Phase I randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib as first-line treatment in patients with metastatic pancreatic cancer (SWOG-0727).

Abstract

198 Background: Targeting a single pathway in pancreatic adenocarcinoma (PAC) did not impact the natural history of this molecularly complex disease. Epidermal growth factor receptor (EGFR) targeting with erlotinib marginally improved the outcome of patients with advanced disease. We tested the hypothesis that if the EGFR and IGF-1R pathways are simultaneously blocked then progression free survival (PFS) would be significantly improved by abrogating reciprocal signaling. Methods: S0727 was a phase I/randomized phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab combined with erlotinib and gemcitabine in patients with metastatic PAC. The control arm was erlotinib plus gemcitabine. The primary endpoint of the RP2 portion of the study was PFS. Eligibility included patients with untreated metastatic disease, performance status 0/1, fasting blood glucose less than institutional upper limit of normal, and willingness to provide tissue and blood specimens for correlative studies. Results: In Phase I portion (n=10) safety of cixutumumab 6 mg/kg IV/wk, erlotinib 100 mg/day orally and gemcitabine 1000 mg/m2 IV D 1,8, and 15 of a 28-day cycle was established. In the RP2 portion (n=124) 114 eligible patients (median age 63) were included. On the cixutumumab arm, 59% of patients were female vs. 41% on control arm. Median PFS and overall survival were 4 and 7 months, respectively, in both arms. Four patients on cixutumumab remain on treatment; sensitivity analyses show no impact on the conclusions. Major grade 3 and 4 toxicities were (cixutumumab/control) elevation of transaminases (12%/6%), fatigue (24%/21%), gastrointestinal (35%/28%), and hematologic (53%/39%). Grade 3/4 hyperglycemia was seen in 27% of patients on cixutumumab. Grade 3 or 4 kin toxicity was similar in both arms of the study (< 5%). Five treatment-related deaths were reported: 2 cardiac on each arm, 1 pulmonary on cixutumumab. Conclusions: IGF-1R inhibitor cixutumumab did not improve the progression free or overall survival in patients with metastatic PAC treated with erlotinib and gemcitabine in a molecularly unselected population.