Merck's KEYTRUDA (pembrolizumab) in combination with chemoradiotherapy (CRT) has demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) for patients with newly diagnosed high-risk locally advanced cervical cancer. The Phase 3 KEYNOTE-A18 trial (ENGOT-cx11/GOG-3047) revealed a 33% reduction in the risk of death compared to CRT alone (HR=0.67 [95% CI, 0.50-0.90]; p=0.0040). These findings, presented at the European Society for Medical Oncology (ESMO) Congress 2024 and published in The Lancet, signal a potential shift in the treatment paradigm for this patient population.
KEYNOTE-A18: A Pivotal Study
KEYNOTE-A18, a randomized, double-blind Phase 3 trial, enrolled 1,060 patients with high-risk locally advanced cervical cancer (stage IB2-IIB with lymph node-positive disease and stage III-IVA with and without lymph node-positive disease). Patients were randomized 1:1 to receive either KEYTRUDA (200 mg IV Q3W for five cycles concurrent with cisplatin and radiotherapy, followed by KEYTRUDA 400 mg IV Q6W for 15 cycles) or placebo plus concurrent CRT. The primary endpoints were progression-free survival (PFS) and OS.
Survival Benefits
At a median follow-up of 29.9 months (range, 12.8-43.0), the 36-month OS rate was 82.6% in the KEYTRUDA arm compared to 74.8% in the CRT alone arm. Median OS was not reached in either group. According to Dr. Domenica Lorusso, the study’s overall principal investigator, these results mark the first positive overall survival data for an immunotherapy-based regimen in newly diagnosed patients with high-risk locally advanced cervical cancer.
Safety and Tolerability
The safety profile of KEYTRUDA in the KEYNOTE-A18 trial was consistent with previous studies. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 69.1% of patients receiving KEYTRUDA plus CRT versus 61.3% of patients receiving placebo plus CRT. Immune-mediated adverse events (AEs) of any grade occurred in 39% of patients receiving the KEYTRUDA regimen and 17% of patients receiving the placebo regimen. The most common immune-mediated AE was hypothyroidism (22.5%) in patients receiving the KEYTRUDA regimen.
Impact on Clinical Practice
The results from KEYNOTE-A18 are poised to influence clinical practice, potentially establishing KEYTRUDA plus CRT as a new standard of care for high-risk locally advanced cervical cancer. This regimen offers a significant survival benefit, addressing a critical unmet need in a patient population where treatment advances have been limited in recent years. The findings are under discussion with regulatory authorities worldwide, with previous data supporting FDA approval of KEYTRUDA in combination with CRT for FIGO 2014 Stage III-IVA cervical cancer in January 2024.
