Abstract OT2-6-16: A pivotal multicenter, randomized, study evaluating the novel antibody-drug conjugate CDX-011 in patients with metastatic, triple-negative, high GPNMB over-expressing breast cancer
Authors: Yardley DA , Melisko ME , Forero A , Telli M , Cruickshank S , Green J , Yellin M , Davis T , Vahdat LT 
Published: August 2014

Abstract
Background: GPNMB is an internalizable transmembrane glycoprotein overexpressed in multiple tumor types where it is a poor prognostic factor. Its functions appear to include mediating intercellular adhesion, promoting tissue repair, and regulating cell growth and differentiation. In tumor cell lines including breast cancer (BC), GPNMB enhances tumor growth and bone metastases. Relative to other BC subtypes, triple-negative BC (TNBC) highly over-expresses GPNMB in tumor epithelium where it correlates with a higher risk of recurrence. CDX-011 (glembatumumab vedotin) is a fully human GPNMB-specific monoclonal antibody drug conjugate combining the tumor-targeting GPNMB antibody with the potent cytotoxic microtubule inhibitor, monomethylauristatin E (MMAE). In the Phase II EMERGE study, 122 patients (pts) with heavily pre-treated BC (2-7 priors) and GPNMB-expression by IHC in ≥ 5% of either the tumor epithelial or stromal cells in archival tissue were randomized 2:1 to receive CDX-011 or “investigator's choice” (IC) single-agent chemotherapy, with crossover to CDX-011 permitted. CDX-011 as compared to IC, demonstrated higher objective response rates, with ORR of 8/25 (32%) vs 1/8 (13%) for high GPNMB expression (defined as expression in ≥25% of epithelial tumor cells) and 5/27 (19%) vs. 0/9 (0%) for TNBC. In the presence of both TNBC and high GPNMB, ORR was 4/12 (33%) vs 0/4 (0%) which corresponded to a doubling of median progression-free survival (PFS, p = 0.008) and median overall survival (OS, p = 0.003). CDX-011 was well tolerated with less hematologic toxicity (neutropenia: 29% vs 44%; leukopenia: 10% vs 27%; thrombocytopenia: 4% vs. 15%) but more rash (47% vs. 2%) and neuropathy (23% vs 12%) than IC. Methods: The current pivotal study aims to evaluate CDX-011 in metastatic GPNMB-over-expressing TNBC defined as ER and PR &lt; 1%, HER2 negative (0-1+ IHC, or FISH ratio &lt; 1.8). Eligibility criteria include &gt;25% tumor epithelium GPNMB expression by central IHC; taxane and anthracyline resistance; ≤1 prior chemotherapy regimen for advanced BC; measurable disease by RECIST 1:1 and no persistent treatment-related toxicity of ≥ Grade 2 severity. 300 pts will be randomized (2:1) to receive CDX-011 (1.88 mg/kg IV q 21 days) or capecitabine (2500 mg/m2 daily for d1-14, q21 days) until progression or toxicity. Disease assessments are performed every six weeks for 6 months, and every 12 weeks thereafter. All pts are subsequently followed for survival. Endpoints are ORR and PFS (co-primary), duration of response, OS, safety, pharmacokinetics, and quality of life; tumor response assessments will be assessed by central review per RECIST 1.1. The trial has 80% power to detect a hazard ratio of 0.64 for PFS with α = 0.01 and/or a 30% increase in ORR (from 15% to 30%) with α = 0.04. For further information, contact info@celldextherapeutics.com.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-16.