As reported in The New England Journal of Medicine by Krishnansu S. Tewari, MD, of the Division of Gynecologic Oncology, University of California, Irvine, and colleagues, the phase III ­EMPOWER-Cervical1/GOG-3016/ENGOT-cx9 trial has shown improved overall survival with cemiplimab-rwlc vs investigator’s choice of single-agent chemotherapy in cervical cancer recurring after first-line platinum-based chemotherapy.¹

Krishnansu S. Tewari, MD

Study Details

In the international open-label trial, 608 women irrespective of PD-L1 status were randomly assigned between July 2017 and August 2020 to receive cemiplimab at 350 mg every 3 weeks for up to 96 weeks (n = 304) or investigator’s choice of single-agent chemotherapy selected prior to randomization (n = 304). Chemotherapy options included pemetrexed at 500 mg/m² every 21 days (n = 111), topotecan at 1 mg/m² daily for 5 days (n = 21) or irinotecan at 100 mg/m² weekly (n = 19) for 4 weeks, gemcitabine at 1,000 mg/m² on days 1 and 8 every 21 days (n = 121), and vinorelbine at 30 mg/m² on days 1 and 8 every 21 days (n = 32). Randomization was stratified by histologic type, geographic region, previous bevacizumab exposure, and Eastern Cooperative Oncology Group (ECOG) performance status. The primary endpoint was overall survival.

For the cemiplimab vs chemotherapy groups, 78.9% vs 76.6% had squamous cell carcinoma and 21.1% vs 23.4% had adenocarcinoma or adenosquamous carcinoma, 49.0% vs 48.4% had prior bevacizumab exposure. All patients had an ECOG performance status of 0 (46.7% vs 46.4%) or 1.

Overall Survival

At the second planned interim analysis at a median follow-up of 16.8 months in the squamous cell carcinoma population, the trial was stopped on the basis of prespecified criteria for efficacy in the population.

Median duration of follow-up in the total population was 18.2 months (range = 6.0–38.2 months) at data cutoff (January 2021). In the total population, median overall survival was 12.0 months (95% confidence interval [CI] = 10.3–13.5 months) in the cemiplimab group vs 8.5 months (95% CI = 7.5–9.6 months) in the chemotherapy group (hazard ratio [HR] = 0.69, 95% CI = 0.56–0.84, P < .001). Median overall survival ranged from 6.5 months with topotecan to 11.8 months with irinotecan. Hazard ratios for cemiplimab vs chemotherapy in subgroups according to preselected chemotherapy ranged from 0.68 to 0.78.

Among patients with squamous cell carcinoma, median overall survival was 11.1 months (95% CI = 9.2–13.4 months) vs 8.8 months (95% CI = 7.6–9.8 months), with a hazard ratio of 0.73 (95% CI = 0.58–0.91, P = .006). Among patients with adenocarcinoma or adenosquamous carcinoma, median overall survival was 13.3 months (95% CI = 9.6–17.6 months) vs 7.0 months (95% CI = 5.1–9.7 months), with a hazard ratio of 0.56 (95% CI = 0.36–0.85).

For stratification subgroups other than histology in the total population, hazard ratios for overall survival for cemiplimab vs chemotherapy were 0.64 (95% CI = 0.48–0.86) for prior and 0.76 (95% CI = 0.58–1.00) for no prior bevacizumab use, 0.59 (95% CI = 0.43–0.82) for an ECOG performance status of 0 and 0.74 (95% CI = 0.57–0.96) for an ECOG performance status of 1, and 0.52 (95% CI = 0.27–1.00) for North America, 0.65 (95% CI = 0.44–0.96) for Asia, and 0.73 (95% CI = 0.57–0.94) for the rest of the world.

Median progression-free survival was: 2.8 months (95% CI = 2.6–3.9 months) with cemiplimab vs 2.9 months (95% CI = 2.7–3.4 months) with chemotherapy in the total population (HR = 0.75, 95% CI = 0.63–0.89, P < .001), 2.8 months (95% CI = 2.6–4.0 months) vs 2.9 months (95% CI = 2.7–3.9 months) in the squamous cell population (HR = 0.71, 95% CI = 0.58–0.86, P < .001), and 2.7 months (95% CI = 2.3–4.0 months) vs 2.8 months (95% CI = 2.0–3.2 months) in the adenocarcinoma/adenosquamous carcinoma population (HR = 0.91, 95% CI = 0.62–1.34). As noted by the investigators: “The benefit with respect to progression-free survival with cemiplimab [in the total and squamous cell populations] was driven by durable separation of the curves after median progression-free survival was reached.”

In the overall population, an objective response was observed in 16.4% (95% CI = 12.5%–21.1%) vs 6.3% (95% CI = 3.8%–9.6%) of patients. Median response durations were 16.4 months (95% CI = 12.4 months to not evaluable) vs 6.9 months (95% CI = 5.1–7.7 months). Among 126 patients in the cemiplimab group with known PD-L1 status, an objective response occurred in 18% of 82 with tumor cell PD-L1 expression ≥ 1% and in 11% of 44 with PD-L1 expression less than 1%. Among 128 patients in the chemotherapy group with known status, an objective response occurred in 7.5% of 80 PD-L1–positive and in 8% of 48 PD-L1–negative patients.

Adverse Events

The most common adverse events of any grade were anemia (25.0%), nausea (18.3%), and fatigue (16.7%) in the cemiplimab group and anemia (44.5%), nausea (33.4%), and vomiting (23.4%) in the chemotherapy group. Grade ≥ 3 adverse events occurred in 45.0% of the cemiplimab group and 53.4% of the chemotherapy group; the most common adverse events in the cemiplimab group were anemia (12.0%) and urinary tract infection (5.0%) and in the chemotherapy group were anemia (26.9%) and neutropenia (9.0%). Serious adverse events occurred in 29.7% vs 26.9%. Adverse events led to discontinuation of study treatment in 8.7% vs 5.2% of patients. Immune-related adverse events of any grade occurred in 15.7% vs 0.7%, with the most common in the cemiplimab group being hypothyroidism (6%) and hyperthyroidism (3%). Adverse events led to death in five patients (1.7%) in the cemiplimab group, with none considered related to treatment, and in two patients (0.7%) in the chemotherapy group, with both considered related to treatment.

The investigators concluded: “Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy.” 

DISCLOSURE: The study was funded by Regeneron Pharmaceuticals and Sanofi. Dr. Tewari has served as a consultant to AbbVie, AstraZeneca, Clovis Oncology, Eisai, Genentech, Merck, and Tesaro.

REFERENCE

1. Tewari KS, Monk BJ, Vergote I, et al: Survival with cemiplimab in recurrent cervical cancer. N Engl J Med 386:544-555, 2022.