Updated findings from the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study reveal that adding pembrolizumab to chemoradiotherapy significantly improves overall survival (OS) in patients with newly diagnosed, high-risk, locally advanced cervical cancer. The study also explored pembrolizumab as monotherapy.
The randomized, double-blind, placebo-controlled trial enrolled patients aged 18 years or older with locally advanced cervical cancer, including squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. Patients had to have FIGO 2014 stage IB2 to IIB with node-positive involvement or stage III to IVA regardless of nodal status, an ECOG performance status of 0 or 1, measurable disease per RECIST 1.1 criteria, adequate organ function, and sufficient tissue for sampling.
Survival Benefits
At a median follow-up of 29.9 months (range, 12.8-43.0), the 36-month OS rate for patients receiving pembrolizumab plus chemoradiotherapy was 82.6% (95% CI, 78.4%-86.1%), compared with 74.8% (95% CI, 70.1%-78.8%) for those receiving chemoradiotherapy alone. The median OS was not reached in either arm, with a hazard ratio (HR) of 0.67 (95% CI, 0.50-0.90), one-sided P = 0.0040, indicating a statistically significant survival benefit with pembrolizumab. The HR for death remained below 1 across almost all prespecified subgroups.
Expert Insights
Domenica Lorusso, MD, PhD, director of the Gynaecological Oncology Unit at Humanitas Hospital San Pio X, Milan, highlighted the rationale behind the study. "For more than 25 years, the treatment of locally advanced cervical cancer has been represented by concurrent chemoradiation plus brachytherapy... Radiotherapy may work better in combination with immunotherapy, and that is the reason why we moved in the treatment of patients with locally advanced cervical cancer."
Study Design and Endpoints
The phase 3 trial randomized patients 1:1 to receive concurrent chemoradiotherapy plus brachytherapy, or the same regimen plus pembrolizumab 200 mg every 3 weeks, followed by pembrolizumab 400 mg every 6 weeks for 15 cycles (approximately 2 years of maintenance). The primary endpoints were progression-free survival (PFS) and overall survival (OS), analyzed hierarchically.
Progression-Free Survival
The trial met both primary endpoints at the first interim analysis (18 months median follow-up), showing a statistically significant and clinically meaningful increase in PFS, with a 30% reduction in the risk of progression (HR, 0.68 confirmed with an additional year of follow-up).
Safety Profile
The safety profile of pembrolizumab in combination with chemoradiation was manageable. "There were no new safety signals. The most frequently reported toxicities were nausea, anemia, and diarrhea, but the incidence of type and severity of toxicities were similar between the 2 treatment arms. Most were grade 1 and 2," Lorusso noted. Immune-related adverse events, mainly thyroid dysfunction (hypothyroidism in about 22% of patients), were manageable with hormone replacement therapy.
Implications for Clinical Practice
Lorusso emphasized the potential shift in the standard of care. "The current standard of care is concurrent chemoradiation with modern chemoradiation... We demonstrate that pembrolizumab is able to further decrease the risk of death by 33%, so we are confident in saying that this is the new standard of care."
While further trials exploring different immunotherapy approaches are ongoing, Lorusso believes this trial's findings are conclusive. "For the first time, we can cure a larger number of patients... Pembrolizumab in this setting can cure more patients. I have no doubt that if I have to choose when to use the drug, it should be used in a curative setting."
