Early hypertension (HTN) as a potential pharmacodynamic (PD) marker for survival in pancreatic cancer (PC) patients (pts) treated with bevacizumab (B) and gemcitabine (G)

Abstract

3020 Background: Bevacizumab is a monoclonal Ab to the vascular endothelial growth factor (VEGF). VEGF increases vessel permeability by stimulating endothelial nitric oxide and prostaglandin metabolism. Antagonism of this system causes HTN in >30% of pts treated with B 10mg/kg. We conducted a phase II trial of BG in advanced PC pts (Kindler, ASCO 2004). Methods: We hypothesized that early HTN (defined as ≥Gr 2 HTN during the first 56 days of treatment) would be a PD marker for survival. To test this hypothesis, we performed a retrospective analysis of PC pts treated with BG. Blood pressure (BP) was recorded at least every 14 days; HTN was graded by CTC v2.0 (Gr 2: recurrent, persistent, or symptomatic rise in either DBP by >20 mmHg or to >100, or SBP to >150, if previously ≤140/90; Gr 3: requiring new or increased therapy). Pts were excluded from analysis for early removal from study (prior to day 28) or early death (prior to day 56). Kaplan-Meier estimates and Cox proportional hazard (PH) models were used to evaluate the influence of age, gender, performance status, prior radiation, liver metastases, and early HTN on survival. Results: 52 metastatic PC pts were treated with BG; 23 pts (44%) developed any HTN; maximum grade: Gr 1=6 (12%), Gr 2=7 (13%), Gr 3=10 (19%). Time to first HTN ≥Gr 2 ranged from 13 to 265 days. 46 pts were evaluable for early HTN; 4 were excluded for early discontinuation; 2 were excluded for early death. 6 cases of early HTN (13%) were identified in evaluable pts (none in excluded pts). Median overall survival (OS) for the 6 pts with early HTN was 13.7 months, vs. 8.7 months for the 40 pts without early HTN (log-rank p=0.067). On multivariate analysis, female gender (HR: 0.373, p= 0.01), prior radiation therapy (HR: 0.188, p=0.008), and early HTN (HR: 0.228, p=0.007) predicted improved survival. Results were similar when all 52 pts were analyzed. Conclusions: Early HTN was correlated with improved OS in this retrospective analysis of PC pts treated with BG. Early HTN may be a useful predictive PD marker in pts treated with B. Prospective studies to evaluate HTN as a PD marker for survival in pts treated with B are in development. Supported by NCI Grant N01-CM-17102. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Lilly Oncology Genentech, Lilly Oncology Lilly Oncology