Treatment with cemiplimab in a phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study led to significantly longer overall survival (OS) than chemotherapy among patients with recurrent cervical cancer who had had disease progression after first-line platinum-containing chemotherapy. As compared with the investigator’s choice of chemotherapy, cemiplimab treatment resulted in a 31% lower risk of death in the overall population and a 27% lower risk of death in the population with squamous cell carcinoma. The OS benefit with cemiplimab was consistent in clinically relevant subgroups, including patients with adenocarcinoma or adenosquamous carcinoma and patients with previous bevacizumab exposure. The study findings are published by Dr. Krishnansu S. Tewari of the Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, University of California, Irvine, Orange County, CA, US and colleagues in the 10th February 2022 issue of The New England Journal of Medicine.
The authors wrote in the background that despite the improvement in OS conferred by antiangiogenic therapy, most patients have progression after first-line platinum-containing therapy and have limited treatment options. Patients with recurrent cervical cancer have a poor prognosis. Currently, pembrolizumab is the only anti–PD1 agent approved in the US as second-line therapy for patients with recurrent cervical cancer. Cemiplimab is a high-affinity, fully human PD1–blocking monoclonal antibody with shown preliminary clinical activity in cervical cancer. It is approved for treatment of lung and skin cancers.
In this phase III study, the investigators enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of PD-L1 status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator’s choice of single-agent chemotherapy. The primary endpoint was OS. Progression-free survival (PFS) and safety were also assessed.
In total, 608 women were enrolled, 304 in each group. In the overall study population, median OS was longer in the cemiplimab group than in the chemotherapy group, 12.0 months versus 8.5 months (hazard ratio [HR] for death 0.69, 95% confidence interval [CI] 0.56 to 0.84; two-sided p < 0.001). The OS benefit was consistent in both histologic subgroups, squamous cell carcinoma and adenocarcinoma (including adenosquamous carcinoma).
PFS was also longer in the cemiplimab group than in the chemotherapy group in the overall population (HR for disease progression or death 0.75, 95% CI 0.63 to 0.89; two-sided p < 0.001).
In the overall population, an objective response occurred in 16.4% (95% CI 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI 4 to 25) of those with PD-L1 expression of less than 1%.
Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy.
The authors commented that the approval of pembrolizumab was initially based on a single-group phase II study in which antitumour activity was observed in patients with PD-L1–positive tumours (combined positive score [CPS] ≥1), but not in PD-L1–negative tumours. Accordingly, the approved use of pembrolizumab as monotherapy in the context of second-line and later treatment is restricted to patients whose tumours express PD-L1 with a CPS of 1 or higher.
In this study, objective responses were seen in patients with PD-L1 expression of less than 1%. Only a subgroup of patients had samples that could be evaluated for PD-L1 expression, which made interpretation of the role of PD-L1 expression in the response to cemiplimab treatment difficult to assess. However, these results suggest that some PD-L1–negative patients may have a response to cemiplimab.
The authors concluded that in this randomised study that involved patients with recurrent cervical cancer who had disease progression after platinum-containing therapy, cemiplimab showed a benefit with respect to OS that was significant and clinically meaningful.
The study was funded by Regeneron Pharmaceuticals and Sanofi.
Tewari KS, Monk BJ, Vergote I, et al. for the Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med 2022; 386:544-555.