Abstract 5464: In-vitro studies of MM-121/SAR 256212, an anti-ErbB-3 antibody, in combination with erlotinib in EGFR-wild-type NSCLC.
Authors: Wainszelbaum Marisa J. , Sevecka Mark S. , Burenkova Olga , Garcia Gabriela , Kubasek William , MacBeath Gavin 
Published: August 2014

Abstract
MM-121/SAR 256212 is a fully human anti ErbB3/HER3 antibody that blocks ligand-induced receptor activation. Formation of EGFR/ErbB3 (ErbB1-3) heterodimers has been implicated as a major driver of tumor growth and survival in non-small cell lung cancer (NSCLC). Although erlotinib remains the standard-of-care treatment for patients with EGFR-wild-type NSCLC who have failed platinum combination chemotherapy, clinical benefit is typically modest. To address this unmet medical need, we investigated the combination of erlotinib with MM-121 in pre-clinical models of NSCLC. We initially assembled a panel of 25 EGFR-WT NSCLC cell lines spanning the most common histological subtypes (adenocarcinoma, squamous and large-cell carcinoma). Clinical studies show that tumors harboring activating Ras mutations less commonly respond to ErbB-directed therapies. To explore the effect of Ras mutations on responsiveness to MM-121, we also selected our cell lines to include a variety of H-/K-/N-Ras genotypes. Using a carefully optimized in-vitro 3D culture system, we then measured cell viability in response to MM-121, erlotinib or a combination of the drugs in the presence or absence of exogenously added epidermal growth factor (EGF) and/or heregulin-β1 (HRG). Our results indicate that MM-121 inhibits HRG-driven cell proliferation in the studied cell lines. In the five cell lines exhibiting dual-EGF-HRG-driven cell proliferation, the combination of MM-121 with erlotinib demonstrated superior inhibition of cell viability over erlotinib alone.To assess the ability of MM-121 to inhibit tumor cell growth independent of exogenously supplied HRG, we established mouse xenografts from three of the cell lines and treated mice with erlotinib, MM-121, or a combination of the two. All three in-vivo models showed greatly enhanced inhibition of tumor cell growth compared to erlotinib alone in a manner consistent with our in-vitro results.
Analyzing our in vitro data we found that mutations in Ras genes (HRAS, KRAS, NRAS) do not preclude response to MM-121 or incremental benefit from the combination of MM-121 with erlotinib over erlotinib alone. Non-adenocarcinoma origin likewise did not preclude response to MM-121, although a weak trend towards diminished activity in the ten non-adenocarcinoma NSCLC cell lines was apparent. Merrimack Pharmaceuticals and Sanofi are co-developing MM-121 and a Phase 1-2 study of MM-121 in combination with erlotinib is currently enrolling patients with EGFR-wild-type NSCLC.
Citation Format: Marisa J. Wainszelbaum, Mark S. Sevecka, Olga Burenkova, Gabriela Garcia, William Kubasek, Gavin MacBeath. In-vitro studies of MM-121/SAR 256212, an anti-ErbB-3 antibody, in combination with erlotinib in EGFR-wild-type NSCLC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5464. doi:10.1158/1538-7445.AM2013-5464