At the protocol-specified second interim analysis of the phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, pembrolizumab combined with chemoradiotherapy provided a statistically significant and clinically meaningful improvement in overall survival (OS) as compared with chemoradiotherapy alone in patients with newly diagnosed, high-risk, locally advanced cervical cancer. The addition of pembrolizumab to chemoradiotherapy reduced the risk of death in the intention-to-treat (ITT) population, with a higher 3-year OS in the pembrolizumab-chemoradiotherapy group than in the placebo-chemoradiotherapy group; OS curves separated in favour of pembrolizumab-chemoradiotherapy after approximately 10.5 months and remained apart over the subsequent follow-up.
The results of the disease-specific survival analysis are generally consistent with those of the OS analysis. The findings are reported at the ESMO Congress 2024 along with a simultaneous publication by Prof. Domenica Lorusso of the Gynaecology Oncology Unit, Humanitas San Pio X in Milan, Italy and colleagues on 14 September 2024 in The Lancet.
The authors wrote in the background that standard-of-care for locally advanced disease is external beam radiotherapy with concurrent chemotherapy followed by brachytherapy, with few therapeutic advances for more than two decades beyond introduction of modern, image-guided radiotherapy and brachytherapy, which translated to improved long-term local control and reduced toxicity. Patients with high-risk, locally advanced cervical cancer often have poor outcomes despite treatment with curative intent; 5-year progression-free survival (PFS) and OS range from 47% to 80%, which worsen in patients with advanced stage disease or nodal involvement.
A global, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study was conducted to evaluate whether pembrolizumab, when administered in combination with and after chemoradiotherapy, would improve outcomes compared with chemoradiotherapy alone in patients with newly diagnosed, high-risk, locally advanced cervical cancer. At the first protocol-specified interim analysis, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in PFS.
After a median study follow-up of 17.9 months, the addition of pembrolizumab to chemoradiotherapy reduced the risk of disease progression as assessed by investigator review or death by 30% in the ITT population (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.55-0.89; p = 0.0020), with a higher 2-year PFS rate in the pembrolizumab-chemoradiotherapy group (68%, 95% CI 62–73) as compared with the placebo-chemoradiotherapy group (57%, 95% CI 51–63). Now the study team is reporting the primary OS results from the protocol-specified second interim analysis.
Eligible patients with newly diagnosed, high-risk (defined as FIGO 2014 stage IB2–IIB with node-positive disease or stage III–IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab 200 mg or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab 400 mg or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously.
Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] versus non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2–IIB node positive versus III–IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy versus ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were PFS per RECIST v1.1 by investigator or by histopathological confirmation of suspected disease progression and OS defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint.
Between 9 June 2020 and 15 December 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis with data cut-off on 8 January 2024, median follow-up was 29.9 months. Median OS was not reached in either group; 36-month OS was 82.6% (95% CI 78.4–86.1) in the pembrolizumab-chemoradiotherapy group and 74.8% (95% CI 70.1–78.8) in the placebo-chemoradiotherapy group with HR for death of 0.67 (95% CI 0.50-0.90; p = 0.0040), meeting the protocol-specified primary objective.
A total, 413 of 528 patients (78%) in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 patients (70%) in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 of 528 patients (39%) in the pembrolizumab-chemoradiotherapy group and 90 of 530 patients (17%) in the placebo-chemoradiotherapy group.
The authors commented this is the first phase III study to report a statistically significant improvement in OS with the combination of a PD1 inhibitor and chemoradiotherapy in newly diagnosed, high-risk, locally advanced cervical cancer. The findings from the second interim analysis, together with results from the first interim analysis, support the role of pembrolizumab in addition to chemoradiotherapy as a new standard of care for patients with locally advanced cervical cancer. This regimen should be incorporated into the control group of future clinical trials in this setting. Although translational data are currently unavailable, analyses of molecular biomarkers that might predict a clinical response to the addition of pembrolizumab to chemoradiotherapy are ongoing.
In an accompanied comment, Dr. Christine Gennigens of the Department of Medical Oncology, CHU of Liège and University of Liège in Liège, Belgium wrote that this is the first practice-changing immunotherapy study in locally advanced cervical cancer. Cost will be a major obstacle to immunotherapy accessibility in low-income and middle-income countries. Therefore, national health systems should concentrate on optimising their prevention programmes, which constitute the most cost-effective approach to reducing the incidence and mortality of cervical cancer.
According to the commentator, further research is needed to elucidate what the best options will be according to histological subtype, PD-L1 status, ethnicity, and patients relapsing, so no longer immune checkpoint inhibitor (ICI) naive. Future studies should also focus on the best sequencing immunotherapy strategies: neoadjuvant, concomitant, maintenance, or a combination; monotherapy or dual ICIs; and the combination of chemotherapy with immunotherapy. Moreover, there are several other immunotherapy treatments under investigation (e.g. therapeutic vaccines and adoptive cell transfer) in locally advanced cervical cancer.
The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co.
References
- Lorusso D, Xiang Y, Hasegawa K, et al. on behalf of the ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators. 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. The Lancet 2024;404(10460):P1321-1332.
- Gennigens C. Hope emerging in the locally advanced cervical cancer landscape. The Lancet 2024;404(10460):P1282-1284.
- 709O - 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. Annals of Oncology 2024;35(Suppl 2):S544.