Pembrolizumab (Keytruda) improved progression-free survival when added to standard concurrent chemoradiotherapy in the first-line for newly diagnosed, locally advanced cervical cancer in the KEYNOTE-A18 trial, according to a study presented at the annual meeting of the European Society for Medical Oncology.
The study “supports pembrolizumab plus chemoradiotherapy as a new potential standard of care” in the first-line setting for high-risk, locally advanced cervical cancer, said lead investigator Domenica Lorusso, MD, PhD, a gynecologic oncologist at the Catholic University of Rome, who reported the findings at the meeting.
The results of the trial “are compelling, especially considering newly diagnosed patients with high-risk locally advanced cervical cancer have not seen an advance in treatment options in 20 years,” she said in a press release from pembrolizumab maker Merck.
Trial data are under review at the Food and Drug Administration as part of Merck’s application for a first-line indication for pembrolizumab added to concurrent chemoradiotherapy in newly diagnosed patients with high-risk, locally advanced cervical cancer; the agency’s decision is expected in Jan. 2024.
Pembrolizumab already carries indications for persistent, recurrent, or metastatic cervical cancer.
Women in the trial were new to treatment and had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease; almost 85% had squamous cell cancer. About half the women were White; 28% were Asian, and about 2% were Black. About 5% of subjects were PD-L1 negative.
Overall, 529 women were randomized to 200 mg pembrolizumab every 3 weeks for five cycles with concurrent chemoradiotherapy (CCRT); they then received pembrolizumab 400 mg every 6 weeks for 15 cycles; 531 were randomized to placebo with CCRT, followed by 15 6-week placebo cycles.
CCRT included five cycles of cisplatin 40 mg/m2 every week for 5-6 weeks plus external beam radiotherapy followed by brachytherapy.
Two-year progression-free survival was 57.3% with placebo but 67.8% with pembrolizumab add-on, a 30% reduction in the risk of progression (P = .002).
On subgroup analysis, pembrolizumab’s PFS benefit was not statistically significant for White women (hazard ratio, 0.83; 95% confidence interval, 0.59-1.15) and women with stage 1B2 to 2B disease (HR, 0.91; 95% CI, 0.63-1.31), among others.
Although OS is not yet mature, 80.8% of placebo subjects but 87.2% of pembrolizumab women were alive at 2 years, a 27% drop in the risk of death (95% CI, 0.49-1.07).
At the meeting, Bradley Monk, MD, a gynecologic oncologist at the University of Arizona, Phoenix, who was also the study discussant, noted that “the magnitude of the benefit here is difficult to interpret because 55% of the patients [were] still on treatment” in the interim analysis, but the difference “is substantial enough for us to have confidence.”
Rates of grade 3/4 treatment-related adverse events were 60.6% in the placebo group and 67% with pembrolizumab, with anemia, nausea, and diarrhea the most common.
Grade 3/4 immune-mediated adverse events occurred in 1.1% of placebo and 4.2% of pembrolizumab subjects; hypothyroidism was the most common with pembrolizumab.
Protocol amendments in the trial included a change from PFS assessment by blinded, independent, central review to investigator assessment.
In the press release, Dr. Monk, said the results “demonstrate that, by moving an immunotherapy regimen to earlier stages of cervical cancer, we have the potential to improve outcomes for these patients compared to the current standard of care.”
The study was funded by Merck, maker of pembrolizumab. Investigators reported wide-ranging ties to the company, including Dr. Lorusso, who reported honoraria from Merck as well as ties to other companies. Dr. Monk also had deep industry ties, including being a speaker and consultant for Merck and reporting honoraria from the company.