Identification of Patients With Ovarian Cancer Experiencing the Highest Benefit From Bevacizumab in the First-Line Setting on the Basis of Their Tumor-Intrinsic Chemosensitivity (KELIM): The GOG-0218 Validation Study

Abstract

Purpose: In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7 v 20.6 months; hazard ratio [HR], 0.78). An external validation study in the GOG-0218 trial was performed.

Methods: In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable < 1.0) and bevacizumab benefit for progression-free survival (PFS)/OS was independently assessed by NGR-GOG using univariate/multivariate analyses.

Results: KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. An unfavorable KELIM score was associated with bevacizumab benefit compared with placebo (PFS: HR, 0.70; 95% CI, 0.59 to 0.82; OS: HR, 0.87; 95% CI, 0.73 to 1.03), whereas a favorable KELIM was not (PFS: HR, 0.96; 95% CI, 0.79 to 1.17; OS: HR, 1.11; 95% CI, 0.89 to 1.39). The highest benefit was observed in patients with a high-risk disease exhibiting unfavorable KELIM, for PFS (median: 9.1 v 5.6 months; HR, 0.64; 95% CI, 0.53 to 0.78), and for OS (median: 35.1 v 29.1 months; HR, 0.79; 95% CI, 0.65 to 0.97).

Conclusion: This GOG-0218 trial investigation validates ICON-7 findings about the association between poor tumor chemosensitivity and benefit from concurrent-maintenance bevacizumab, suggesting that bevacizumab may mainly be effective in patients with poorly chemosensitive disease. Bevacizumab may be prioritized in patients with a high-risk and poorly chemosensitive disease to improve their PFS/OS (patient KELIM score calculator available on the Biomarker Kinetics website).

Trial registration: ClinicalTrials.gov NCT00262847.

FIG 1.

Kaplan-Meier curves of the PFS of patients according to treatment arm (arm 3 with bevacizumab concurrent-maintenance, v arm 1 with placebo) in patients with unfavorable or favorable KELIM (KEL) score, in the whole population. HR, hazard ratio; KELIM, ELIMination rate constant K; mPFS, median PFS (months); PFS, progression-free survival; Ref, reference.

FIG 2.

Kaplan-Meier curves of the OS of patients according to treatment arm (arm 3 with bevacizumab concurrent-maintenance, v arm 1 with placebo) in patients with unfavorable or favorable KELIM (KEL) score, in the whole population. HR, hazard ratio; KELIM, ELIMination rate constant K; mPFS, median PFS (months); PFS, progression-free survival; Ref, reference.

FIG 3.

Kaplan-Meier curves of the PFS of patients according to treatment arm (arm 3 with bevacizumab concurrent-maintenance, v arm 1 with placebo) in patients with favorable or unfavorable KELIM (KEL) score, in the population of patients with a high-risk disease (stage IV + stage III operated with suboptimal surgery). HR, hazard ratio; KELIM, ELIMination rate constant K; mPFS, median PFS (months); PFS, progression-free survival; Ref, reference.

FIG 4.

Kaplan-Meier curves of the OS of patients according to treatment arm (arm 3 with bevacizumab concurrent-maintenance, v arm 1 with placebo) in patients with favorable or unfavorable KELIM (KEL) score, in the population of patients with a high-risk disease (stage IV + stage III operated with suboptimal surgery). HR, hazard ratio; KELIM, ELIMination rate constant K; mPFS, median PFS (months); OS, overall survival; PFS, progression-free survival; Ref, reference.