Results from the final analysis of the phase 3 KEYNOTE‑A18 trial (NCT04221945) add further evidence supporting pembrolizumab (Keytruda) plus chemoradiotherapy as a standard-of-care (SOC) in the treatment of patients with high-risk, locally advanced cervical cancer, according to Linda Duska, MD, MPH.
Findings presented at the 2025 ASCO Annual Meeting showed that at a median follow-up of 41.9 months, the pembrolizumab plus chemoradiotherapy, followed by pembrolizumab alone, regimen reduced the risk of disease progression or death by 28% compared with the placebo plus chemoradiotherapy, followed by placebo (HR, 0.72; 95% CI, 0.59-0.87).1 A similar benefit was observed regarding overall survival (OS; HR, 0.73; 95% CI, 0.57-0.94).
“These data really support this regimen of pembrolizumab [plus chemoradiation, followed by pembrolizumab maintenance] in patients with locally advanced, high‑risk [cervical cancer],” Duska said.
In an interview with OncLive®, Duska discussed the rationale for integrating pembrolizumab into the up-front treatment setting with chemoradiotherapy, highlighted key aspects of the study, and underscored the role of this pembrolizumab-based regimen for this patient population.
Duska is a professor of gynecologic oncology and division chief of gynecologic oncology at the University of Virginia in Charlottesville.
OncLive: What was the rationale for evaluating pembrolizumab in combination with chemoradiotherapy in patients with high‑risk, locally advanced cervical cancer?
Duska: Locally advanced cervical cancer remains a significant problem for women in the United States, but also for women across the world, particularly those with high‑risk locally advanced cervical cancer. Even with the addition of chemotherapy to radiation, we haven’t made much progress in this disease in [approximately] 20 years.
The idea behind [KEYNOTE-A18] was to take pembrolizumab, which we know works in the recurrent and metastatic setting, and move it into the up-front setting with SOC therapy [of chemoradiation] to see if we can improve outcomes for patients with locally advanced cervical cancer and [potentially] cure more of them.
What was the study design and key patient enrollment criteria for this trial?
This trial focused on patients with high‑risk, locally advanced cervical cancer. It’s important to qualify for the purposes of this trial, we used 2014 FIGO staging, which is different from the staging we use now, which is 2018 FIGO staging.
Under 2014 FIGO staging, patients with stage IB2 to IIB [disease] who had positive nodes qualified; those patients would now be [classified as] stage IIIC under 2018 FIGO staging. It’s important to make the distinction. We also included patients with stage III to IVA disease, regardless of lymph node status.
We were focused on that group at high risk for recurrence to see if adding a treatment could increase PFS and OS in this population.
This was an international trial, and it accrued more than 1000 patients during the pandemic, which is really amazing when you think about it. The international trial was randomized and double‑blind.
Patients were [randomly assigned] to receive SOC chemoradiation plus pembrolizumab [followed by] pembrolizumab maintenance; or SOC chemoradiation with placebo [followed by] placebo maintenance. The design was important to assess whether the addition of pembrolizumab improved PFS and OS in this group of patients.
There were some important stratification [factors]. We looked specifically at the type of radiotherapy that was planned because we much wanted high‑quality, modern radiotherapy to be used in this trial. We also [stratified by disease stage] with stage IB2 to II vs stage III to IVA, and we also looked at the planned radiation, whether it was less than 70 Gy or greater than 70 Gy.
What have previously reported results shown regarding the impact of adding pembrolizumab to standard‑of‑care chemoradiation?
The study had two primary end points: PFS and OS. There were also 2 preplanned interim analyses. The first [interim analysis] was conducted very early in the study, when the median follow‑up was [17.9] months, and the study met its PFS end point.2 The experimental arm had an improved PFS over the placebo arm, even that early in the study, with a HR of 0.70.
With the way the study was designed, all of the alpha was allocated to PFS, and then if the PFS [difference] was statistically significant, the alpha was then recycled to OS. The second interim analysis was performed [at a median follow-up of 29.9 months], and at this point, the study met the OS endpoint, again with a statistically significant improvement and a HR ratio of [0.67].3
In both the first and second interim analyses, there was a lot of censoring because it was early on in the trial. The final analysis had a data cutoff in January [2025], and that analysis was intended to be a descriptive analysis of the final OS, so there was no statistical testing done at that time.
What did you observe in terms of the adverse effect (AE) profile?
When we first started this study, we were concerned about adding pembrolizumab to pelvic radiation because pelvic radiation causes diarrhea—it’s one of the known AEs of pelvic radiation. Pembrolizumab can also cause diarrhea as a result of immune-mediated colitis. There was a concern that we might have overlapping toxicities and that we wouldn’t be able to differentiate between diarrhea caused by colitis from pembrolizumab and diarrhea caused by chemoradiation.
What we learned during this study was that the rate of diarrhea and the rate of immune-mediated colitis was very low in both groups, and it was essentially the same in both groups. That was very reassuring.
In addition, with the additional follow-up at the time of the final analysis, [which was at] a median follow-up of [41.9] months, we saw no additional safety signals. We did see immune-related AEs, but they were mostly grade 1 and grade 2. The most common immune-related AEs we observed were hypothyroidism and hyperthyroidism.
Overall, it was very reassuring that we did not see an increased rate of diarrhea in the experimental arm, and we did not see the increased rate of colitis that we were initially concerned about.
Given these findings, what guidance would you offer to clinicians who are considering how best to integrate this approach into their treatment practice?
Based on that first interim analysis, the combination did get regulatory approval for the FIGO stage III to IVA group of patients. It’s really important for us all to remember that this is a preventable disease, and if we did a better job vaccinating patients against HPV, we might see a far lower rate of [cervical] cancer, not just in the US, where it’s less of a problem, but around the world, where it’s a very big problem. I’d love to see us eradicate HPV‑related cancers.
References
- Duska LR, Xiang Y, Hasegawa K, et al. Pembrolizumab with concurrent chemoradiotherapy in participants with high-risk locally advanced cervical cancer: a descriptive analysis of final survival from the phase 3, randomized, double-blind ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. J Clin Oncol. 2025;43(suppl 17):LBA5504. doi:10.1200/JCO.2025.43.17_suppl.LBA5504
- Lorusso D, Xiang Y, Hasegawa K, et al. 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;403(10434):1341-1350. doi:10.1016/S0140-6736(24)00317-9
- Lorusso D, Xiang Y, Hasegawa K, et al. 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): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;404(10460):1321-1332. doi:10.1016/S0140-6736(24)01808-7
