A Phase Ib study of demcizumab (DEM, anti-DLL4) plus pemetrexed and carboplatin in patients with first line stage IIIb/IV non-squamous non-small cell lung cancer.

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material(s) and Method(s): Patients received DEM (2.5, 5, or 7.5 mg/kg), pemetrexed 500 mg/m2, and carboplatin (AUC = 6) every 3 weeks followed by maintenance DEM (first 4 cohorts) or pemetrexed (7.5 mg/kg cohort) every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were administered as pemetrexed pre-medication. The primary study objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic and biomarkers of Notch signaling. Result(s): Thirty patients have been enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg and 4 received 7.5 mg/kg of DEM once every 3 weeks. The median age was 63 years and 90% had stage IV disease. Related adverse events (all grades) in >=10% of pts included: nausea (53%), fatigue (50%), hypertension (37%), vomiting (33%), neutropenia (27%), increased B-type natriuretic peptide (BNP) (23%), anemia (20%), peripheral edema (20%), increased ALT (20%), increased AST (17%), dyspnea, (17%), diarrhea (17%), decreased appetite (17%), pulmonary hypertension (13%), dysgeusia (13%), thrombocytopenia (13%), constipation (10%), and rash (10%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two patients receiving 5 mg/kg developed reversible pulmonary hypertension and heart failure on days 16