Predictive Blood-Based Biomarkers in Patients with Epithelial Ovarian Cancer Treated with Carboplatin and Paclitaxel with or without Bevacizumab: Results from GOG-0218

Abstract

Purpose: GOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses.

Experimental design: Plasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell-derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates.

Results: Baseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (P = 0.007) and OS (P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo.

Conclusions: The inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

Figure 1.. Association between IL6 and survival outcomes.

Figure 1A. The progression-free survival (PFS) Kaplan-Meier curve shows the prognostic and predictive value of IL6 for PFS. IL6 levels were dichotomized at the median cut-point of 22.1 pg/ml. The median PFS in the control/low IL6 cohort was 12.6 months versus 16.9 months in the bevacizumab treated patients with low IL6. The difference in median PFS was more pronounced in the high IL6 cohort (8.7 months in the control arm vs. 14.2 months in the bevacizumab arm). Figure 1B. The overall survival (OS) curve demonstrates the prognostic and predictive value of IL6 for OS. IL6 levels were dichotomized at the median value of 22.1 pg/ml. The median OS in the control/low IL6 vs bevacizumab/low IL6 cohorts was similar (50.8 vs. 48.5 months). However, there was a larger difference in median OS between the control and bevacizumab high IL6 cohort (33.1 months in the control arm vs. 39.6 months in the bevacizumab arm).

Figure 2.. Cut-point optimization for IL6.

The survival curve demonstrates the prognostic and predictive value of IL6 at various cut-point values for the Kaplan-Meier curves for PFS and OS. Figure 2A and 2C. Kaplan-Meier curves for PFS outcome with IL6 dichotomized by PFS-optimized cut-point (21.4 pg/ml) (2A) or by OS-optimized cut-point (90.2 pg/ml) (2C). Figure 2B and 2D. Kaplan-Meier curves for OS outcome with IL6 dichotomized by PFS-optimized cut-point (21.4 pg/ml) (2B) or by OS-optimized cut-point (90.2 pg/ml) (2D).