2 research outputs found
Dual targeting of vascular endothelial growth factor-A (VEGF-A) and angiopoietins (Ang) without chemotherapy in metastatic colorectal cancer (mCRC): Results of the VENGEANCE study.
Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: Preclinical evaluation and results of the Phase II DUX Study in chemotherapy-refractory, advanced colorectal cancer
PurposeThis preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC).Patients and methodsThe activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design.ResultsPreclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31% (95% CI, 26% to 57%), with a median PFS of 4.6 months (95% CI, 2.8 to 5.6 months). RR was 41% (95% CI, 26% to 57%) in KRAS WT tumors, with a median PFS of 5.6 months (95% CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48%), hypomagnesaemia (18%), and fatigue (10%).ConclusionThe combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.Andrew J. Weickhardt, Tim J. Price, Geoff Chong, Val Gebski, Nick Pavlakis, Terrance G. Johns, Arun Azad, Effie Skrinos, Kate Fluck, Alexander Dobrovic, Renato Salemi, Andrew M. Scott, John M. Mariadason, and Niall C. Tebbut