A Phase 1B Study of the Anti-Cancer Stem Cell Agent Demcizumab (Dem), Pemetrexed (Pem) & Carboplatin (Carbo) in Pts with 1St Line Non-Squamous Nsclc

Abstract

ABSTRACT Aim: Delta-like ligand 4 (DLL4) activates the Notch pathway and is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth, decrease CSC frequency & cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect in human tumor xenograft models. Methods: Pts received DEM (2.5 or 5 mg/kg), PEM 500 mg/m2 & CARBO (AUC = 6) every 3 wks X 6 cycles followed by maintenance DEM (cohorts 1-4) or truncated DEM (5 or 7.5 mg/kg), PEM 500 mg/m2 & CARBO (AUC = 6) every 3 wks X 4 cycles followed by maintenance PEM (cohorts 5 & 6). The objectives were to determine the MTD, safety, efficacy, immunogenicity, pharmacokinetics & biomarkers of Notch signaling. Results: Thirty-nine pts were enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg, 6 received 7.5 mg/kg of truncated DEM & 7 received 5 mg/kg of truncated DEM. Related AEs in > 20% of pts were: nausea (49%), fatigue (44%), hypertension (41%), vomiting (31%), edema (26%), neutropenia (26%), & increased B-type natriuretic peptide (BNP) (23%). Increased BNP values are an early indicator of the cardiac effects of DEM & mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two pts receiving 5 mg/kg developed reversible pulmonary hypertension & heart failure on days 167 & 183, respectively. As a result, DEM treatment was limited to 63 days in cohorts 5 & 6. One of 32 (3%) evaluable pts had a RECIST CR, 13 (41%) had a PR and 14 had SD. The Kaplan Meier estimated median progression free survivals for the 2.5, 5, truncated 5 & truncated 7.5 mg/kg pts were 4.3, 5.3, not yet reached & 4.4 months, respectively. Five pts who discontinued the study for a reason other than progression (3 continued to receive CARBO & PEM off-study) were progression-free through Days 223 + , 243 + , 457 + , 497 + , 680+ and a sixth pt (who continued to receive CARBO & PEM off-study) progressed at Day 850. Conclusions: This therapy was generally well tolerated with nausea, fatigue & hypertension being the most common drug related toxicities. Encouraging early clinical activity has been observed. Additional data with truncated DEM will be presented. Disclosure: R. Stagg: I am an employee of OncoMed and I own stock in the company; J. Dupont: I work for OncoMed and own stock in the company. All other authors have declared no conflicts of interest.