Dual blockade of epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) signaling in metastatic pancreatic cancer: Phase I/randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG-0727).
4019 Background: Targeting a single pathway in pancreatic adenocarcinoma (PAC) is unlikely to impact its natural history. EGFR targeting with erlotinib added to gemcitabine (G) 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 that leads to resistance to either drug. Methods: This was a phase I/randomized phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab combined with erlotinib and G in patients with metastatic PAC. The control arm was erlotinib plus G. 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 G 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. 40% on control arm. Median PFS and overall survival were 3.7 and 6.7 months, respectively, in both arms of the study. Major grade 3 and 4 toxicities were (cixutumumab/control) elevation of transaminases (12%/6%), fatigue (16%/12%), gastrointestinal (35%/28%), neutropenia (21%/10%), and thrombocytopenia (16%/7%). Grade 3/4 hyperglycemia was seen in 16% 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 of patients with metastatic PAC treated with erlotinib and G in a molecularly unselected population.