KEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer
Adding pembrolizumab to standard chemoradiotherapy for high-risk locally advanced cervical cancer reduced progression by 30% and later improved survival, the first systemic advance in this setting since cisplatin was added to radiotherapy in 1999.
Double-blind, placebo-controlled phase 3 trial of 1,060 patients with newly diagnosed, high-risk locally advanced cervical cancer (FIGO 2014 stage IB2-IIB with node-positive disease, or stage III-IVA) randomised to pembrolizumab or placebo with cisplatin-based chemoradiotherapy and brachytherapy, followed by pembrolizumab or placebo maintenance for about 15 cycles. Primary endpoints were PFS and OS.
24-month PFS was about 68% vs 57% (HR 0.70) and a second report showed 36-month OS 82.6% vs 74.8% (HR 0.67). It established chemoradiotherapy plus pembrolizumab as a new standard for high-risk locally advanced cervical cancer, a disease that predominantly affects women in low- and middle-income countries.
- 24-month progression-free survival about 68% vs 57%; HR 0.70 (95% CI 0.55-0.89).
- Overall survival (Lancet 2024 second analysis): 36-month OS 82.6% vs 74.8%; HR 0.67 (95% CI 0.50-0.90).
- Benefit was largest in stage III-IVA disease and consistent across PD-L1 subgroups (almost all tumours were CPS 1 or more).
- Grade 3 or higher adverse events 75% vs 69%, mostly haematological from chemoradiotherapy; immune-mediated events 33% vs 12%, mainly hypothyroidism.
- 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 should now be offered pembrolizumab alongside and after chemoradiotherapy, which improves the chance of cure. 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.
- Follow-up remains relatively short for a disease with late recurrences.
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