Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer

Abstract

Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab. Patients and Methods Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses. Results A total of 223 patients were randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P = .864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151 with available biomarker data), increased treatment benefit was observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P = .007). The HR in patients not meeting these criteria was 1.80 (95% CI, 1.08 to 2.98; P = .023). Conclusion The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels.

Trial registration: ClinicalTrials.gov NCT01447706.

Fig 1.

CONSORT diagram. EP, evaluable population; HRQOL, health-related quality of life; ITT, intent to treat.

Fig 2.

Biomarker analyses of progression-free survival. (A) Significance testing of biomarkers and assays. Assays showing a treatment interaction (P < .4) are shown in blue. The number of patients for whom biomarker data were available for each assay is shown to the left. (B) Hazard ratio estimations by biomarker status for heregulin (HRG), betacellulin (BTC), and human epidermal growth factor receptor 3 (ErbB3) in all patients for whom biomarker data were available. HRG negative (neg), HRG score < 1; HRG positive (pos), HRG score ≥ 1; BTC neg, BTC score < 1; BTC pos, BTC score ≥ 1; ErbB3 low, ErbB3 score < 2; ErbB3 high, ErbB3 score ≥ 2. (C) Local hazard ratio (HR) scan of human epidermal growth factor receptor 2 (HER2) in all patients with available data (blue) or in the subset of these patients who were HRG pos (gold). Local HR was estimated by including all patients with HER2 levels within one standard deviation of the measurement error. The number of patients used for each HR calculation is indicated by the size of the dot. (D) Cumulative HR scans of two-way combinations of biomarkers that passed significance testing by univariable analysis. In the top three plots, cumulative HR was estimated as a function of HER2 threshold, either in all patients for whom biomarker data were available (blue) or in patients positive for the second biomarker (gold; HRG pos, BTC pos, or ErbB3 high [score ≥ 2]). In the bottom three plots, points represent the estimated HR for all patients with available biomarker data (gray), patients positive for one of the biomarkers (blue), or patients positive for both biomarkers (gold). In all six plots, the x-axis indicates the percentage of patients who meet the criteria. Yellow rectangles indicate HR < 0.5. Chr-IHC, chromogenic immunohistochemistry; Fl-qIHC, fluorescence-based quantitative immunohistochemistry; ISH, in situ hybridization; RT-qPCR, reverse-transcriptase quantitative polymerase chain reaction.

Fig 3.

Kaplan-Meier estimated progression-free survival (PFS) curves by biomarker status. (A) PFS for unselected patients in the intent-to-treat population (seribantumab [S] + paclitaxel [P] v P). (B) PFS for control arm patients in the biomarker (BM) –evaluable population (P alone; BM positive [pos] v BM negative [neg]). (C) PFS for BM-pos patients in the BM-evaluable population (S + P v P). (D) PFS for BM-negative patients in the BM-evaluable population (S + P v P). BM pos, heregulin (HRG) score ≥ 1 and human epidermal growth factor receptor 2 (HER2) < 126,000 receptors per cell); BM neg, HRG score < 1 and/or HER2 ≥ 126,000 receptors per cell. HR, hazard ratio.

Fig 4.

Biomarker analyses in archived tissue. (A) Concordance of heregulin (HRG) and human epidermal growth factor receptor 2 (HER2) status between archived tissue and pretreatment biopsies in patient-matched samples. HRG high, HRG score ≥ 1; HRG low, HRG score < 1; HER2 high, HER2 ≥ 126,000 receptors per cell; HER2 low, HER2 < 126,000 receptors per cell. (B) Relationship between local progression-free survival hazard ratio (HR; seribantumab [S] + paclitaxel [P] v P) and HRG reverse-transcriptase quantitative polymerase chain reaction (RT-PCR) values in archived tissue. HRs were estimated at different values of HRG by including all patients with HRG levels within one standard deviation of the measurement error. The number of patients used for each HR estimation is indicated by the size of the dot. LLOQ, lower limit of quantification. CT, cycle threshold.

Fig A1.

Kaplan-Meyer estimated overall survival (OS) curves by biomarker status. (A) OS for unselected patients in the intent-to-treat population (seribantumab [S] + paclitaxel [P] v P). (B) OS for control arm patients in the biomarker (BM) -evaluable population (P alone; BM positive [pos] v BM- negative [neg]). (C) OS for BM-positive patients in the BM-evaluable population (S + P v P). (D) OS for BM-negative patients in the BM-evaluable population (S + P v P). BM pos, heregulin (HRG) pos and human epidermal growth factor receptor 2 (HER2) < 126,000 receptors per cell); BM neg, HRG neg and/or HER2 ≥ 126,000 receptors per cell. HR, hazard ratio.

Fig A2.

Subgroup analyses by baseline clinical covariates. (A) Forest plot of progression-free survival by baseline clinical covariates in the overall safety population. (B) Number of patients in the treatment (seribantumab [S] + paclitaxel [P]) and control (P) arms by clinical covariates in the overall safety population and in the biomarker (BM) –positive (pos) subpopulation. BM pos, heregulin pos and human epidermal growth factor receptor 2 < 126,000 receptors per cell. HR, hazard ratio.