Abstract Heregulin (HRG) is the cognate ligand of the human epidermal growth factor receptor 3 (ErbB3) and has been identified as a potent driver of a distinct tumor cell phenotype characterized by enhanced survival that appears to be inherently more resistant to standard of care therapies. Preclinical studies indicate that not only can HRG induce proliferation of cellular cancer models but also that it can mediate insensitivity to numerous classes of anticancer agents including chemotherapies and targeted therapeutics. Furthermore, we and others have found that HRG-ErbB3 signaling is adept at mediating insensitivity to several classes of anti-hormonal agents that currently represent the mainstay of treatment options for hormone receptor (HR+), HER2 negative advanced breast cancer. This finding, coupled with the fact that HRG is expressed in almost half of all HR+, HER2 negative advanced breast cancers, indicates that HRG-ErbB3 signal transduction may be contributing to loss of sensitivity to endocrine based therapies in this disease. Mechanistically, anti-hormonal drugs including, fulvestrant have been implicated in increasing ErbB3 expression levels, resulting in a compensatory mechanism where cells become resistant to endocrine treatments due to estrogen independent proliferation. Seribantumab is a fully human monoclonal antibody designed to block HRG from binding to ErbB3 and prevent the establishment of HRG-driven cancer cell survival in response to standard of care therapies, including chemotherapies and anti-endocrine therapies. Clinical results from a randomized, Phase 2 study in women with metastatic breast cancer who received seribantumab plus exemestane or placebo plus exemestane highlighted the ability to sensitize HRG-positive tumors to exemestane by co-administration with seribantumab. Overall, data indicated that there was a positive trend in prolonging progression-free survival (PFS) and a statistically significant difference in overall survival (OS) in this randomized and unselected or “all-comers” patient population for those patients who had seribantumab added to their exemestane therapy rather than placebo. Safety analysis indicated that seribantumab plus exemestane was well tolerated, with manageable diarrhea being the most frequent adverse event observed. A preplanned biomarker analysis using archived tissue samples showed that women who have HRG-positive tumors were less sensitive to exemestane alone and derived substantial clinical benefit when receiving the combination of seribantumab plus exemestane, illustrated by a statistically significant improvement in PFS in this HRG-positive population. Further clinical subgroup analysis suggested that patients who received prior chemotherapy and patients whose disease had progressed in the metastatic setting may be more likely to benefit from the addition of seribantumab to their exemestane. To identify patients with HRG-driven cancers, an RNA in situ hybridization (ISH) diagnostic assay has been developed and is currently being utilized to select patients in a Phase 2 non-small cell lung cancer trial. We will present updates on clinical outcomes based on recent patient subgroup analyses along with a clinical development plan for seribantumab in HR+, HER2- advanced breast cancer. Citation Format: Greg Finn, Hong Zhang, Anna Blois, sara Mathews, Art Kudla, Jason Baum, Mike Cieslewicz, gavin macbeath, Bambang Adiwijaya, Akos Czibere. A randomized trial of exemestane +/- seribantumab (MM-121) in postmenopausal women with locally advanced or metastatic ER/PR+ HER2- breast cancer: Final analysis and extended subgroup analysis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A14.
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