It is estimated that globally, more than 600,000 women per year are diagnosed with cervical cancer, and more than 300,000 die annually of the disease.1 Many women continue to be diagnosed with cervical cancer at an advanced stage, with a high risk of recurrence.
To date, the most effective combination for patients with recurrent or metastatic cervical cancer that cannot be addressed with surgery has been the combination of cisplatin, paclitaxel, and bevacizumab.2 Less toxicity is seen with the use of carboplatin in place of cisplatin.3 More recently, the KEYNOTE-826 trial demonstrated a survival benefit from adding pembrolizumab to carboplatin, paclitaxel, and bevacizumab.4
Following disease progression, the prognosis for such patients is poor, and there are limited treatment options available. The potential role for immune checkpoint inhibitor treatment following platinum-based chemotherapy was investigated in the EMPOWER trial,5 which was recently reported by Tewari et al—and summarized in this issue of The ASCO Post. The study explored the performance of cemiplimab-rwlc compared with investigator’s choice of single-agent chemotherapy as treatment following disease progression on platinum-based chemotherapy.
Renata R. Urban, MD
EMPOWER/GOG-3016/ENGOT En-Cx9
In this phase III trial,5 patients with recurrent or metastatic cervical cancer with disease progression following platinum-based chemotherapy were randomly assigned to receive cemiplimab (350 mg intravenously every 21 days) or investigator’s choice of chemotherapy. Requirements for enrollment included squamous cell, adenocarcinoma, or adenosquamous histology and prior therapy with bevacizumab and with paclitaxel unless there were treatment contraindications, treatment was declined, and/or treatment was unavailable. Treatment options for those receiving chemotherapy included pemetrexed, topotecan, irinotecan, gemcitabine, and vinorelbine. The various options were selected intentionally to reflect the global variation in available agents. Although PD-L1 expression was not a requirement for enrollment, exploratory analyses were performed to assess for association between biomarker and endpoint in those patients with available archived tumor. The primary endpoint was overall survival.
A total of 608 patients were randomly assigned to cemiplimab or chemotherapy. Most patients (77.8%) had squamous cell carcinoma. The demographics and disease characteristics were balanced between the groups. Notably, more than 60% of patients were enrolled at sites outside of North America and Asia, and 15% of the study population were Hispanic/Latino. However, there were just 21 (3.5%) Black patients enrolled in the study.
The trial was stopped on the basis of prespecified criteria for efficacy in the population with squamous cell carcinoma. In the overall population, the median overall survival with cemiplimab was 12.0 months, compared with 8.5 months for chemotherapy (hazard ratio [HR] = 0.69, 98% confidence interval = 0.56–0.85, P < .001). The median overall survival in the chemotherapy group ranged from 6.8 months with topotecan to 11.8 months with irinotecan. The survival benefit of cemiplimab was seen in all histologic subcategories, with a median overall survival of 11.1 months for squamous cell carcinoma and 13.3 months for adenocarcinoma/adenosquamous carcinoma compared with 8.8 and 7.0 months with chemotherapy, respectively. Median progression-free survival, although similar in the two groups, was shown to be statistically prolonged in the cemiplimab group, with a hazard ratio of 0.71, reflecting the durable separation of curves in favor of cemiplimab after median progression-free survival was reached.
More than 90% of patients provided information on health status and quality of life. The change in quality of life from baseline was less in patients receiving cemiplimab compared with chemotherapy. The within-group overall least-squares mean change from baseline quality-of-life score on the EORTC QLQ-C30 was 1.0 in the cemiplimab group and –6.8 in the chemotherapy group.
The most common grade ≥ 3 adverse events were anemia and urinary tract infection with cemiplimab and anemia and neutropenia with chemotherapy. Therapy was discontinued due to adverse events in 8.7% vs 5.2% of patients.
Outcomes by PD-L1 Status
Of the 608 patients who were randomly assigned to treatment, 254 had baseline tumor tissue that could be evaluated for PD-L1 expression. PD-L1 expression of at least 1% was more common in patients with squamous cell carcinoma than in those with adenocarcinoma/adenosquamous histology. In all patients with PD-L1 expression of at least 1%, median overall survival was 13.9 months with cemiplimab compared with 9.3 months with chemotherapy. Among those with PD-L1 expression less than 1%, median overall survival was 7.7 months vs 6.7 months.
The EMPOWER trial demonstrates an overall survival benefit with cemiplimab for patients with recurrent or metastatic cervical cancer unselected for PD-L1 expression.— Renata R. Urban, MD
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Clinical Implications
The EMPOWER trial demonstrates an overall survival benefit with cemiplimab for patients with recurrent or metastatic cervical cancer unselected for PD-L1 expression. This was an international study with diverse recruitment. Of note, however, was the low enrollment of Black patients and absence of research sites on the African continent; this is especially notable given the burden of cervical cancer in sub-Saharan Africa.
The benefit of cemiplimab was seen in both histologic types. This is interesting when considering the outcomes for patients with tissue available for biomarker assessment. Despite the differences in PD-L1 expression between squamous and nonsquamous cell carcinomas seen in this trial and in prior studies,6 the benefit of cemiplimab remained.
The question now turns to the ideal timing of treatment with immune checkpoint inhibitors. As noted previously, the recent publication of KEYNOTE-826 demonstrated the benefit of adding pembrolizumab to the combination of carboplatin, paclitaxel, and bevacizumab in patients with recurrent or metastatic cervical cancer,4 and a prior phase I trial has shown the feasibility of incorporating ipilimumab with upfront chemoradiation in the treatment of locally advanced cervical cancer.7 Unfortunately, the accessibility of immunotherapy, as well as the resources to support the management of adverse effects, remains unpredictable in low-resourced areas.8 Future efforts to pursue the optimal role of immunotherapy should, as this trial has done, be partnered with strategies to bring these novel therapies to those areas with the greatest need.
Dr. Urban is Associate Professor, Obstetrics & Gynecology, and Program Director, Gynecologic Oncology Fellowship, at the University of Washington Medical Center, Seattle.
DISCLOSURE: Dr. Urban receives royalties from UpToDate, Inc.
REFERENCES
1. Sung H, Ferlay J, Siegel RL, et al: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209-249, 2021.
2. Tewari KS, Sill MW, Penson RT, et al: Bevacizumab for advanced cervical cancer: Final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial. Lancet 390:1654-1663, 2017.
3. Kitagawa R, Katsumata N, Shibata T, et al: Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: The open-label randomized phase III trial JCOG0505. J Clin Oncol 33:2129-2135, 2015.
4. Colombo N, Dubot C, Lorusso D, et al: Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med 385:1856-1867, 2021.
5. Tewari KS, Monk BJ, Vergote I, et al: Survival with cemiplimab in recurrent cervical cancer. N Engl J Med 386:544-555, 2022.
6. Rischin D, Gil-Martin M, González-Martin A, et al: PD-1 blockade in recurrent or metastatic cervical cancer: Data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer. Gynecol Oncol 159:322-328, 2020.
7. Da Silva DM, Enserro DM, Mayadev JS, et al: Immune activation in patients with locally advanced cervical cancer treated with ipilimumab following definitive chemoradiation (GOG-9929). Clin Cancer Res 26:5621-5630, 2020.
8. Osarogiagbon RU, Sineshaw HM, Unger JM, et al: Immune-based cancer treatment: Addressing disparities in access and outcomes. Am Soc Clin Oncol Educ Book 41:1-13, 2021.
