When we add pembrolizumab, the risk of death is reduced by 33%, and that is really remarkable for this tumor [cervical cancer], which is among the worst of the gynecologic malignancies.— Domenica Lorusso, MD, PhD
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In the phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial presented at the European Society for Medical Oncology (ESMO) Congress 2024, the PD-1 inhibitor pembrolizumab plus chemoradiotherapy, with pembrolizumab continued as monotherapy, improved overall survival in previously untreated, high-risk locally advanced cervical cancer, validating the regimen as the new standard of care in high-risk patients.1 Domenica Lorusso, MD, PhD, of the Gynaecology/Oncology Unit of Fondazione Policinico Universitario A. Gemelli IRCCS, Rome and Humanitas San Pio X, Milan, Italy, presented the findings during the Presidential Symposium on Practice-Changing Trials, garnering robust applause from the audience. The updated analysis was simultaneously published in The Lancet.2
“When we add pembrolizumab, the risk of death is reduced by 33%, and that is really remarkable for this tumor, which is among the worst of the gynecologic malignancies…. It is our only opportunity to cure a larger number of patients,” Dr. Lorusso said during a press briefing.
At a median follow-up of 29.9 months, the 36-month overall survival rate was 82.6% with pembrolizumab plus chemotherapy vs 74.8% with chemoradiotherapy alone (hazard ratio [HR] = 0.67; P = .0040). Median overall survival was not reached in either arm. Of note, the hazard ratio for death was under 1 in all protocol-specified subgroups with the exception of those aged 65 and older (HR = 1.35). Dr. Lorusso acknowledged that analysis with a limited number of patients and events should be interpreted with caution.
Based on the improvement in progression-free survival in a previous analysis—a 30% reduction in risk—performed at 17.9 months of median follow-up, the U.S. Food and Drug Administration has already approved pembrolizumab plus external-beam radiotherapy and concurrent chemotherapy for newly diagnosed, high-risk, FIGO (Federation of Gynecology and Obstetrics) 2014 stage III to IVA cervical cancer.
“In our opinion, these data support pembrolizumab plus concurrent 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,” Dr. Lorusso stated.
About ENGOT-cx11/GOG-3047/KEYNOTE-A18
The randomized, double-blind, placebo-controlled phase III study enrolled patients with newly diagnosed, locally advanced squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. All patients had high-risk disease, defined as FIGO 2014 stage IB2 to IIB with positive lymph nodes or stage III to IVA regardless of nodal status. The primary endpoints were investigator-assessed progression-free survival and overall survival, to be analyzed in a hierarchical fashion.
KEY POINTS
- The phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial evaluated pembrolizumab plus chemotherapy vs chemotherapy alone in high-risk locally advanced cervical cancer.
- The 3-year overall survival analysis showed a 33% reduction in the risk of death with pembrolizumab, and the rates were 82.6% with pembrolizumab and 74.8% with chemotherapy alone (hazard ratio = 0.67; P = .0040).
- Many experts now consider this regimen to be a standard of care in this population.
The 1,060 patients from 175 sites were randomly assigned to receive pembrolizumab plus chemoradiotherapy followed by pembrolizumab or placebo plus chemoradiotherapy followed by placebo. The investigational treatment was pembrolizumab at 200 mg every 3 weeks for 5 cycles plus chemoradiotherapy, followed by pembrolizumab at 400 mg every 6 weeks for 15 cycles. Control patients received 5 cycles of placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of placebo every 6 weeks. Chemoradiotherapy comprised five cycles of cisplatin given at a dose of 40 mg/m2 once weekly paired with external-beam radiotherapy followed by brachytherapy.
More than 90% of patients received the planned radiotherapy dose (≥ 70 Gy), and the overall treatment time for radiotherapy was 52 days. Radiotherapy was completed within 50 days for about 36% of patients and within 56 days (extended time allowed if needed) for about 74%, which Dr. Lorusso considered “remarkable for a global trial conducted during the COVID-19 pandemic in such a large number of centers.”
Updated Results and Safety
Since the progression-free survival endpoint was successfully met in the first interim analysis, it was not formally analyzed again at the second interim analysis. At 29.9 months, the 36-month progression-free survival rate was 69.3% in the pembrolizumab arm and 56.9% in the placebo arm (HR = 0.68; 95% confidence interval = 0.56–0.84). Medians were still not reached in either arm, and the benefit was consistent, again, across subgroups, according to Dr. Lorusso.
With longer follow-up, no new safety signals were observed, she said. “Of note, only one patient in the pembrolizumab arm discontinued all treatment for a non–pembrolizumab-related adverse event.”
The most common immune-mediated toxicities in the pembrolizumab and placebo arms, respectively, were hypothyroidism (22.5% vs 6.8%) and hyperthyroidism (12.1% vs 2.8%). No meaningful differences were observed in quality of life.
EXPERT POINT OF VIEW
Remi Nout, MD, PhD
The invited discussant of the ENGOT-cx11/GOG-3047/KEYNOTE-A18 trial was Remi Nout, MD, PhD, Head of the Radiotherapy Department at Erasmus MC Cancer Institute in Rotterdam, the Netherlands. He shared these comments: “This was a well-designed, randomized, double-blind, placebo-controlled, adequately powered phase III trial, with broad international inclusion and used modern radiotherapy approaches in the majority of patients. Of note, it included not all patients with locally advanced cervical cancer, but a population that was truly at high risk of recurrence.”
Elaborating on these strengths, Dr. Nout noted that 55% had FIGO 2014 stage III to IVA disease, and more than 80% had node-positive disease, among which 22% had pelvic nodal disease. More than 85% received intensity-modulated external-beam radiotherapy; and with regard to brachytherapy, 85% were treated with a volume-based approach with a total mean 2-Gy/fraction equivalent dose (EQD2) of 87 Gy to the high-risk target volume.
Clinical Implications
Dr. Nout continued: “The combination of chemoradiation plus pembrolizumab demonstrated a significant and clinically meaningful progression-free and overall survival benefit at 3 years (12% progression-free survival, 8% overall survival), with a manageable, mainly immune-related, toxicity profile. The median follow-up was almost 30 months; in cervical cancer, the vast majority of disease-related events take place in the first 24 months after treatment. With these differences at 3 years, I think these improvements are clinically meaningful and should be considered practice-changing.”
Of note, these improvements were obtained without a considerable increase in adverse events, he added. “Patient-reported changes in quality of life, global health status, and physical functioning were similar to the placebo arm.”
The clinical uptake of this regimen should be further strengthened with more details about the radiotherapy protocol, patterns of recurrence, and impact of therapy upon disease progression.
DISCLOSURE: Dr. Lorusso has served as an advisor to and/or an invited speaker for AstraZeneca, Clovis Oncology, Corcept, Daiichi Sankyo, Genmab, GSK, Immunogen, MSD, Novartis, Oncoinvest, Novocure, Seagen, and Sutro and has received institutional research funding from AstraZeneca, Clovis Oncology, Pharma&, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, Pharmamar, Roche, Seagen, Alkermes, and Corcept. Dr. Nout has reported research grants paid to his institution from Elekta, Varian, Accuray, Sensius, and Senewald.
REFERENCES
1. 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.
2. 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. September 13, 2024 (early release online).
