FDA Approves Pembrolizumab/Chemoradiation in Stage III/IVA Cervical Cancer
Findings from the phase 3 KEYNOTE-A18 trial support the FDA approval of pembrolizumab plus external beam radiotherapy and concurrent chemotherapy in stage III to IVA cervical cancer.
The approval of the pembrolizumab-based regimen was supported by findings from the phase 3 KEYNOTE-A18 trial (NCT04221945), which investigators presented at the 2023 International Society of Gynecologic Cancer Society (IGCS).
The News
The FDA has granted approval to pembrolizumab (Keytruda) in combination with external beam radiotherapy (EBRT), concurrent chemotherapy, and brachytherapy for patients with FIGO stage III to IVA cervical cancer, according to a press release from the FDA.
Expert Perspective
“This approval [is] a major step in patients with high-risk, node-positive—or just high-risk in general—locally advanced cervical cancer,” Jyoti S. Mayadev, MD, a board-certified radiation oncologist and professor of radiation medicine and applied sciences at the University of California, San Diego School of Medicine, said in an interview with CancerNetwork® ahead of the approval. “This [is] a huge win for patients in terms of improving progression-free survival, and hopefully overall survival.”
Supporting Data From the Phase 3 KEYNOTE-A18 Study
The approval of the pembrolizumab-based regimen was supported by findings from the phase 3 KEYNOTE-A18 trial (NCT04221945), which investigators presented at the 2023 International Society of Gynecologic Cancer Society (IGCS).
The median progression-free survival (PFS) was not reached (NR) in the pembrolizumab and placebo arms (HR, 0.70; 95% CI, 0.55-0.89; P = .0020).2 At 24 months, the PFS rate was 67.8% (95% CI, 61.8%-73.0%) with pembrolizumab vs 57.3% (95% CI, 51.2%-62.9%) with placebo.
Investigators reported that the median overall survival (OS) was NR in the experimental and placebo arms (HR, 0.73; 95% CI, 0.49-1.07). Additionally, the 24-month OS rates in each respective arm were 87.2% (95% CI, 82.4%-90.8%) vs 80.8% (95% CI, 74.8%-85.5%).
The pembrolizumab combination produced an overall response rate (ORR) of 79.3% (95% CI, 75.5%-82.7%), including a partial response (PR) rate of 28.6% and a complete response (CR) rate of 50.7%. In the placebo arm, the ORR was 75.9% (95% CI, 72.0%-79.5%), which included PRs in 27.2% and CRs in 48.7%. Among those in the pembrolizumab and placebo arms, respectively, 81.4% and 77.3% had ongoing responses at 12 months.
In an exploratory subgroup analysis including 596 patients with FIGO 2014 stage III to IVA disease, PFS improved with the pembrolizumab regimen compared with the placebo combination (HR, 0.59; 95% CI, 0.43-0.82).1 Additionally, among 462 patients with FIGO 2014 stage IB2 to IIB disease, the estimated HR for PFS was 0.91 (95% CI, 0.63-1.31); these subgroup findings suggest that the PFS benefit with the pembrolizumab combination primarily extended to those with stage III to IVA disease.
Safety Data
Overall, 99.4% and 99.2% of patients in the pembrolizumab and placebo arms, respectively, experienced any-grade adverse effects (AEs), and 74.6% and 68.7% had grade 3 or higher AEs. Treatment-related AEs (TRAEs) leading to discontinuation of any study treatment were reported in 15.3% and 12.6% of those in each respective arm.
The most common TRAEs of any grade in the pembrolizumab and placebo arms, respectively, included anemia (59.3% vs 55.1%), nausea (57.2% vs 59.4%), diarrhea (50.4% vs 51.1%), white blood cell count decreases (32.6% vs 34.2%), and neutrophil count decreases (29.0% vs 27.9%).
KEYNOTE-A18 Trial Design
Investigators of the double-blind phase 3 KEYNOTE-A18 trial randomly assigned 1060 patients 1:1 to receive 40 mg/m2 of cisplatin every week for 5 cycles plus EBRT, brachytherapy, and pembrolizumab at 200 mg (n = 529) or matched placebo (n = 531) every 3 weeks for 5 cycles. Patients also continued treatment with 400 mg of pembrolizumab or placebo every 6 weeks across 15 cycles.
The trial’s primary end points were PFS per RECIST v1.1 criteria and OS. Secondary end points included PFS at 24 months, ORR, patient-reported outcomes, and safety.
The trial included those with stage IB2 to IIB node-positive cervical cancer or stage III to IVA disease regardless of node positivity. Other eligibility criteria included having measurable or non-measurable disease based on RECIST v1.1 guidelines and treatment-naïve disease.
The FDA granted priority review to pembrolizumab plus EBRT in September 2023 based on findings from the KEYNOTE-A18 trial.3
References
- FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 stage III-IVA cervical cancer. News release. FDA. January 12, 2024. Accessed January 12, 2024. https://shorturl.at/pswHW
- Lorusso D, Xiang Y, Hasegawa K, et al. ENGOT-cx11/GOG-3047/KEYNOTE-A18: a randomized, double-blind, phase 3 study of pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer. Presented at 2023 Annual Global Meeting of the International Gynecologic Cancer Society; November 5-7, 2023; Seoul, South Korea. Abstract SE004/1614.
- FDA grants priority review to Merck’s application for KEYTRUDA® (pembrolizumab) plus concurrent chemoradiotherapy as treatment for patients with newly diagnosed high-risk locally advanced cervical cancer. News release. Merck. September 20, 2023. Accessed January 8, 2024. https://bit.ly/3vvoJVv
