The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. Three prior randomized Phase 2 studies of seribantumab plus standard of care (SOC) versus SOC alone in NSCLC, breast cancer and ovarian cancer were analyzed retrospectively for correlation between the level of HRG mRNA in tumor tissue and progression free survival (PFS). High levels of HRG mRNA predicted shortened PFS in patients who received SOC treatment, while the addition of seribantumab to SOC improved PFS in patients with HRG+ tumors. This is consistent with the hypothesis that blockade of HRG-induced HER3 signaling by seribantumab can restore sensitivity to SOC impacted by HRG, improving outcomes for HRG+ patients.
In the current randomized, open-label, international, Phase 2 study, NSCLC patients with HRG+ tumors will be prospectively selected using a HRG RNA in situ hybridization assay on a recent biopsy tissue sample. Approximately 560 patients will be screened to support enrollment of 280 HRG+ patients, who will be randomized in a 2:1 ratio to receive seribantumab plus investigator's choice of docetaxel or pemetrexed, or docetaxel or pemetrexed alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies for locally advanced and/or metastatic disease, one of which must be an anti-PD-1 or anti-PD-L1 therapy. The primary endpoint is overall survival (OS). Secondary endpoints include PFS, objective response rate and time to progression. Safety and health-related quality of life will also be assessed. The study has > 80% power to detect a 33% risk improvement in median OS (hazard ratio ≤ 0.67), using a one-sided, stratified log-rank test at a significance level of 0.025. An interim analysis is planned when 50% of final OS events have been reported. Enrollment was initiated in June 2015. Approximately 80 sites worldwide will be open to enrollment by the end of 2016.
Clinical trial identification
Clinical Trials Registry number: NCT02387216
Legal entity responsible for the study
N. Demars, A.J. Kudla, S. Mathews, A. Czibere: Employee of Merrimack Pharmaceuticals. L. Horn: Consulting: Bayer, BI, BMS, Genentech, Lilly, Merck, Xcovery. J. Lee: Consultant to Boehringer Ingelheim. Participated in Genentech Speakers' Bureau and expenses reimbursed by Genentech. R. Mehra: Advisory Boards - Novartis, BMS, Genentech, Bayer, Innate Pharma Research funding – Genentech. All other authors have declared no conflicts of interest.