ABBV-399, a c-Met Antibody-Drug Conjugate that Targets Both <i>MET</i>-Amplified and c-Met-Overexpressing Tumors, Irrespective of <i>MET</i> Pathway Dependence.

Abstract

<b>Purpose:</b> Despite the importance of the <i>MET</i> oncogene in many malignancies, clinical strategies targeting c-Met have benefitted only small subsets of patients with tumors driven by signaling through the c-Met pathway, thereby necessitating selection of patients with <i>MET</i> amplification and/or c-Met activation most likely to respond. An ADC targeting c-Met could overcome these limitations with potential as a broad-acting therapeutic.<b>Experimental Design:</b> ADC ABBV-399 was generated with the c-Met-targeting antibody, ABT-700. Antitumor activity was evaluated in cancer cells with overexpressed c-Met or amplified <i>MET</i> and in xenografts including patient-derived xenograft (PDX) models and those refractory to other c-Met inhibitors. The correlation between c-Met expression and sensitivity to ABBV-399 in tumor and normal cell lines was assessed to evaluate the risk of on-target toxicity.<b>Results:</b> A threshold level of c-Met expressed by sensitive tumor but not normal cells is required for significant ABBV-399-mediated killing of tumor cells. Activity extends to c-Met or amplified <i>MET</i> cell line and PDX models where significant tumor growth inhibition and regressions are observed. ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard-of-care chemotherapy.<b>Conclusions:</b> ABBV-399 represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met-overexpressing tumor cells enabling cell killing regardless of reliance on <i>MET</i> signaling. ABBV-399 has progressed to a phase I study where it has been well tolerated and has produced objective responses in c-Met-expressing non-small cell lung cancer (NSCLC) patients. <i>Clin Cancer Res; 23(4); 992-1000. ©2016 AACR</i>.