Chicago, IL—The addition of the PD-1 inhibitor pembrolizumab (Keytruda) to chemotherapy with or without bevacizumab (Avastin) resulted in a substantial and clinically meaningful improvement in overall survival (OS) in patients with persistent, recurrent, or metastatic cervical cancer, according to the final OS analysis of the phase 3 KEYNOTE-826 trial. The results were presented during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.1
“Before KEYNOTE-826, the standard of care [for this population] was a platinum-based paclitaxel chemotherapy combination with or without bevacizumab treatment,” explained lead investigator Bradley J. Monk, MD, FACS, FACOG, Professor, Gynecologic Oncology, Creighton University School of Medicine, and Director and Principal Investigator, Gynecologic Oncology Research Group, HonorHealth Research Institute, Phoenix, AZ. “This study demonstrates that giving immunotherapy earlier [first line] provides a substantial [OS] 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 a high 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.”
KEYNOTE-826 was a randomized study evaluating pembrolizumab in combination with platinum-based chemotherapy (paclitaxel [Taxol] plus cisplatin or paclitaxel plus carboplatin) with or without bevacizumab versus with placebo in combination with the same chemotherapy regimens with or without bevacizumab as first-line treatment. The trial enrolled 617 patients with persistent, recurrent, or metastatic cervical cancer who had not been treated with systemic chemotherapy and who were no longer amenable to curative treatment (ie, surgery and/or radiation).
At baseline, stratification factors included presence of metastatic disease (yes or no), PD-L1 combined positive score (CPS) (<1 vs 1 to <10 vs ≥10) and planned bevacizumab treatment (yes or no).
Investigator-assessed OS and progression-free survival (PFS) per RECIST v1.1 criteria served as the trial’s coprimary end points. Secondary end points included overall response rate (ORR), duration of response (DOR), 12-month PFS rate, and safety.
Patients were randomized in a 1:1 ratio to receive 200 mg of pembrolizumab once every 3 weeks for up to 35 cycles and paclitaxel plus cisplatin or carboplatin once every 3 weeks, with or without 15 mg/kg of bevacizumab once every 3 weeks, or placebo once every 3 weeks and paclitaxel plus cisplatin or carboplatin once every 3 weeks, with or without 15 mg/kg of bevacizumab once every 3 weeks, for up to 35 cycles.
In the primary analysis of the trial, the addition of pembrolizumab to chemotherapy with or without bevacizumab was associated with statistically significant and clinically meaningful improvements in OS and PFS.2 These results led to the 2021 FDA approval of pembrolizumab plus chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1).3
At ASCO 2023, investigators presented findings from the protocol-specific final analysis of the trial. At a median follow-up of 39 months, patients in the pembrolizumab arm (n=308) experienced a median OS of 26.4 months compared with 16.8 months for those in the placebo arm. The 12- and 24-month OS rates in the pembrolizumab group were 74.9% and 52.1%, respectively. In the placebo group, those rates were 63.7% and 38.7%, respectively.
Notably, 88.8% of enrolled patients had a PD-L1 CPS ≥1. Among this subgroup, pembrolizumab plus chemotherapy with or without bevacizumab resulted in a median OS of 28.6 months versus 16.5 months for placebo plus chemotherapy with or without bevacizumab.
The 12- and 24-month OS rates for patients with a PD-L1 CPS ≥1 in the pembrolizumab arm were 75.5% and 53.5%, respectively. Those rates were 63.2% and 39.4%, respectively, in patients with a PD-L1 CPS ≥1 in the placebo arm.
Additional findings showed that the pembrolizumab-based regimen elicited an OS benefit versus the placebo regimen in patients with a PD-L1 CPS ≥10. In this subgroup, the pembrolizumab regimen generated a median OS of 29.6 months compared with 17.4 months for the placebo regimen.
The final analysis also demonstrated that pembrolizumab plus chemotherapy with or without bevacizumab elicited a PFS benefit in the all-comer population (10.4 months vs 8.2 months), the PD-L1 CPS ≥1 subgroup, and the PD-L1 CPS ≥10 subgroup. Survival benefits were reported in the subgroups of patients who did and did not receive bevacizumab. In addition, the pembrolizumab regimen resulted in a higher ORR and longer DOR compared with the placebo regimen.
Grade ≥3 treatment-related adverse events occurred in 69.1% of patients in the pembrolizumab arm and 65% of those in the placebo arm. This resulted in discontinuation of treatment in 33.2% and 24.9% of patients, respectively.
The most common grade ≥3 adverse events in the pembrolizumab arm versus the placebo arm were anemia (30.3% vs 27.8%, respectively), neutropenia (12.4% vs 9.7%, respectively), and hypertension (10.4% vs 11.7%, respectively).
“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, Chief and Robert E. and Roselee S. Wheeler Professor of Medicine, Department of Hematology/Oncology, University of Florida Health Cancer Center, Gainesville, during a press conference prior to the meeting.
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