The PD-L1 inhibitor cemiplimab-rwlc has become the first immunotherapy to yield a statistically significant and clinically meaningful survival benefit in recurrent or metastatic cervical cancer progressing after first-line platinum-containing chemotherapy. Patients were enrolled irrespective of PD-L1 status, investigators reported in a European Society for Medical Oncology (ESMO) Virtual Plenary presentation.¹  Cemiplimab is currently approved for the treatment of patients with locally advanced or metastatic cutaneous squamous cell carcinoma and locally advanced basal cell carcinoma.

Krishnansu S. Tewari, MD, of the University of California Irvine, reported that second-line treatment with cemiplimab yielded a 27% reduction in the risk of death vs chemotherapy in the large squamous cell carcinoma population of patients in the global phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial. Median overall survival in this group was 11.1 months with cemiplimab vs 8.8 months with chemotherapy (hazard ratio [HR] = 0.73; P = .00306).

Krishnansu S. Tewari, MD

“Recurrent or metastatic cervical cancer is managed with platinum-based chemotherapy, often in combination with bevacizumab. First-line treatment of these patients is associated with a median overall survival of no more than 18 months. Unfortunately, treatment options are limited for patients who experience disease progression on these regimens, and none have demonstrated a survival benefit beyond first-line treatment,” Dr. Tewari noted.

“These results are amazing and represent the beginning of a new era in cervical cancer,” commented the study’s invited discussant, Mansoor Raza Mirza, MD, Chief Oncologist at Copenhagen University Hospital and Chairman of the European Network of Gynaecological Oncology Trials group (ENGOT). “I congratulate the research team for bringing new options to improve our patients’ opportunities for survival.”

As Dr. Tewari explained, there is a rationale for treating cervical cancer with immunotherapy. Infection with the human papillomavirus (HPV) provides immunogenic foreign antigens and may amplify PD-L1 expression. Cemiplimab is a high-affinity human IgG4 monoclonal antibody to the PD-1 receptor. Other anti–PD-1 agents have also shown efficacy in this disease, and pembrolizumab is approved for second-line treatment of PD-L1–expressing tumors under the U.S. Food and Drug Administration’s accelerated approval program. The approval of pembrolizjmab is based on an objective response rate of 14%, and results from a confirmatory phase III randomized trial in the first-line setting should be reported soon.

About EMPOWER-Cervical 1

The randomized EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study enrolled 608 patients with recurrent or metastatic cervical cancer, either squamous cell carcinoma (n = 477) or adenocarcinoma (n = 131), progressing after platinum-containing chemotherapy; prior therapy had to include paclitaxel and bevacizumab, or patients required a clinically documented reason why these agents were not given. Patients were enrolled regardless of PD-L1 expression; they could not have previously received a PD-1/PD-L1 blocker.

The women were randomly assigned to receive treatment with intravenous cemiplimab at 350 mg every 3 weeks or chemotherapy of investigator’s choice (pemetrexed, gemcitabine, topotecan, irinotecan, or vinorelbine); treatment was continued for 96 weeks, with the option for retreatment. The primary endpoint of the study, which had a hierarchical design, was overall survival.

After the second interim analysis (85% of total overall survival events in the squamous cell carcinoma subpopulation had occurred), the independent data monitoring committee recommended the trial be stopped early for efficacy. Those results were presented by
Dr. Tewari.

Overall Survival Benefit

“In the first step of the hierarchical analysis, the superiority of cemiplimab over chemotherapy in improving overall survival was apparent and significant in the squamous cell population,” Dr. Tewari commented. “To give a sense of the maturity of the data, the median duration of follow-up was 16.8 months in this population.”

Patients with squamous cell disease had a median overall survival of 11.1 months with cemiplimab vs 8.8 months with chemotherapy (HR = 0.73; P = .00306). In the overall population, which was a second step in the hierarchical design, median overall survival was 12.0 vs 8.5 months (HR = 0.69; P = .00011). Although overall survival in the adenocarcinoma population was not part of the hierarchical design, median overall survival was in keeping with the overall survival outcome, 13.3 months vs 7.0 months (HR = 0.56; P < .005), respectively.

“In addition to the histologic subgroups, the overall survival benefit of cemiplimab was also seen in prespecified subgroup analyses: by geographic region, performance status, prior bevacizumab use, and number of prior lines of therapy,” he added.

Although median progression-free survival was similar in the overall population (2.8 months with cemiplimab and 2.9 months with chemotherapy), the hazard ratio was 0.75 (P = .00048). “The progression-free survival benefit was driven by the tail of the curve. In the overall and squamous cell populations, these curves separated around 4 months and remained separated,” Dr. Tewari pointed out.

Similarly, in the squamous cell carcinoma population, median progression-free survival was 2.8 and 2.9 months, respectively (HR = 0.71; P = .00026). In the adenocarcinoma subset, benefit was suggested, but the 95% confidence interval crossed 1.

Investigator-assessed objective response rates were 16.4% with cemiplimab and 6.3% with chemotherapy. The estimated duration of response was 16.4 months and 6.9 months, and the median time to response was 2.7 months and 1.6 months, respectively.

Quality of Life and Safety

Patient-reported outcomes for global health status and quality of life showed a nominally significant difference in favor of cemiplimab over chemotherapy. For patients receiving cemiplimab, treatment improved or maintained quality of life from baseline, whereas with chemotherapy, quality of life generally deteriorated.

Grade ≥ 3 adverse events, regardless of attribution, were observed in 45% of those given cemiplimab and 53.4% of those given chemotherapy, and those related to treatment were seen in 14.7% and 40.3%, respectively. No deaths were considered related to cemiplimab. Cemiplimab was associated with a 16% incidence of immune-related adverse events, but all were known effects of PD-1/PD-L1 inhibitors, and none resulted in death. 

DISCLOSURE: Dr. Tewari has received honoraria from Clovis Oncology and Tesaro; has served as a consultant or advisor to AstraZeneca, Clovis, Roche/Genentech, and Tesaro; has participated in a speakers bureau for AstraZeneca, Clovis, Merck, Roche/Genentech, and Tesaro; has received institutional research funding from AbbVie, Genentech/Roche, Merck, Morphotek, and Regeneron; and has been reimbursed for travel, accommodations, or other expenses by Roche/Genentech. Dr. Mirza has served in a leadership role for Karyopharm Therapeutics and Sera Prognostics; holds stock or other ownership interests in Karyopharm Therapeutics and Sera Prognostics; has received honoraria from AstraZeneca, Geneos, Genmab/Seattle Genetics, GSK, Merck, Mersana, Oncology Venture, Roche, Sotio, Takeda, and Zai Lab; has served as a consultant or advisor to AstraZeneca, BioCad, Cerulean Pharma, Genmab, GSK, Karyopharm Therapeutics, Pfizer, and Sotio; has received institutional research funding from AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, and Tesaro; and holds institutional intellectual property in AstraZeneca, GSK, Pfizer, and Ultimovacs; has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Karyopharm Therapeutics, Pfizer, Roche, SeraCare, and Tesaro; and has held other relationships with European Network of Gynaecological Oncology Trials, European Society for Gynaecological Oncology, and Gynecological Cancer InterGroup.

REFERENCE

1. Tewari KS, Monk BJ, Vergote I, et al: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9: Interim analysis of phase III trial of cemiplimab vs. investigator’s choice chemotherapy in recurrent/metastatic cervical carcinoma. ESMO Virtual Plenary. Abstract VP4-2021. Presented May 12, 2021.