371P - 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...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Clinical research
Basic Scientific Principles
Presenter Eric Angevin
Citation Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368
Authors E. Angevin1, K. Kelly2, R. Heist3, D. Morgensztern4, C. Weekes5, T.M. Bauer6, R.K. Ramanathan7, J. Nemunaitis8, X. Fan9, O. Olyaie9, A. Parikh9, E. Reilly10, D. Afar9, L. Naumovski9, J. Strickler11
  • 1Early Drug Development Department, Gustave Roussy, 94800 - VILLEJUIF CEDEX/FR
  • 2Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento/US
  • 3Children Cancer Center, Massachusetts General Hospital, Boston/US
  • 4Oncology, Washington University School of Medicine, St. Louis/US
  • 5Department Of Medicine, University of Colorado Cancer Center Anschutz Cancer Pavilion, Aurora/US
  • 6Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, Nashville/US
  • 7Hematology/oncology, Mayo Clinic Cancer Center, 85259 - Phoenix/US
  • 8Oncology, Mary Crowley Cancer Research Center, Dallas/US
  • 9Biotherapeutics, AbbVie, Redwood City/US
  • 10Oncology, AbbVie, Inc., North Chicago/US
  • 11Department Of Medicine, Duke University Medical Center, Durham/US

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.

Clinical trial identification

NCT02099058

Legal entity responsible for the study

AbbVie, Inc.

Funding

AbbVie, Inc.

Disclosure

D. Morgensztern: Speaker: Genentech, Boehringer Ingelheim; consultant: Genentech, Celgene, Heat Biologics, Bristol-Myers Squibb. R.K. Ramanathan, J. Strickler: Research funding from AbbVie. X. Fan, O. Olyaie, A. Parikh, E. Reilly, D. Afar, L. Naumovski: Employed by AbbVie and may own stock. All other authors have declared no conflicts of interest.