A phase 1b study of the anticancer stem cell agent demcizumab (DEM), pemetrexed (PEM), and carboplatin (CARBO) in pts with first-line nonsquamous NSCLC.

Abstract

Background: 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. Method(s): Pts received DEM (2.5, 5 or 7.5 mg/kg), PEM 500 mg/m2 & CARBO (AUC = 6) every 3 weeks followed by maintenance DEM or PEM (7.5 mg/kg cohort) every 3 weeks until progression. The objectives were to determine the MTD, safety, efficacy, immunogenicity, pharmacokinetics & biomarkers of Notch signaling. Result(s): Thirty-two pts were enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg & 6 received 7.5 mg/kg of DEM. Related AEs in > 20% of pts were: nausea (53%), fatigue (47%), hypertension (41%), vomiting (34%), edema (28%), neutropenia (25%), & increased B-type natriuretic peptide (BNP) (22%). 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 and 183, respectively. As a result, DEM treatment was limited to 63 days in subsequent cohorts. One of 28 (4%) evaluable pts had a RECIST CR, 12 (43%) had a PR and 11 had SD. The Kaplan Meier estimated median progression free survivals for the 2.5, 5 and 7.5 mg/kg pts were 4.8, 5.3 and 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 Day 223+, 243+, 457+, 497+, 680+ and a sixth pt (who continued to receive CARBO & PEM off-study) progressed at Day 850. Conclusion(s): DEM, CARBO & PEM was generally well tolerated with nausea, fatigue & hypertension being the most common drug related toxicities. The duration of DEM therapy is being limited to 63 days due to cardiopulmonary toxicity which was observed following more prolonged administration. Encouraging early clinical activity has been observed. Enrollment is ongoing and updated results will be presented.