Cemiplimab sBLA in Second-Line Advanced Cervical Cancer Voluntarily Withdrawn

Regeneron Pharmaceuticals, Inc. and Sanofi announced the voluntarily withdrawal of the supplemental biologics license application (sBLA) for cemiplimab-rwlc (Libtayo) as a second-line treatment for patients with advanced cervical cancer whose disease progressed on or after chemotherapy.¹

“The decision was made after the companies and the US FDA were not able to align on certain post-marketing studies,” according to a regulatory update.

The application was supported by findings from the open-label, multicenter, phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial (NCT03257267), which enrolled patients with recurrent and metastatic cervical cancer who progressed on platinum-based chemotherapy. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1.²

Of the 608 patients who were enrolled to the trial, 477 had SCC and 131 had AC. Patients were randomized 1:1 to receive cemiplimab at 350 mg every 3 weeks or investigator’s choice of chemotherapy, which included: pemetrexed at 500 mg/m² every 3 weeks, gemcitabine at 1000 mg/m² on days 1 and 8 and every 21 days; topotecan at 1 mg/m² daily for 5 days, every 21 days; irinotecan at a weekly dose of 100 mg/m² for 4 weeks, followed by 10 to 14 days of rest; or vinorelbine at 30 mg/m² on days 1 and 8 and every 21 days.

Treatment was given for up to 96 weeks with an option for retreatment. Patients were stratified based on histology (SCC vs AC), geographic region, prior bevacizumab (Avastin; yes vs no), and ECOG performance status (0 vs 1).

The primary end point of the trial was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), duration of response, safety, and quality of life (QoL). Pharmacokinetics, immunogenicity, biomarkers, and pharmacodynamics served as key exploratory end points.

At the time of the first interim analysis, the independent data monitoring committee recommended that the trial continue. At the time of the second interim analysis, the committee recommended that the research be stopped early for efficacy.

The median age of the patients was 51.0 years, with 87.7% of patients under the age of 65 years. Moreover, 61.8% of patients were enrolled to clinical sites that were not based in North America or Asia, 53.5% had an ECOG performance status of 1. Regarding histology, 77.8% had a SCC histology, 19.1% had adenocarcinoma, and 3.1% had adenosquamous carcinoma. Additionally, 94.4% of patients had metastatic disease, 56.9% received 1 prior line of therapy for recurrent or metastatic disease, and 51.3% did not previously receive bevacizumab.

At a median follow-up of 16.8 months (range, 6.0-38.2), the immunotherapy significantly improved the median OS vs chemotherapy in those with squamous cell carcinoma (SCC), at 11.1 months (95% CI, 9.2-13.4) and 8.8 months (95% CI, 7.6-9.8), respectively (HR, 0.73; 95% CI, 0.58-0.91; one-sided P = .00306).

At a median follow-up of 21.9 months (range, 6.9-36.6), the median OS with cemiplimab was 13.3 months (95% CI, 9.6-17.6) vs 7.0 months (95% CI, 5.1-9.7) with chemotherapy in a subset of patients with adenocarcinoma or adenosquamous carcinoma (AC; HR, 0.56; 95% CI, 0.36-0.85; P < .005).

In the total population, and at a median follow-up of 18.2 months (range, 6.0-38.2), the median OS in the investigative and control arms was 12.0 months (95% CI, 10.3-13.5) and 8.5 months (95% CI, 7.5-9.6), respectively (HR, 0.69; 95% CI, 0.56-0.84; P = .00011).

In patients with PD-L1 positivity, the median OS was 11.1 months (95% CI, 8.0-15.0) with cemiplimab vs 8.2 months (95% CI, 6.7-10.8) with chemotherapy (HR, 0.78; 95% CI, 95% CI, 0.57-1.07). In those who did not have PD-L1 expression, the median OS with cemiplimab vs chemotherapy was 12.7 months (95% CI, 9.6-14.5) and 8.7 months (95% CI, 7.4-9.7), respectively (HR, 0.64; 95% CI, 0.49-0.84).

In the subset of patients with a PD-L1 expression of 1% or higher on tumor cells, the median OS in the investigative and control arms was 13.9 months (95% CI, 9.6–not evaluable) and 9.3 months (95% CI, 7.0-11.4), respectively (HR, 0.70; 95% CI, 0.46-1.05). In those with a PD-L1 of less than 1% on tumor cells, the median OS was 7.7 months (95% CI, 4.3-12.3) with cemiplimab vs 6.7 months (95% CI, 3.9-9.5) with chemotherapy (HR, 0.98; 95% CI, 0.59-1.62).

In the total population, the median PFS with cemiplimab vs chemotherapy was 2.8 months (95% CI, 2.6-3.9) and 2.9 months (95% CI, 2.7-3.4), respectively (HR, 0.75; 95% CI, 0.63-0.89). In those with PD-L1 positivity, the median PFS was 2.8 months (95% CI, 1.7-4.0) and 2.9 months (95% CI, 2.6-4.0), respectively (HR, 0.82; 95% CI, 0.62-1.08). In those without PD-L1 expression, the median PFS was 2.8 months (95% CI, 2.7-4.0) and 2.8 months (95% CI, 2.6-3.5), respectively (HR, 0.71; 95% CI, 0.56-0.90).

The odds ratio for ORR between cemiplimab and chemotherapy in the total population was 2.98 (95% CI, 1.71-5.22). In the subset of patients with a PD-L1 expression of 1% or higher, objective responses were achieved by 18.3% (95% CI, 10.6%-28.4%) of patients (n = 15/82). In those with a PD-L1 expression of less than 1%, objective responses were achieved by 11.4% (95% CI, 3.8%-24.6%) of patients (n = 5/44).

In those without PD-L1 expression, the odds ratio was 3.73 (95% CI, 1.71-8.13). In those with PD-L1 expression, the odds ratio was 2.28 (95% CI, 1.03-5.12).

Regarding QoL, the overall mean change from baseline Global Health Status/QoL favored the immunotherapy in the total population (one-sided nominal P < .001). No new safety signals were observed with cemiplimab.

Discussions with regulatory authorities outside of the United States are ongoing.

References

1. Regeneron and Sanofi provide regulatory update on Libtayo (cemiplimab-rwlc) in advanced cervical cancer. News release. Regeneron Pharmaceuticals, Inc. and Sanofi; January 28, 2022. Accessed January 28, 2022. https://bit.ly/3He5joT
2. Tewari KS, Monk BJ, Vergote I, et al. VP4-2021: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: interim analysis of phase III trial of cemiplimab vs investigator’s choice (IC) chemotherapy (chemo) in recurrent/metastatic (R/M) cervical carcinoma. Ann Oncol. 2021;32(7):P940-P941. doi:10.1016/j.annonc.2021.04.009