Pembrolizumab Plus Concurrent Chemoradiation Represents New SOC for High-Risk, Locally Advanced Cervical Cancer

Pembrolizumab/Concurrent Chemoradiation

in High-Risk, Locally Advanced Cervical Cancer

Findings from the phase 3 KEYNOTE-A18 trial (NCT04221945) showed that adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy improved overall survival (OS) and time to second disease progression or death (PFS2) without introducing new safety concerns in patients with newly diagnosed, high-risk, locally advanced cervical cancer, supporting its use as a new standard of care for a patient population that has experienced longstanding treatment challenges, according to Linda R. Duska, MD, MPH.

In an interview with OncLive®, Duska expanded on these data, which were presented at the 2025 SGO Annual Meeting on Women’s Cancer. Overall, 14.2% of patients in the pembrolizumab arm vs 20.5% of patients in the placebo arm had died, and the median OS was not reached (NR) in both arms (HR, 0.67; 95% CI, 0.50-0.90; P = .0040).1 Moreover, the median time to PFS2 was NR in both arms, with events occurring in 15.3% of patients in the pembrolizumab arm vs 24.3% of those in the placebo arm (HR, 0.60; 95% CI, 0.46-0.80). A progression-free survival (PFS) benefit was also sustained for the pembrolizumab combination over standard chemoradiotherapy.

“These are exciting data, and [the regimen provides] an awesome opportunity for patients who fall into this category of high-risk locally advanced cervical cancer,” Duska, a gynecologic oncologist at the University of Virginia Health in Charlottesville, emphasized.

Duska also outlined previously reported findings from the study supporting the regimen’s FDA approval for patients with FIGO 2014 stage III to IVA cervical cancer in January 2024;2 noted important subgroup data from the second interim analysis; and emphasized the need for continued research and global access to this new treatment standard for high-risk locally advanced cervical cancer.

OncLive: What unmet needs in the treatment of high-risk, locally advanced cervical cancer did this study seek to address?

Duska: Treatment [outcomes] in locally advanced cervical cancer are a particular problem. Even with modern radiation and chemotherapy, the relapse rate can be as high as 50%, and we haven't had any change in therapy since 1999. It's been more than 20 years since the National Cancer Institute…suggested that we add chemotherapy to radiation in the treatment of [patients with] locally advanced cervical cancer. [The KEYNOTE-A18 regimen] offers those patients with high-risk, locally advanced cervical cancer an opportunity to [achieve] better [responses].

What data from this trial have been previously reported?

[In 2024], [data from] the first interim analysis [were reported], and the study met its primary end point of significantly improved PFS in the experimental arm. Based on that first interim analysis, pembrolizumab in combination with concurrent chemoradiation received regulatory approval for locally advanced cervical cancer. At [the 2025 SGO Annual Meeting], we reported [data from] the second interim analysis, including OS and PFS2 data.

What made the design and execution of this study particularly notable, especially considering the logistical challenges posed by the COVID-19 pandemic?

This study was unique because it enrolled only patients with high-risk locally advanced cervical cancer. We're talking about 2014 FIGO staging in this study, to put it into context, because now we're [using] 2018 staging. [For this study], 2014 [criteria] meant stage IB2 to IIB with positive nodes, or stage III to IVA, regardless of nodal status.

The other unique thing about this study is that it accrued over 1000 patients in 2 years [despite being] a global trial [conducted] during a pandemic. [This] is amazing because people have to come for treatment every day [when receiving] combined chemoradiation. It's a work-intensive treatment for people, and yet, we were still successful in accruing [patients onto] this study.

The treatment regimen consisted of standard concurrent chemoradiation therapy with weekly cisplatin and external beam radiotherapy, followed by brachytherapy. We added pembrolizumab to that [in the experimental arm], both concurrently and in the maintenance [setting]. Patients were randomly assigned to receive either the pembrolizumab with concurrent chemoradiation or placebo, followed by pembrolizumab or placebo maintenance.

What did data from the second interim analysis demonstrate about the efficacy of pembrolizumab combined with concurrent chemoradiotherapy in patients with high-risk, locally advanced cervical cancer?

Because this study met its PFS end point at the first interim analysis, there was no formal statistical analysis of PFS for the second interim analysis. However, we did present the descriptive PFS data, which did confirm the [previously reported] results with a similar HR. The Kaplan-Meier curves [for PFS showed] a sustained separation, which is interesting. That started occurring right around the 3-month time point, which is when the first radiologic assessment was performed following the completion of concurrent chemoradiation.

OS, which was the other primary end point of the study, met statistical significance for improvement in the experimental arms [HR, 0.67], suggesting a 33% reduction in the risk of death. Again, the Kaplan-Meier curves showed a sustained separation.

One of the more interesting parts of this second analysis was PFS2. In the experimental arm, the PFS2 rate was [15.3%] compared with [24.3%] in the placebo arm. That was also statistically significant [HR, 0.60]. The median PFS2 was NR in either arm.

What do the subgroup analyses suggest about the differential PFS benefit according to disease stage?

Forest plots suggested that all the protocol-specified subgroups benefited from the experimental arm with respect to PFS. However, when you look at the confidence intervals [according to disease] stage, it appears that in that the confidence interval crosses 1 in the [stage] IB2 to IIB group. Now, when you look at [data from the] first interim analysis and compare them with the second interim analysis, with respect to PFS, the HR is slightly lower in the second interim analysis. This is hypothesis-generating only; the [study wasn’t powered for another formal PFS analysis], therefore we can't draw any conclusions from [these data].

What safety findings were reported from this study?

There were no new safety signals seen in the second interim analysis. In particular, we were worried about differentiating between colitis [seen with] the addition of pembrolizumab to pelvic radiation, [along with] the diarrhea that these patients get anyway from treatment. Fortunately, we didn't see an increased rate of diarrhea or colitis in the experimental arm. This seems to be a very well-tolerated therapy.

Given that these data support pembrolizumab plus concurrent chemoradiotherapy as a new SOC for patients with high-risk, locally advanced cervical cancer, what are the next steps for this research?

The results of this study suggest that, for this patient population, pembrolizumab in combination with concurrent chemoradiation should be the SOC. However, there are parts of the world where this kind of treatment is not available; therefore, we have to continue to do more work and do better for patients with locally advanced cervical cancer.

We're waiting for data from the final analysis, [which we will] hopefully have soon. There is still a lot more to do in this arena. One of the things we can do is work more on preventing cervical cancer in the first place. In the meantime, there's a lot of opportunity to do better for this population of patients, and there's a lot more work coming [down the pike].

References

1. Duska LR, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: overall survival and progression-free survival 2 results from the randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO). Seattle, WA; March 14-17, 2025.
2. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 Stage III-IVA cervical cancer. News release. FDA. January 12, 2024. Accessed March 15, 2025. https://tinyurl.com/25fvb223