Abstract OT3-06-01: SHERBOC: A double-blind, placebo-controlled, phase 2 trial of seribantumab (MM-121) plus fulvestrant in postmenopausal women with hormone receptor-positive, heregulin positive, HER2 negative metastatic breast cancer whose disease progressed after prior systemic therapy

Background: The receptor tyrosine kinase, HER3 and its ligand, heregulin (HRG), have been implicated in the initiation and progression of multiple cancer types including: breast, lung, and head & neck cancers. Seribantumab is a fully human, monoclonal IgG2 antibody that binds to the ligand-binding domain of HER3 and inhibits HRG-mediated signaling. Previously, seribantumab was tested in combination with exemestane in a placebo-controlled, Phase 2 study in post-menopausal women with ER/PR+, HER2 negative metastatic breast cancer (mBC). Although the trial failed to meet its primary efficacy objective of a 50% reduction in hazard ratio in the seribantumab/exemestane treatment vs. the placebo/exemestane control group, a positive trend in PFS and a statistically significant improvement in median OS was observed in patients in the seribantumab/exemestane treatment group. Seribantumab has also been tested in three randomized Phase 2 studies adding to standard of care (SOC) in non-small cell lung, ER/PR+ mBC, and platinum resistant/refractory ovarian cancer. These studies were retrospectively analyzed to determine correlation between HRG mRNA levels in tumor tissue and PFS. In each of these studies, the presence of tumor cell HRG mRNA was prognostic for shortened PFS with SOC treatment. Further, the addition of seribantumab to SOC therapy improved PFS for patients with HRG+ tumors. These data support the hypothesis that HRG expression may define a drug tolerant cancer cell phenotype characterized by poor response to multiple classes of cytotoxic and targeted therapies, including aromatase inhibitors and SERDs. Additionally, blockade of HRG-induced HER3 signaling by seribantumab may counter such protective effects of HRG on cancer cells, with the potential for improved outcomes in HRG+ patients. It is estimated that ˜45% of hormone-receptor positive, HER2 negative advanced breast cancers are HRG+ and that HRG expression may contribute to accelerated clinical progression observed in this subset of patients. Trial design: In the upcoming randomized, double-blinded, multi-center, Phase 2 study, ER/PR receptor-positive, HER2 negative mBC patients with HRG+ tumors will be prospectively selected using a HRG RNA in situ hybridization assay. Approximately 200 women will be screened to enroll 80 HRG+ subjects. Eligible subjects will be randomized in a 1:1 ratio to receive seribantumab/fulvestrant or placebo/fulvestrant until investigator-assessed disease progression or unacceptable toxicity, whichever comes first. Subjects will have progressed on one or two prior hormonal therapies, one of which must have been a CDKi-containing regimen. The goal of this study is to determine if the combination of seribantumab + fulvestrant is more effective than placebo + fulvestrant based on PFS (primary end point) in HRG positive subjects. Secondary endpoints include OS, objective response rate, and time to progression. Safety will also be assessed. Enrollment is expected to begin in 2017 at approximately 80 sites globally. Citation Format: Kaufman PA, Pipas M, Finn GJ, Mathews SE, Zhang H, Richards J, Kudla AJ, Bloom T, Zalutskaya AA, Llorin-Sangalang J, Pinto AC, Ettl J. SHERBOC: A double-blind, placebo-controlled, phase 2 trial of seribantumab (MM-121) plus fulvestrant in postmenopausal women with hormone receptor-positive, heregulin positive, HER2 negative metastatic breast cancer whose disease progressed after prior systemic therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-01.