Time-Dependent Changes in Risk of Progression During Use of Bevacizumab for Ovarian Cancer

Key Points Question How should bevacizumab be used in the treatment of ovarian cancer? Findings This cohort study analyzed published data of randomized phase 3 trials of bevacizumab in ovarian cancer found that the treatment outcomes of bevacizumab changed over time, with a markedly increased risk of tumor progression in the bevacizumab group after a predetermined discontinuation (ie, rebound). No such outcome was noted in settings of recurrent cancer when bevacizumab was continued until progression. Meaning The findings of this study suggest that administration of bevacizumab should be considered for its time-dependent effect. Importance Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown. ObjectiveTo investigate time-dependent changes in the outcomes of bevacizumab therapy. Design, Setting, and Participants This cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed. Exposures Bevacizumab treatment vs placebo or no treatment. Main Outcomes and Measures Restricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups. Results In the ICON7-A cohort (n=745), restricted mean survival analysis showed that bevacizumab treatment (n=384) had significantly better progression-free survival (PFS) than the control (n=361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P<.001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P<.001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P<.001; after, 0.79; 95% CI, 0.63-0.98; P=.04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P<.001; after, 0.71; 95% CI, 0.56-0.90; P<.001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P<.001; after, 0.94; 95% CI, 0.78-1.15; P=.57). In Kaplan-Meier curve image-based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination-associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression. Conclusions and Relevance In ovarian cancer, bevacizumab may reduce progression for approximately 1 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, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome. This cohort study examines data from randomized clinical trials on mean survival time and relative risk of progression of ovarian cancer with use of bevacizumab.