First-in-human phase 1, dose-escalation and -expansion study of ABBV-399, an antibody-drug conjugate (ADC) targeting c-Met, in patients (pts) with advanced solid tumors

Abstract

Background: The c‐Met receptor is overexpressed in multiple tumors. ABBV‐399 is a first‐in‐class ADC composed of ABT‐700, a previously described anti‐c‐Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data support ADC ABBV‐399 as a unique strategy to deliver a potent cytotoxin directly to c‐Met+ tumor cells (∼30‐50% of tumors overexpress c‐Met). Methods: In a 3 + 3 dose‐escalation design, ABBV‐399 was administered at doses ranging from 0.15 to 3.3 mg/kg once every 21 days to pts with metastatic solid tumors (NCT02099058). ABBV‐399 was then studied in a dose‐expansion cohort in pts with c‐Met+ (immunohistochemistry [IHC] H‐score ≥150) non‐small cell lung cancer (NSCLC). Overexpression of c‐Met was assessed by an IHC assay utilizing the SP44 antibody (Ventana; Tucson, AZ, USA). Results: As of March 31, 2016, 48 pts received at least 1 dose of ABBV‐399. Approximately dose‐proportional increases of area under the curve for ABBV‐399 and total antibody were observed after single‐dose administration. Half‐lives for ABBV‐399 and total antibody were approximately 2 to 4 days. Dose‐limiting toxicity of febrile neutropenia occurred in 1 pt at 3 mg/kg and 1 pt (with septic shock) at 3.3 mg/kg. A dose of 2.7 mg/kg was chosen for dose expansion based primarily on safety and tolerability. There were no treatment‐related deaths. Treatment‐related adverse events occurring in ≥10% of pts (including all dose levels and all grades) were fatigue (22.9%), nausea (20.8%), neuropathy (14.6%), decreased appetite (12.5%), vomiting (12.5%), and hypoalbuminemia (10.4%). Three of 16 (18.8%) ABBV‐399‐treated c‐Met+ NSCLC pts had a partial response with duration of response 1 + , 3, and 4.5 mo. At week 12, 6 of 16 (37.5%) had disease control. There were no responses among pts with c‐Met‐negative tumors. Conclusions: ABBV‐399 is well tolerated at a dose of 2.7 mg/kg every 21 days and has demonstrated promising antitumor activity in pts with cMet+ NSCLC. Assessment of antitumor activity and safety of ABBV‐399 in c‐Met+ pts will continue as monotherapy and in combination with standard of care.