The addition of pembrolizumab to chemotherapy prolonged survival in recurrent, persistent, or metastatic cervical cancer, according to results of the KEYNOTE-826 study presented at the European Society for Medical Oncology (ESMO) Congress 2021 by Nicoletta Colombo, MD, and colleagues (Abstract LBA2_PR). Adding pembrolizumab to chemotherapy (paclitaxel plus cisplatin or carboplatin) with or without bevacizumab led to a 33% reduction in the risk of death and a 35% reduction in the risk of disease progression and death, according to results presented at a Presidential Symposium. The progression-free survival and overall survival benefits of immunotherapy were observed regardless of bevacizumab use and independent of PD-L1 status.
The study was also published in The New England Journal of Medicine to coincide with the presentation at the ESMO Congress.
Pembrolizumab may be a new standard of care for persistent, recurrent, or metastatic cervical cancer.— Nicoletta Colombo, MD
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“Previous studies showed that adding antiangiogenesis therapy with bevacizumab prolonged survival by 3.7 months over chemotherapy alone. KEYNOTE-826 was the first study to explore the addition of PD-1 inhibition to chemotherapy with or without bevacizumab, and benefits in survival and disease progression were observed regardless of expression of PD-L1, a protein related to immunomodulation,” said Dr. Columbo, Director of the Gynaecology Programme, European Institute of Oncology, Milan, Italy.
“Pembrolizumab may be a new standard of care for persistent, recurrent, or metastatic cervical cancer,” she added.
“Patients with persistent, recurrent, or metastatic cervical cancer have suffered historically from a dismal prognosis with an overall survival no longer than 12 months. The KEYNOTE-826 study is a new milestone, demonstrating a very relevant increment in the overall survival of patients with this condition, and for the first time showing that incorporating immunotherapy into front-line treatment can change the natural history of the disease,” stated Antonio Gonzalez-Martinez, MD, Cancer Centre Director, Clinica Universidad de Navarra, Madrid, Spain, who was not involved in the study.
Study Details
KEYNOTE-826 was conducted at 151 sites in 19 countries. The trial investigators randomly assigned 617 women with recurrent, persistent, or metastatic cervical cancer to receive immunotherapy with pembrolizumab vs placebo. Patients also received chemotherapy with paclitaxel plus investigator’s choice of cisplatin or carboplatin and bevacizumab at the investigator’s discretion. These women were not previously treated for advanced disease and were not considered curable.
Stratification factors at enrollment were metastatic status, planned bevacizumab use, and PD-L1 combined positive score (CPS). The dual primary endpoints were progression-free survival and overall survival. About 63% of patients in each arm received bevacizumab. Eighty-eight percent of patients had PD-L1 CPS ≥ 1 at baseline and 51.4% had CPS ≥ 10.
Median progression-free survival in patients with PD-L1 CPS ≥ 1 was 10.4 months with pembrolizumab vs 8.2 months with placebo; in patients with PD-L1-CPS ≥ 10, the rates were almost identical—10.4 months and 8.1 months, respectively. Similarly, the rates of median progression-free survival were 10.4 months and 8.2 months, respectively, in all enrolled patients regardless of PD-L1 status. The between-group differences were all statistically significant at P < .001.
Median overall survival was not reached in patients in the pembrolizumab group with CPS PD-L1 ≥ 1 and ≥ 10. In all enrolled patients, median overall survival was 24.4 months with pembrolizumab vs 16.5 months with placebo. The between-group differences were all statistically significant at P < .001. Prespecified subgroup analysis showed a progression-free survival and overall survival benefit across all subgroups.
The incidence of grade 3 or higher adverse events was 81.8% in the pembrolizumab-plus-chemotherapy arm and 75.1% in the placebo-plus-chemotherapy arm. The most common adverse events of grade 3 or higher were anemia (30.6% with pembrolizumab vs 26.9% with placebo) and neutropenia (12.4% vs 9.7%).
“Side effects with the combination therapy were manageable, and the observed adverse events were as expected based on previous data on the individual drugs,” Dr. Colombo said.
Commentary
Mansoor Raza Mirza, MD
“The standard of care has been adding bevacizumab to platinum-based chemotherapy since 2014. Even with this combination, we need to do better,” said invited discussant Mansoor Raza Mirza, MD, of Rigshospitalet, Copenhagen University, Denmark.
The preplanned interim analysis is early, but results are unlikely to change, since 50% of patients have died and a large percentage of patients in each arm have discontinued treatment, according to Dr. Mirza.
Although this study raised several questions for the future, Dr. Mirza stated, “These are groundbreaking results. In the biomarker-positive population, pembrolizumab added to chemotherapy should be a new standard of care.”
Disclosure: For full disclosures of the study authors, visit oncologypro.esmo.org.
