Pharmacodynamic separation (PDS) of gemcitabine (Gem) and the epidermal growth factor receptor (EGFR) inhibitor erlotinib (E) in patients (Pts) with advanced pancreatic cancer: Phase II results.

Abstract

e15073 Background: Continuously dosed E given concurrently with Gem results in only a modest survival improvement in pts with advanced pancreatic cancer. Preclinical data suggest that there is antagonism between chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) when these are delivered concurrently due to cell cycle effects. Work by our group and others has shown that EGFR TKIs induce cytostasis due to G1 arrest, which reduces subsequent cell cycle phase-dependent activity of chemotherapy. We tested a PDS approach for E + Gem as a means of overcoming the hypothesized negative interaction of EGFR TKIs and chemotherapy. Methods: Pts with measurable, previously untreated locally advanced unresectable/metastatic pancreatic cancer with adequate organ function and PS 0-2 were eligible. Tumor tissue was collected for molecular studies. PDS Regimen: Gem 1000 mg/m2 IV days 1, 8, 15, and E 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle. Primary endpoint was PFS; secondary endpoints included response rate (RR) and safety. To have 80% power at 5% significance, 70 pts were planned to detect an increase of PFS from 3.75 to 5.25 months. The study was terminated due to funding considerations. Results: 30 pts enrolled with median age 67 years (range 46-84); PS: 0 (23%), 1 (47%), and 2 (30%); locally advanced (13%) & metastatic (87%). Median PFS was 2.07 months (95% CI; 1.87 – 5.50 months). Median OS was 5.67 months (95% CI; 2.83 – 11.87 months). Median cycles completed were 2 (range 0-8). Two pts withdrew consent in the first cycle without progression and were not evaluable for response. RR was 11% (3 PRs); DCR was 46%. Grade 3/4 adverse events occurred in 63% of pts; the most common were neutropenia (23%), fatigue (13%), anemia (10%), thrombocytopenia (10%), rash (10%), nausea (10%), and diarrhea (10%). Conclusions: Although Gem and E in a PDS dose-schedule was feasible & tolerable in pts with advanced pancreatic cancer, no signal for increased efficacy was seen (compared to historic controls) in this molecularly unselected cohort. Correlative studies to identify potential molecular biomarkers of benefit are ongoing and will be presented. Clinical trial information: NCT00810719.