Procedures
tumor, Tumor, toxicity, toxicities, Hematotoxicity, nausea and vomiting
HEMATOTOXICITY, INFILTRATION, TUMOR, TUMOR
Patients received triplet maintenance therapy with olaparib (300 mg tablets, orally twice daily) and bevacizumab (15 mg/kg, intravenously), followed by a combination of 300 mg olaparib twice daily (up to two years and longer in case of PR at two years), 200 mg pembrolizumab every 3 weeks (cycles 2 through 35), and 15 mg/kg bevacizumab every 3 weeks intravenously until progression or intolerable toxicity. Unlike olaparib and bevacizumab, which were started in cycle 1, pembrolizumab was initiated in cycle 2, based on the preclinical rationale that PARP inhibitors induce immune cell infiltration and PD-L1 upregulation, leading to enhanced antitumor immunity that can be further enhanced through the combination of an immune checkpoint inhibitor. Patients were allowed to withdraw from the study at any time.Dose modifications to manage toxicities were allowed. Olaparib toxicities were managed with supportive care, dose interruptions, or dose reductions (two lower dose levels were allowed: 250 mg twice daily and 200 mg twice daily). If a patient could not tolerate olaparib at 200 mg twice daily, the patient had to be discontinued. Dose re-escalation was also not permitted, but dose interruptions of less than 4 weeks were permitted. Hematotoxicity was monitored and managed as specified in the protocol (Supplementary Note). With respect to AE reporting, we have adhered to the exact terms used by clinicians. Pembrolizumab and bevacizumab toxicities could be managed with supportive care or dose interruptions; dose reductions were not permitted. Patients were discontinued if pembrolizumab was interrupted for 12 weeks or longer due to AEs or toxicity or for ≥3 weeks due to administrative causes. Bevacizumab was considered a background therapy; its administration was based on the clinicians’ discretion, and patients were allowed to continue with olaparib and pembrolizumab if bevacizumab was interrupted or discontinued. Prophylaxis for nausea and vomiting was not mandatory but was allowed. Tumor assessment was performed using computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis every three cycles for the first 2 years, every four cycles from the second to the third year, and every six cycles from the third year onward. Assessments were performed up to 7 days before or after the designated time point by the investigator using the Response Evaluation Criteria in Solid Tumours version 1.1For biomarker analysis, archival tumor tissues were collected from all patients. These biomarkers were pre-determined based on previous reports on monotherapy. For instance, PD-L1 was considered a biomarker for pembrolizumab based on the Keynote-100 study