Data from the phase 3 KEYNOTE-A18 study may support pembrolizumab plus chemoradiotherapy as a new standard of care for those with newly diagnosed, high-risk, locally advanced cervical cancer.
Adding pembrolizumab (Keytruda) to chemoradiotherapy significantly and meaningfully improved progression-free survival (PFS) compared with chemoradiation alone in patients with newly diagnosed, previously untreated, high-risk, locally advanced cervical cancer, according to findings from the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study (NCT04221945) presented at the 2023 Annual Global Meeting of the International Gynecologic Cancer Society (IGCS).
With a median follow-up of 17.9 months (range, 0.9-31.0), the median PFS was not reached (NR) among patients receiving pembrolizumab and those receiving placebo (HR, 0.70; 95% CI, 0.55-0.89; P = .0020). Additionally, the PFS rate at 24 months was 67.8% (95% CI, 61.8%-73.0%) in the experimental arm vs 57.3% (95% CI, 51.2%-62.9%) in the placebo arm.
“The PFS benefit [with pembrolizumab] was consistent in all protocol-specified subgroups,” lead study author Domenica Lorusso, an associate professor of Obstetrics and Gynecology at the Catholic University of Rome and clinical researcher at Fondazione Policlinico Gemelli IRCCS, said in a presentation. “In particular, the evaluation of PFS according to PD-L1 combined positive score [CPS] was a secondary end point of the trial. A consistent benefit was reported for pembrolizumab regardless of CPS expression.”
The median overall survival (OS) was NR in both the pembrolizumab and placebo arms (HR, 0.73; 95% CI, 0.49-1.07). Among patients who received pembrolizumab and those treated with placebo, respectively, the 24-month OS rate was 87.2% (95% CI, 82.4%-90.8%) vs 80.8% (95% CI, 74.8%-85.5%).
“These data support pembrolizumab plus chemoradiotherapy as a new potential standard of treatment in locally advanced high-risk cervical cancer,” Lorusso said.
In the double-blind KEYNOTE-A18 study, 1060 patients were randomly assigned to receive cisplatin at 40 mg/m2 every week for 5 cycles in combination with external beam radiotherapy (EBRT) and brachytherapy plus 200 mg of pembrolizumab (n = 529) or matched placebo (n = 531) every 3 weeks for 5 cycles. Additionally, patients continued treatment with 400 mg of pembrolizumab or matched placebo every 6 weeks for 15 cycles.
The trial’s primary end points were PFS based on RECIST v1.1 criteria and OS. Secondary end points included the 24-month PFS rate, overall response rate (ORR), patient-reported outcomes, and safety.
Patients with stage IB2 to IIB node-positive disease or stage III to IVA disease that was node positive or negative were able to enroll on the trial. Additional eligibility criteria included having measurable or non-measurable disease per RECIST v1.1 guidelines and being treatment naïve. Patients were stratified based on EBRT type, stage at screening, and planned total radiotherapy dose.
The median patient age was 49 years (range, 22-87) in the pembrolizumab arm and 50 years (range, 22-78) in the placebo arm. In each respective arm, most patients were White (48.0% vs 49.7%), had a PD-L1 CPS of at least 1 (94.9% vs 93.8%), and squamous cell carcinoma (81.9% vs 84.9%). Additionally, most patients in each respective arm received a planned total radiotherapy dose of at least 70 Gy (91.1% vs 91.3%), while a smaller population received less than 70 Gy (8.9% vs 8.7%).
Pembrolizumab yielded an ORR of 79.3% (95% CI, 75.5%-82.7%), which included partial responses (PRs) in 28.6% and complete responses (CRs) in 50.7%. The ORR in the placebo arm was 75.9% (95% CI, 72.0%-79.5%), which included a PR rate of 27.2% and a CR rate of 48.7%.Moreover, 81.4% of patients who received pembrolizumab and 77.3% of those who received placebo, respectively, had ongoing responses at 12 months.
Any-grade adverse effects (AEs) and grade 3 or higher AEs, respectively, occurred in 99.4% and 74.6% of patients who were treated with pembrolizumab. The corresponding rates in the placebo arm were 99.2% and 68.7%. Of note, 17.4% of patients who received pembrolizumab compared with 14.2% of those who received placebo experienced any-grade AEs that led to discontinuation of any study therapy, and 15.3% and 12.6% of patients in each respective arm had treatment-related AEs (TRAEs) that led to any type of study treatment discontinuation.
The most common TRAEs across all grades 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%). Lorusso concluded that the safety profile for pembrolizumab in combination with chemoradiotherapy was manageable.
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.