A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors.

Sheri L Moores,Mark L Chiu,Barbara S Bushey,Janine Schuurman,Joost Neijssen,Matthew V Lorenzi,Paul W.H.I Parren,Sylvie Laquerre,Peter Haytko,Keri Dorn,Sheng-Jiun Wu,Randall J Brezski,G Mark Anderson,Leopoldo Luistro,Kristen Chevalier,Ricardo M Attar,Thomas Kelly,Pauline L Martin

doi:10.1158/0008-5472.can-15-2833

Abstract

Non-small cell lung cancers (NSCLC) with activating EGFR mutations become resistant to tyrosine kinase inhibitors (TKI), often through second-site mutations in EGFR (T790M) and/or activation of the cMet pathway. We engineered a bispecific EGFR-cMet antibody (JNJ-61186372) with multiple mechanisms of action to inhibit primary/secondary EGFR mutations and the cMet pathway. JNJ-61186372 blocked ligand-induced phosphorylation of EGFR and cMet and inhibited phospho-ERK and phospho-AKT more potently than the combination of single receptor-binding antibodies. In NSCLC tumor models driven by EGFR and/or cMet, JNJ-61186372 treatment resulted in tumor regression through inhibition of signaling/receptor downmodulation and Fc-driven effector interactions. Complete and durable regression of human lung xenograft tumors was observed with the combination of JNJ-61186372 and a third-generation EGFR TKI. Interestingly, treatment of cynomolgus monkeys with JNJ-61186372 resulted in no major toxicities, including absence of skin rash observed with other EGFR-directed agents. These results highlight the differentiated potential of JNJ-61186372 to inhibit the spectrum of mutations driving EGFR TKI resistance in NSCLC. Cancer Res; 76(13); 3942-53. ©2016 AACR.

Highlights

Non–small cell lung cancer (NSCLC) is frequently driven by activating mutations in the kinase domain of EGFR, occurring most commonly as in-frame deletions in exon 19 and L858R exon 21 mutations
Most patients initially respond to first-generation EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, but the clinical benefits are not durable
Standard-ofcare treatment for lung cancer patients with activating mutations in EGFR involves small-molecule EGFR TKIs, such as erlotinib or gefitinib. These therapies, often initially very effective, fail due to resistance mediated by second-site EGFR mutations, such as T790M, or activation of bypass pathways, such as the cMet pathway [4, 9, 10, 26]

Summary

Introduction

Non–small cell lung cancer (NSCLC) is frequently driven by activating mutations in the kinase domain of EGFR, occurring most commonly as in-frame deletions in exon 19 and L858R exon 21 mutations. Most patients initially respond to first-generation EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, but the clinical benefits are not durable. In addition to the T790M secondary mutation in EGFR 1, 3–6) that reduces potency of reversible TKIs [7], resistant tumors may develop activation of the cMet pathway, through MET gene amplification, increased cMet expression, and/or increased expression of the cMet ligand, hepatocyte growth factor Stimulation of the cMet pathway provides an alternate mechanism to bypass the TKI block. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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Conclusion