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Pembrolizumab With Chemoradiotherapy Followed by Pembrolizumab for Newly Diagnosed, High-Risk, Locally Advanced Cervical Cancer
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Pembrolizumab has shown efficacy in persistent, recurrent, or metastatic cervical cancer. The effect of chemoradiotherapy might be enhanced by immunotherapy. In this phase 3 trial, we assessed the efficacy and safety of adding pembrolizumab to chemoradiotherapy in locally advanced cervical cancer.
METHODS
In this randomised, double-blind, placebo-controlled, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 clinical trial, 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) using an interactive voice-response system with integrated web response 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 vs 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 vs stage III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy equivalent dose in 2 Gy fractions). Primary endpoints were progression-free survival per Response Evaluation Criteria in Solid Tumours version 1.1-by investigator or by histopathologic confirmation of suspected disease progression-and overall survival. Primary analysis was conducted in the intention-to-treat 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 registered with ClinicalTrials.gov, NCT04221945, and is closed to new participants.
FINDINGS
Between June 9, 2020, and Dec 15, 2022, 1060 participants were randomly assigned to treatment, with 529 assigned to the pembrolizumab-chemoradiotherapy group and 531 to the placebo-chemoradiotherapy group. At data cutoff (Jan 9, 2023), median follow-up was 17·9 months (IQR 11·3-22·3) in both treatment groups. Median progression-free survival was not reached in either group; rates at 24 months were 68% in the pembrolizumab-chemoradiotherapy group versus 57% in the placebo-chemoradiotherapy group. The hazard ratio (HR) for disease progression or death was 0·70 (95% CI 0·55-0·89, p=0·0020), meeting the protocol-specified primary objective. Overall survival at 24 months was 87% in the pembrolizumab-chemoradiotherapy group and 81% in the placebo-chemoradiotherapy group (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. Grade 3 or higher adverse event rates were 75% in the pembrolizumab-chemoradiotherapy group and 69% in the placebo-chemoradiotherapy group.
INTERPRETATION
Pembrolizumab plus chemoradiotherapy significantly improved progression-free survival in patients with newly diagnosed, high-risk, locally advanced cervical cancer.
FUNDING
Merck Sharp & Dohme, a subsidiary of Merck & Co (MSD).
Additional Info
Disclosure statements are available on the authors' profiles:
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
Lancet 2024 Apr 06;403(10434)1341-1350, D Lorusso, Y Xiang, K Hasegawa, G Scambia, M Leiva, P Ramos-Elias, A Acevedo, V Sukhin, N Cloven, AJ Pereira de Santana Gomes, F Contreras Mejía, A Reiss, A Ayhan, JY Lee, V Saevets, F Zagouri, L Gilbert, J Sehouli, E Tharavichitkul, K Lindemann, R Lazzari, CL Chang, R Lampé, H Zhu, A Oaknin, M Christiaens, S Polterauer, T Usami, K Li, K Yamada, S Toker, SM Keefe, S Pignata, LR DuskaFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The gold standard for locally advanced cervical cancer has been external beam radiotherapy with concurrent chemotherapy followed by brachytherapy. Despite this treatment, the outcome is a challenge, with 5-year rates of progression-free survival (PFS) and overall survival (OS) between 47% and 80%.
Pembrolizumab, an anti–PD-1 monoclonal antibody, has shown efficacy and a clinically manageable safety profile in patients with persistent, recurrent, or metastatic cervical cancer.
In this randomized, double-blind, placebo-controlled, phase III KEYNOTE-A18 trial, 1060 patients with newly diagnosed, high-risk, locally advanced cervical cancer were randomly assigned (1:1) to five 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.
After a median follow-up of 17.9 months, the median PFS in both groups was not reached. At 24 months, the PFS rate was 68% in the pembrolizumab–chemoradiotherapy group versus 57% in the placebo–chemoradiotherapy group, and the overall survival rate reached 87% in the pembrolizumab–chemoradiotherapy group and 81% in the placebo–chemoradiotherapy group. Thus, pembrolizumab in combination with chemoradiotherapy and continued after chemoradiotherapy provided a statistically significant and clinically meaningful improvement in PFS compared with chemoradiotherapy alone and reduced the risk of disease progression. This implicates a potential role for the addition of a PD-1 Inhibitor to chemoradiotherapy in patients with high-risk locally advanced cervical cancer.