KEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer (progression-free survival)
Adding pembrolizumab to standard chemoradiotherapy for high-risk locally advanced cervical cancer reduced progression or death by 30%, the first systemic advance in this setting since cisplatin was added to radiotherapy in 1999.
Overview
Double-blind, placebo-controlled phase 3 trial (ENGOT-cx11/GOG-3047/KEYNOTE-A18) of 1,060 patients at 176 centres in 30 countries with newly diagnosed, high-risk locally advanced cervical cancer (FIGO 2014 stage IB2-IIB with node-positive disease, or stage III-IVA) randomised 1:1 to five cycles of pembrolizumab 200 mg or placebo every three weeks with chemoradiotherapy, then 15 cycles of pembrolizumab 400 mg or placebo every six weeks. Primary endpoints were progression-free survival and overall survival.
At the first interim analysis (data cutoff 9 January 2023, median follow-up 17.9 months) median progression-free survival was not reached in either group; the 24-month rate was 68% with pembrolizumab against 57% with placebo (HR 0.70, p=0.0020). Overall survival at 24 months was 87% against 81% (HR 0.73), not yet significant at this analysis. A second Lancet report later in 2024 confirmed the overall survival gain.
- 24-month progression-free survival 68% vs 57%; HR for progression or death 0.70 (95% CI 0.55-0.89, p=0.0020), meeting the primary objective.
- 24-month overall survival 87% vs 81%; HR 0.73 (95% CI 0.49-1.07), not yet across the significance boundary at 42.9% information fraction.
- Grade 3 or higher adverse events 75% vs 69%.
- The earlier CALLA trial of durvalumab with chemoradiotherapy in a broader population was negative, highlighting the importance of enrolling high-risk patients.
Women with locally advanced cervical cancer that is node-positive or stage III-IVA can be offered pembrolizumab alongside and after chemoradiotherapy to lower the chance of relapse. The result matters most in countries where cervical cancer is common but immunotherapy access is poorest, so its global impact depends on pricing and health-system capacity. It does not apply to early-stage disease treated with surgery or to lower-risk locally advanced disease without nodal involvement.
- High-risk population only; the negative CALLA trial suggests lower-risk patients may not benefit.
- Radiotherapy quality (including brachytherapy) varied and is a major determinant of outcome; the trial was conducted mainly in well-resourced centres.
- About two years of pembrolizumab is costly where cervical cancer burden is highest.
- Median follow-up was under 18 months at this analysis; overall survival was not yet significant.
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