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

Abstract

ImportanceAlthough 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 ParticipantsThis 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.ExposuresBevacizumab treatment vs placebo or no treatment.Main Outcomes and MeasuresRestricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups.ResultsIn 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 RelevanceIn 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.

Paradigm Shift: A Comprehensive Review of Ovarian Cancer Management in an Era of Advancements

“…This agent was the first biological drug to show a promising therapeutic response in the frontline intervention (first-line therapy) and recurrent OC (second-line therapy) [125,130]. However, its effect on PFS is limited and does not prolong OS [131,132]. Also, bevacizumab is associated with considerable toxicity, with a list of adverse events including hypertension, thrombotic events, gastrointestinal perforation, and renal and central nervous system disorders [125,133,134].…”

Vascular normalization: reshaping the tumor microenvironment and augmenting antitumor immunity for ovarian cancer

“…Combining bevacizumab with chemotherapy has been explored for the treatment of ovarian cancer ( 92 – 95 ). However, recent meta-analysis demonstrates a more pronounced improvement in median progression-free survival (PFS) achieved by bevacizumab alone or in combination with other inhibitors, yet it does not indicate any overall survival benefit, even detrimental to post-progression survival ( 96 ). The result highlights the need to identify predictive biomarkers that can discriminate the patients potentially benefited from bevacizumab.…”

Circulating serum miRNAs predict response to platinum chemotherapy in high-grade serous ovarian cancer

“…The standard treatment strategy for HGSOC is primary debulking surgery followed by chemotherapy or neoadjuvant chemotherapy with subsequent interval debulking surgery [4]. The introduction of bevacizumab and Poly(ADP-ribose) polymerase inhibitors (PARPi) has expanded the spectrum of available treatment alternatives, but consistent therapy efficacy is limited [5, 6]. Platinum chemotherapy remains the most vital therapeutic agent for the treatment of both primary and recurrent HGSOC [4].…”