Abstract A71: 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.
Authors: McKeage Mark , Kotasek Dusan , Markman Ben , Millward Michael , Hildalgo Manuel , Jameson Michael , Harris Dean , Stagg Robert , Dupont Jakob , Hughes Brett 
Published: August 2014

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 and Methods: 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. Results: 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 167 and 183, respectively. As a result, the duration of DEM was limited to 63 days in the 7.5 mg/kg dose cohort. The pharmacokinetics and immunogenicity specimens are being analyzed and these data will be presented. Nine of the 23 (39%) evaluable patients had a RECIST partial response and 11 had stable disease. The median progression free survival for the 5 mg/kg cohort was 5.3 months.

Conclusion: DEM, pemetrexed and carboplatin was generally well tolerated with nausea, fatigue and hypertension being the most common drug related toxicities. The duration of demcizumab therapy is being limited to 63 days in subsequent cohorts 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.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A71.

Citation Format: Mark McKeage, Dusan Kotasek, Ben Markman, Michael Millward, Manuel Hildalgo, Michael Jameson, Dean Harris, Robert Stagg, Jakob Dupont, Brett Hughes. 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. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A71.