The addition of pembrolizumab to chemotherapy with or without bevacizumab led to improved overall survival and progression-free survival in women with persistent, recurrent, or metastatic cervical cancer in the final protocol-specified overall survival analysis of the KEYNOTE-826 trial presented at the 2023 ASCO Annual Meeting.1 Improvements with the addition of pembrolizumab to chemotherapy were observed regardless of the level of PD-L1 expression in the tumor. These results confirm the findings of the interim analysis of the trial.
At a median follow-up of 39 months, overall survival was as follows: 28.6 months in the pembrolizumab group vs 16.5 months in the placebo group for patients with a PD-L1 combined positive score (CPS) of 1 or higher; 29.6 months in the pembrolizumab group vs 17.4 months in the placebo group for patients with a PD-L1 CPS of 10 or higher; and 26.4 months in the pembrolizumab group vs 16.8 months in the placebo group for all participants.
Although overall survival trended higher among patients with higher levels of PD-L1 expression, all patients had a clinically significant and statistically significant improvement when pembrolizumab was added. Across the entire study population, the addition of pembrolizumab reduced the risk of death by 37% (P < .0001).
For all participants, progression-free survival was 10.4 months in the pembrolizumab group vs 8.2 months in the placebo group. The combination of pembrolizumab with chemotherapy reduced the risk of death by 40% in patients with a PD-L1 CPS of 1 or higher and by 42% in patients with a PD-L1 CPS of 10 or higher.
“This study demonstrates that giving immunotherapy earlier provides a substantial overall survival benefit compared with the second-line setting.”— Bradley J. Monk, MD
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“Before KEYNOTE-826, the standard of care [for this population] was a platinum-based paclitaxel chemotherapy combination with or without bevacizumab treatment,” said lead author Bradley J. Monk, MD, Professor in the Division of Gynecologic Oncology at Creighton University School of Medicine, HonorHealth Research Institute, Phoenix. “This study demonstrates that giving immunotherapy earlier provides a substantial overall survival benefit compared with the second-line setting. Our results also show a survival benefit of pembrolizumab in patients who are not eligible for bevacizumab, offering a therapeutic option in this population of patients with an unmet need. These long-term follow-up results support the use of pembrolizumab with chemotherapy, with or without bevacizumab, which is becoming a new standard of care for the first-line treatment of this patient population.”
Cervical cancer is a serious health problem worldwide. It is the fourth most common cancer worldwide, and the major risk factor for developing it is the human papillomavirus (HPV). Despite the availability of the HPV vaccine, there hasbeen no significant drop-off in cases of cervical cancer, suggesting that uptake of the vaccine is suboptimal. In the United States, around 13,000 new cases are diagnosed each year, responsible for about 4,000 deaths.
“Because many cases of cervical cancer are virally related, immunotherapy should be effective,” Dr. Monk continued.
Study Details
The multinational, phase III, placebo-controlled, randomized KEYNOTE-826 trial included 617 patients with persistent, recurrent, or metastatic cervical cancer who had not yet received systemic chemotherapy and were not eligible for curative treatment with surgery or radiation therapy. Prior treatment with radiosensitizing chemotherapy was allowed. The median age was about 48 years. Stratification factors at baseline were the presence of metastatic disease (yes or no), PD-L1 CPS < 1 to > 10%, and planned bevacizumab (yes or no).
Patients (n = 617) were randomly assigned 1:1 to receive first-line treatment with either pembrolizumab with chemotherapy, with or without bevacizumab (308 participants), or placebo with chemotherapy, with or without bevacizumab (309 participants), for up to 35 cycles. Among all participants, 88.8% had a PD-L1 CPS of 1 or higher and 51.4% had a PD-L1 CPS of 10 or higher, leaving 11.2% of patients with no detectable PD-L1 expression. The dual primary endpoints of the study were overall survival and progression-free survival.
Patients treated with pembrolizumab had more grade 3 or higher adverse events than those in the placebo group: 82.4% vs 75.4%, respectively. The most common grade 3 or higher adverse effects in the pembrolizumab group vs the placebo group, respectively, were anemia (30.3% vs 27.8%), neutropenia (12.4% vs 9.7%), and hypertension (10.4% vs 11.7%).
“These long-term follow-up results support the use of pembrolizumab with chemotherapy, with or without bevacizumab, which is becoming a new standard of care for the first-line treatment of this patient population.”— Bradley J. Monk, MD
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Pembrolizumab is currently approved by the U.S. Food and Drug Administration in combination with chemotherapy, with or without bevacizumab, to treat persistent, recurrent, or metastatic cervical cancer that expresses PD-L1. This study shows that the addition of pembrolizumab to chemotherapy could be an effective first-line treatment option for people with this diagnosis, regardless of whether the cancer expresses PD-L1.
The role of pembrolizumab is being studied in a separate, ongoing phase III clinical trial in patients with locally advanced cervical cancer.
Bright Future in Cervical Cancer Treatment
Following Dr. Monk’s presentation at a premeeting press conference, he said, “There have been no new safety signals since the interim analysis. With the final analysis of this trial, the impact of pembrolizumab is even better. This is important—that over the long term, the efficacy got better.”
“I think it is probably possible to cure a solid tumor with immunotherapy. Now you can use the HPV vaccine to prevent cervical cancer. Over the next few years, I would like to go out of business in treating cervical cancer,” he told listeners.
