy had a 32% reduced risk of disease progression, a 40% reduced risk of second disease progression, and a 33% reduced risk of death.
- No new safety signals emerged with longer follow-up.
An improvement in PFS2 was also demonstrated, with events occurring in 15.3% of patients in the pembrolizumab group vs 24.3% in the placebo group (HR = 0.60; 95% CI = 0.46–0.80). Medians were not reached in either arm.
There were no new safety signals noted at the second interim analysis. The incidence of grade ≥ 3 treatment-related, adverse events was higher in the pembrolizumab group (69.1%) than in the placebo group (61.3%). However, Dr. Duska noted, all toxicities were reported to be manageable and consistent with the known profiles of the individual therapies. Immune-mediated adverse events occurred in 39% of the pembrolizumab arm and 17% of the placebo arm; most events were grade 1 or 2. The incidence of diarrhea was similar in the two arms. Treatment-related deaths occurred in two participants in each arm.
DISCLOSURE: Dr. Duska reported personal financial relationships with Daiichi Sankyo, Scorpion Therapeutics, AADI Bioscience, UpToDate, Elsevier, and ASCO.
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. 2025 SGO Annual Meeting on Women’s Cancer. Late-Breaking Abstract. Presented March 14, 2025.
2. Lorusso D, Xiang Y, Hasegawa K, et al: Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: Overall survival results from the randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. ESMO Congress 2024. Abstract 709O. Presented September 14, 2024.
3. Lorusso D, Xiang Y, Hasegawa K, et al: 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): Overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 404:1321-1332, 2024.
EXPERT POINT OF VIEW
Premal Thaker, MD, MS, the David and Lynn Mutch Distinguished Professor of Ob/Gyn, Interim Chief of Gynecologic Oncology, and Director of Gynecologic Oncology Research at Washington University Medicine, St. Louis, noted that the treatment of locally advanced cervical cancer had not changed since 1999 until the positive results of KEYNOTE-A18 were recently announced. Until then, the standard treatment was weekly cisplatin and external-beam radiation followed by intracavitary or interstitial brachytherapy. KEYNOTE-A18 showed that the addition of pembrolizumab to chemoradiotherapy significantly improved progression-free survival and overall survival, leading to its approval by the U.S. Food and Drug Administration for stage III and IVA disease.
Premal Thaker, MD, MS
Dr. Thaker shared these comments about the second planned interim analysis of the study: “The curves still favor the pembrolizumab arms, for both overall survival and second progression-free survival, for all disease stages, without any new adverse events or safety concerns. Thus, this is the new standard of care for our patients with high-risk, locally advanced cervical cancer. With this advance [and others reported at the 2025 SGO Annual Meeting on Women’s Cancer], we must make sure that all patients with cervical cancer have equitable benefits.”
DISCLOSURE: Dr. Thaker reported personal financial relationships with AstraZeneca, GlaxoSmithKline, Merck, Pfizer, Corcept Therapeutics, Zentalis Pharmaceuticals, Verastem, Imunon, UpToDate, and Caris Life Sciences.
