First-Line Demcizumab/Gemcitabine ± Nab-Paclitaxel in Pancreatic Cancer
Accumulating evidence has shown that cell types within tumors are heterogeneous and that a subset of these cells retain the property to self-renew and give rise to more differentiated progeny. These cells, called cancer stem cells (CSCs), can drive tumor growth and metastasis, and are more resistant to chemotherapy and radiotherapy than the remaining tumor cells. the Notch molecular pathway appears to be critical for CSC growth and development. Delta-like ligand 4 (DLL4) activates the Notch pathway, and demcizumab (DEM) is a humanized anti-DLL4 antibody that inhibits tumor growth and decreases CSC frequency in human tumor xenograft models.1,2 DEM also has an antiangiogenic effect and synergistic activity when combined with gemcitabine (GEM) and nab-paclitaxel in patient-derived xenograft models of pancreatic cancer.
Hidalgo and colleagues reported on the results of a phase 1b study in patients with pancreatic cancer who received first-line treatment with DEM plus GEM with or without nab-paclitaxel.3 Patients in cohorts 1 to 3 received DEM (2.5 mg/kg every 2 or 4 weeks or 5 mg/kg every 4 weeks) plus GEM 1000 mg/m2 in 7 of 8 weeks, then 3 of 4 weeks. Patients in cohorts 4 to 7 received truncated DEM (2.5, 3.5, or 5 mg/kg every 2 weeks through day 70) plus nab-paclitaxel 125 mg/m2 and GEM 1000 mg/m2 in 3 of 4 weeks. The primary objective was to determine the maximum tolerated dose; secondary objectives were safety, efficacy, immunogenicity, pharmacokinetics, and biomarkers.
Of the 56 patients enrolled, 8, 8, 8, 6, 8, 9, and 9 patients received 2.5 mg/kg every 2 weeks, 2.5 mg/kg every 4 weeks, 5 mg/kg every 4 weeks, 2.5 mg/kg every 2 weeks (truncated), 5 mg/kg every 2 weeks (truncated), 3.5 mg/kg every 2 weeks (truncated), and 3.5 mg/kg every 2 weeks (truncated), respectively. Related adverse events (AEs) in >15% of patients were fatigue (36%), nausea (32%), vomiting (23%), hypertension (21%), and diarrhea (20%). Two patients who received DEM continuously developed reversible pulmonary hypertension and 1 of these developed heart failure. As a result, DEM was limited to 70 days in cohorts 4, 5, 6, and 7, in which no patients developed heart failure or pulmonary hypertension.
Fourteen of the 28 evaluable patients (50%) treated with DEM/GEM/nab-paclitaxel had a RECIST partial response (PR), and 11 (39%) had stable disease, resulting in a clinical benefit rate of 89%. The Kaplan–Meier estimated median progression-free survival in these patients was 7.1 months and the median survival was 12.7 months. A predictive biomarker was not identified. The authors concluded that this therapy was generally well-tolerated with fatigue, nausea, and vomiting being the most common related AEs. Truncated DEM dosing (ie, limited to 70 days) avoided clinically significant cardiopulmonary toxicity. Encouraging clinical activity was observed and biomarker analysis showed modulation of the Notch pathway by this therapy. A randomized, phase 2 trial (YOSEMITE) of first-line therapy with a truncated dose of DEM of 3.5 mg/kg every 2 weeks in patients with pancreatic cancer is ongoing.
- Smith DC, et al. Clin Cancer Res. 2014;20:6295-6303.
- Previs RA, et al. Clin Cancer Res. 2015;21:955-961.
- Hidalgo M, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 341.