Julie R. Gralow, MD, FACP, FASCO
Julie R. Gralow, MD, FACP, FASCO, Chief Medical Officer of ASCO, said she is interested in seeing the results of the study in the PD-L1–negative patients. “In general, figuring out a biomarker for immunotherapy checkpoint inhibitors is challenging. ASCO has formed a task force to identify the best assays to predict benefit from immune checkpoint inhibitors in specific tumor types and compare across assays and agents. No diagnostic company or pharmaceutical company is conducting this sort of study, so our task force is exploring options for a real-world trial.”
Comments on the Study
“The results of this study solidify the addition of pembrolizumab to chemotherapy with or without bevacizumab in people with persistent, recurrent, or metastatic cervical cancer as the front-line standard of care for this disease. Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population,” said ASCO expert Merry Jennifer Markham, MD, FACP, FASCO, of the University of Florida Health Cancer Center.
“Survival significantly improved with this approach, regardless of PD-L1 expression, further supporting its use for all patients in this population.”— Merry Jennifer Markham, MD, FACP, FASCO
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Ursula A. Matulonis, MD, Chief, Division of Gynecologic Oncology at Dana-Farber Cancer Institute, commented: “The overall survival improvement observed with the addition of pembrolizumab to chemotherapy as treatment for patients with persistent, advanced or recurrent cervical cancer in KEYNOTE-
Ursula A. Matulonis, MD
826 is impressive and impactful. Pembrolizumab combined with chemotherapy defines the standard of care for first-line treatment of this population of cervical cancer patients and represents a significant advancement in the treatment of cervical cancer. Importantly, the overall survival benefit of adding pembrolizumab was observed regardless of PD-L1 status or use of bevacizumab.”
“This firmly establishes the role of immune checkpoint therapy in these patients, particularly those with PD-L1–positive tumors.”— Robert M. Wenham, MD, MS, FACS
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Robert M. Wenham, MD, MS, FACS, Chair of the Gynecologic Oncology Department, Moffitt Cancer Center, noted: “It is great to see the long-term follow-up results of -KEYNOTE-826 validating the use of pembrolizumab in patients with advanced or recurrent cervical cancer. This firmly establishes the role of immune checkpoint therapy in these patients, particularly those with PD-L1–positive tumors.” n
DISCLOSURE: The study was funded by Merck & Co. Dr. Monk has received honoraria from Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Bayer, Clovis Oncology, Eisai, Elevar Therapeutics, EMD Serono/Merck, Genmab/Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Iovance Biotherapeutics, Karyopharm Therapeutics, Macro-Genics, Merck, Mersana, Myriad Pharmaceuticals, Novartis, Novocure, OncoC4, Pfizer, Pieris Pharmaceuticals, Puma Biotechnology, Regeneron, Roche/Genentech, Sorrento Therapeutics, TESARO/GSK, US Oncology, and Vascular Biogenics; has had a consulting or advisory role for Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Bayer, Clovis Oncology, Eisai, Elevar Therapeutics, EMD Serono/Merck, Genmab/Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Iovance Biotherapeutics, Karyopharm Therapeutics, Merck, Mersana, Myriad Pharmaceuticals, Novartis, Novocure, OncoC4, Pfizer, Pieris Pharmaceuticals, Puma Biotechnology, Regeneron, Roche/Genentech, Sorrento Therapeutics, Tesaro/GSK, US Oncology, and Vascular Biogenics; is on the speakers bureau for AstraZeneca, Clovis Oncology, Eisai, Merck, Roche/Genentech, and Tesaro/GSK; and has received institutional research funding from Advaxis, Amgen, Array BioPharma, AstraZeneca, Genentech, Immunogen, Janssen, Eli Lilly, Morphotek, Novartis, NuCana, Pfizer, Regeneron, and Tesaro. Dr. Gralow reported no conflicts of interest. Dr. Markham has served in a consulting or advisory role for GSK; and has received research funding from Aduro Biotech, Eli Lilly, Novartis, Tesaro, VBL Therapeutics, AstraZeneca, and Merck. Dr. Matulonis reported financial relationships with Agenus, AstraZeneca, Blueprint Medicines, Immunogen, Allarity, Boehringer Ingelheim, CureLab, GlaxoSmithKline, Merck, NextCure, Novartis, Ovarian Cancer Research Alliance, and Trillium; and serves on data and safety monitoring boards for Alkermes and Symphogen. Dr. Wenham has participated in data safety monitoring, trial steering committee, advisory board, and speaker activities for which he has received honoraria from Tesaro/GSK, Clovis, Genentech, Mersana, Marker Therapeutics, Ovation Diagnostics, AstraZeneca, Novacure, Shattuck Labs, SeaGen, Regeneron, Legend Biotech, Sonnet Biotherapeutics, Eisai, Immunogen, Link Therapeutics, and Merck; has received grant support from Anixa Bioscience, Merck, and On Target Labs; has stock from Ovation Diagnostics; and receives support to his institution as principal investigator for sponsored clinical trials.
REFERENCE
1. Monk B, Colombo N, Tewari KS, et al: KEYNOTE-826: Final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy versus placebo + chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer. 2023 ASCO Annual Meeting. Abstract 5500. Presented June 3, 2023.
