Bevacizumab in ovarian cancer: time-dependent changes in risk of progression

Background Bevacizumab has been used in the first-line and recurrent treatment of ovarian cancer. However, the time-dependent changes in the effects of bevacizumab administration are not fully understood. Methods The ICON7-A cohort was generated from two ancillary analyses of the ICON7 trial. ICON7-A tumors were classified as homologous recombination deficient (HRD) or non-HRD based on their gene expression profiles. Kaplan-Meier curves from published phase III trials were graphically analyzed to examine changes in the risk of progression over time between groups. Results In the ICON7-A cohort, the risk of progression in the bevacizumab group (Bev+) compared to the control group (Bev-) was lowest at 6 months. Thereafter, the risk in Bev+ gradually increased and became higher than in Bev-after discontinuation of bevacizumab at 12 months, showing a “rebound effect”. Restricted mean survival analysis showed that Bev+ had significantly better progression-free survival (PFS) than Bev-before bevacizumab discontinuation, but had significantly worse PFS after bevacizumab discontinuation. The rebound effect was observed both in HRD and non-HRD tumors of the serous subtype, but not in the non-serous subtype. In Kaplan-Meier curve image-based analysis, time-dependent changes in the risk of progression, including rebound effects, were replicated in the overall ICON7 and GOG-0218 cohorts and in their subgroups stratified by prognostic factors, presence of HR-associated mutations and chemotherapy sensitivity. In contrast, no rebound effect was observed in the studies GOG-0213, OCEANS, AURERIA and MITO16B, in which relapsed patients received bevacizumab until progression. Conclusion In ovarian cancer, bevacizumab reduces progression for approximately one year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment of ovarian cancer, bevacizumab is more beneficial in patients with a short expected survival who are unlikely to be affected by the rebound effect. ### Competing Interest Statement NM received a research grant from AstraZeneca. NM received lecture fees from Chugai Pharmaceutical, AstraZeneca, and Takeda Pharmaceutical. NM is also an outside director of Takara Bio. There are no other competing interests related to this paper. ### Funding Statement Japan Society for the Promotion of Science (JSPS) KAKENHI grant number 22K09630 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at: Original papers, NCBI Gene Expression Omnibus, European Genome-phenome Archive. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript and supplementary data.