Pembrolizumab Plus Concurrent CRT Meets OS End Point in High-Risk, Locally Advanced Cervical Cancer

Pembrolizumab (Keytruda) administered in combination with external beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy, produced a significant and clinically meaningful overall survival (OS) benefit vs concurrent chemoradiotherapy (CRT) alone in patients with newly diagnosed, high-risk locally advanced cervical cancer, according to findings from the phase 3 KEYNOTE-A18 trial (ENGOT-cx11/GOG-3047; NCT04221945).¹

Findings from a prespecified interim analysis of the trial, which was conducted by an Independent Data Monitoring Committee, also demonstrated that the toxicity profile for pembrolizumab was consistent with that observed with the agent in prior research. No new safety signals were observed.

Presentation of these results at a future medical meeting, along with their submission to global regulatory authorities, is anticipated.

Previously reported data from an interim analysis in 2023 showed that the trial met its coprimary end point of progression-free survival (PFS) with pembrolizumab plus CRT in the overall population. These findings were subsequently presented at the 2023 ESMO Congress.1,2 At a median follow-up of 17.9 months (range, 0.9-31.0), the median PFS was not reached (NR) for patients in the pembrolizumab arm (n = 528) or in the placebo plus chemoradiotherapy (n = 530) arm (HR, 0.70; 95% CI, 0.55-0.89; P = .0020). The 24-month PFS rates in these respective groups were 67.8% (95% CI, 61.8%-73.0%) vs 57.3% (95% CI, 51.2%-62.9%).

Moreover, PFS data from an exploratory subgroup analysis of patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III to IVA disease revealed an HR of 0.59 (95% CI, 0.43-0.82) with the pembrolizumab regimen, supporting the FDA’s approval of pembrolizumab plus chemoradiation for this patient subset in January 2024.³

“This is the first phase 3 trial in which an immunotherapy-based regimen has shown a statistically significant and clinically meaningful improvement in OS compared to chemoradiotherapy alone,” said Gursel Aktan, MD, PhD, vice president, global clinical development, Merck Research Laboratories, in the press release.¹ “Building on the positive PFS findings from this study, these results underscore our commitment to exploring the role of [pembrolizumab] across different types of cancers in earlier stages of disease, where there is a greater potential for better outcomes.”

KEYNOTE-A18 was a randomized, double-blind, phase 3 study, enrolling patients with high-risk locally advanced cervical cancer who had not previously undergone radiation, systemic therapy, or definitive surgery. This included those with FIGO 2014 stage IB2-IIB node-positive disease, as well as stage III-IVA with or without node-positive disease. ^1-4 Patients could have histologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Exclusion criteria included FIGO 2014 stage IVB disease; a history of, or planned, total hysterectomy; and systemic anticancer therapy within 4 weeks prior to randomization.

The trial randomly assigned 1060 patients 1:1 to receive intravenous pembrolizumab plus concurrent CRT vs placebo plus concurrent CRT. Pembrolizumab dosing began at 200 mg on day 1 of a 3-week cycle for 5 cycles followed by pembrolizumab at 400 mg on day 1 of each 6-week cycle for an additional 15 cycles. Notably, an optional 6th infusion could be administered per local practice. Placebo was administered in the same dosing schedule as pembrolizumab for patients in the control arm. Concurrent CRT consisted of a once-weekly 40 mg/m² dose of cisplatin for 5 or 6 weeks plus EBRT followed by brachytherapy, with a minimum total radiotherapy dose of 80 Gy for volume-directed treatment and 75 Gy for point-directed treatment.

The study’s primary end points were PFS and OS, with key secondary end points including complete response rate, objective response rate, and safety.

“These findings are important for patients and the medical community alike and reinforce previous data from the KEYNOTE-A18 trial, now showing this regimen has the potential to extend the lives of patients with locally advanced cervical cancer,” concluded Domenica Lorusso, MD, PhD, who is the study’s overall principal investigator, lead investigator for ENGOT, and professor of Obstetrics and Gynecology at Humanitas University in Milan, Italy.

References

1. Merck’s KEYTRUDA (pembrolizumab) plus chemoradiotherapy (CRT) significantly improved overall survival (OS) versus CRT alone in patients with newly diagnosed high-risk locally advanced cervical cancer. News release. Merck. March 15, 2024. Accessed March 15, 2024. https://www.merck.com/news/mercks-keytruda-pembrolizumab-plus-chemoradiotherapy-crt-significantly-improved-overall-survival-os-versus-crt-alone-in-patients-with-newly-diagnosed-high-risk-locally-advanced-ce/
2. Lorusso D , Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: a randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Ann Oncol. 2023;34(suppl 2):S1279-S1280. doi:10.1016/j.annonc.2023.10.032
3. FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer. FDA. January 12, 2024. Accessed March 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemoradiotherapy-figo-2014-stage-iii-iva-cervical-cancer
4. Study of chemoradiotherapy with or without pembrolizumab (MK-3475) for the treatment of locally advanced cervical cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11/GOG-3047). ClinicalTrials.gov. Updated March 4, 2024. Accessed March 15, 2024. https://clinicaltrials.gov/study/NCT04221945