Phase I study of ABT-700, an anti-c-Met antibody, in patients (pts) with advanced gastric or esophageal cancer (GEC).

Abstract

167 Background: MET is a receptor tyrosine kinase associated with treatment resistance. MET amplification (MA) results in c-Met overexpression and activation through autodimerization, and may be an important oncogenic driver in patients (pts) with advanced GEC. MA is relatively rare in primary tumors (<5%), but may increase under the selective pressure of systemic therapy. ABT-700 is an anti-c-Met antibody with significant preclinical single-agent activity against MA human xenograft tumors. Efficacy and safety data for ABT-700 in patients with MA advanced GEC are presented. Methods: MA was assessed in tumor biopsy tissue by fluorescence in situ hybridization (FISH; Abbott Molecular Diagnostics) or DNA sequencing. MA, identified by FISH, was defined as a MET/CEP7 ratio>2 in ≥20% of cells. The dose of ABT-700 is 15 mg/kg IV, once every 3 weeks, established during the dose escalation phase of the study. Responses were assessed using RECIST version 1.1. Results: As of May 31, 2014, 6 pts with chemotherapy refractory GEC have been treated with ABT-700. All pts had disease progression on 3 or more prior lines of chemotherapy. 4/6 pts had MA. 1 pt had MA identified retrospectively, and 3 pts had MA identified through a prospective screening effort. Among the 4 pts with MA GEC, 3 pts had a partial response (PR) and 1 pt had progressive disease (PD) as best response (ORR= 75%). Of the 3 pts who responded, the best response in target lesions was –56%,-52%, and –58%, and the PFS was 27, 18, and 24 weeks, respectively. Each of these three responders had a longer PFS with ABT-700 than with their preceding chemotherapy. In each of the 4 cases of MA identified in this study, MA was only detected in metastatic recurrent tumors and not the primary tumor tissue. The 2 pts without MA had PD as best response. ABT-700 was well tolerated, with no treatment related Grade 3-5 adverse events. Conclusions: In 4 pts with MA GEC, ABT-700 was well tolerated and appeared to have substantial single-agent activity. In this small cohort of gastric patients MA appears to be more common in treatment-refractory tumors than in primary untreated tumors, suggesting that screening efforts should focus on this treatment-refractory patient population. Clinical trial information: NCT01472016.