In a randomised, double-blind, placebo-controlled, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study pembrolizumab, when administered in combination with chemoradiotherapy and continued after chemoradiotherapy, compared with chemoradiotherapy alone, provided a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in women with newly diagnosed, high-risk, locally advanced cervical cancer. The addition of pembrolizumab to chemoradiotherapy reduced the risk of disease progression as assessed by investigator review or death by 30% in the intention-to-treat (ITT) population, with higher 2-year PFS in the pembrolizumab–chemoradiotherapy arm (68%) compared with the placebo–chemoradiotherapy (57%).
The PFS curves began to separate in favour of pembrolizumab–chemoradiotherapy at the first radiographic assessment approximately 3 months after chemoradiotherapy initiation and the separation continued over time. The benefit of pembrolizumab–chemoradiotherapy was generally consistent across the protocol-specified subgroups. The findings are published by Dr. Domenica Lorusso of the Gynaecology Oncology Unit, Fondazione Policlinico Universitario A Gemelli IRCCS and Catholic University of Sacred Heart in Rome, Italy and colleagues on 20 March 2024 in The Lancet.
The authors wrote in the background that pembrolizumab has shown efficacy and a clinically manageable safety profile in patients with persistent, recurrent, or metastatic cervical cancer. Data suggest that chemoradiotherapy can be enhanced by the immune stimulatory activity of pembrolizumab. They conducted the ENGOT-cx11/GOG-3047/KEYNOTE-A18 study to evaluate whether pembrolizumab, when administered in combination with and after chemoradiotherapy, improves efficacy compared with chemoradiotherapy alone in newly diagnosed, high-risk, locally advanced cervical cancer.
In this study, adults (age ≥18 years) at 176 medical centres in 30 countries with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned 1:1 to receive 5 cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Randomisation was stratified by planned external beam radiotherapy type (intensity-modulated radiotherapy or volumetric-modulated arc therapy versus non-intensity-modulated radiotherapy or non-volumetric-modulated arc therapy), cervical cancer stage at screening (International Federation of Gynecology and Obstetrics 2014 stage IB2–IIB node positive versus stage III–IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy versus ≥70 Gy equivalent dose in 2 Gy fractions).
Primary endpoints were PFS per RECIST v1.1 by investigator or by histopathologic confirmation of suspected disease progression and overall survival (OS). Primary analysis was conducted in the ITT population, which included all randomly allocated participants. Safety was assessed in the as-treated population, which included all randomly allocated patients who received at least one dose of study treatment. This study is closed to new participants.
Between 9 June 2020 and 15 December 2022, a total of 1060 participants were randomised, with 529 assigned to the pembrolizumab–chemoradiotherapy arm and 531 to the placebo–chemoradiotherapy. At data cut-off on 9 January 2023, median follow-up was 17.9 months (IQR 11.3–22.3) in both treatment arms. Median PFS was not reached in either arm; rates at 24 months were 68% in the pembrolizumab–chemoradiotherapy arm versus 57% in the placebo–chemoradiotherapy arm. The hazard ratio (HR) for disease progression or death was 0.70 (95% confidence interval [CI] 0.55–0.89, p = 0.0020), meeting the protocol-specified primary objective.
The OS at 24 months was 87% in the pembrolizumab–chemoradiotherapy arm and 81% in the placebo–chemoradiotherapy arm (information fraction 42.9%). The HR for death was 0.73 (0.49–1.07); these data have not crossed the boundary of statistical significance.
The HRs for disease progression or death were less than 1 in patient subgroups based on PD-L1 expression; however, these results should be interpreted with caution owing to the small percentage of patients with PD-L1–negative tumours (<5%) in addition to the inherent limitations of subgroup analyses.
The safety profile of pembrolizumab–chemoradiotherapy was consistent with the known profiles of the individual treatment components. No new safety signals emerged in the pembrolizumab–chemoradiotherapy arm. Pembrolizumab did not worsen the known toxicities associated with chemoradiotherapy, compromise exposure to cisplatin, or delay radiotherapy delivery. The incidences of treatment-related diarrhoea and colitis were similar between the treatment groups. A higher incidence of immune-mediated adverse events was observed in the pembrolizumab–chemoradiotherapy arm. Grade 3 or higher adverse event rates were 75% in the pembrolizumab–chemoradiotherapy arm and 69% in the placebo–chemoradiotherapy.
This is the first phase III study to report a statistically significant improvement in PFS with the combination of a PD1 inhibitor and chemoradiotherapy in newly diagnosed, high-risk, locally advanced cervical cancer. This is one of the largest studies in patients with cervical cancer. The study team commented they ensured high-quality radiotherapy delivery, which is required to assess the true benefit of the combination strategy. As the burden of cervical cancer disproportionately affects resource-poor countries, they enrolled a representative population of patients from 30 countries, with approximately half being of non-White race. However, the main limitation is the short duration of follow-up at this early timepoint, precluding the assessment of mature survival data. Follow-up is ongoing and planned for future reporting.
In an accompanied comment, Drs. Krishnansu S Tewari of the Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of California, Irvine Medical Center in Orange, CA, US and Bradley J Monk of the Florida Cancer Specialists and Research Institute in West Palm Beach, FL, US wrote that in the subgroup analysis of KEYNOTE-A18, the forest plot for stage IB2–IIB crosses the ordinate. Although this observation is exploratory and hypothesis generating, on 12 January 2024, the US Food and Drug Administration approved pembrolizumab with chemoradiotherapy, but restricted the label to FIGO 2014 stage III–IVA cervical cancer.
Global and regional differences in the proportion of locally advanced cervical cancer indicate that nearly 50% of affected individuals in industrialised nations have stage IB2–IIB disease. However, those with recurring cancer will be immunotherapy-naïve. In low-income regions, women with locally advanced cervical cancer are more likely to have blocked kidneys due to pelvic sidewall extension as well as bladder and rectal involvement (stages III–IVA) and conceivably benefit most from immunotherapy.
This study was funded by MSD.
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): a randomised, double-blind, phase 3 clinical trial. The Lancet; Published online 20 March 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00317-9
- Tewari KS, Monk BJ. Immunotherapy plus chemoradiotherapy in cervical cancer management. The Lancet; Published online 20 March 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00468-9