242P - Biomarker Analysis of a Phase 1 Study of Mm-111, a Bispecific Her2/Her3 Antibody Fusion Protein, in Combination with Multiple Treatment Regimens in Patients with Advanced Her2 Positive Solid Tumors

Abstract

ABSTRACT Aim: Activation of HER2/HER3 heterodimers by HER3's ligand heregulin (HRG) is a putative resistance mechanism for HER2-targeted therapies. MM-111 is a HER2/HER3 bispecific antibody fusion protein designed to inhibit HRG activated HER3 signaling in HER2+ tumors. This study evaluated biomarkers in patient samples from a multi-arm Phase 1 study of MM-111 combined with standard of care HER2-targeting regimens: capecitabine + cisplatin + trastuzumab (T); lapatinib (L) +/- T; paclitaxel (P) + T; L + P + T; docetaxel + T. All patients were required to have advanced HER2+ cancer. Methods: The following biomarkers were assessed in formalin fixed, paraffin-embedded archived tissue: HER2 by 5 methods including immunohistochemistry (IHC) scored using 0/1 + /2 + /3+ and image analysis (optical density) systems, quantitative immunofluorescence (qIF), fluorescent in situ hybridization (FISH), and reverse transcription polymerase chain reaction (PCR); HER3 by qIF and PCR; and HRG, betacellulin, and EGF receptor by PCR. Results: 86 patients [46 breast, 15 gastro-esophageal (GE), 11 bladder, 14 other cancers] were treated and archived tissue was received from 71 patients. All 71 samples were assessable by IHC, 69 by qIF, 64 by FISH, and 46 by PCR. The 5 HER2 assessments correlated well with each other and the correlations were independent of indication. Compared to other indications, patients with GE cancer tended to have higher HRG and HER3 expression. Stratified by indication and treatment, increased HER2 expression correlated with longer progression free survival (PFS) across all patients, particularly GE patients, but the relative contribution of MM-111 or trastuzumab could not be determined. Higher betacellulin expression was associated with longer PFS for regimens containing lapatinib. Conclusions: This study supports use of the described biomarker assays for analysis of samples from a randomized Phase 2 study of MM-111 in HER2+ GE cancer. Biomarker analyses of archived and newly acquired biopsy samples will be performed in the Phase 2 study to provide further insight for the role of HER2, HER3, and HRG in the response of HER2+ cancer to MM-111-containing therapy. Disclosure: A. Kudla, B. Adiwijaya, V. Paragas, K. Kawash, S. Frye, C.F. McDonaghand V. Moyo: Employee of Merrimack Pharmaceuticals with stock options; A.A. Garcia: Recipient of research funding from Merrimack Pharmaceuticals; C.S. Denlinger: Recipient of research funding from Merrimack Pharmaceuticals. P. Conkling: Recipient of funding from Virginia Oncology Associates and US Oncology. S. Anthony: Consultant for Paradigm.All other authors have declared no conflicts of interest.