Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer
Manish A Shah, Zev A Wainberg, Daniel V T Catenacci, Howard S Hochster, James Ford, Pamela Kunz, Fa-Chyi Lee, Howard Kallender, Fabiola Cecchi, Daniel C Rabe, Harold Keer, Anne-Marie Martin, Yuan Liu, Robert Gagnon, Peter Bonate, Li Liu, Tona Gilmer, Donald P Bottaro, Manish A Shah, Zev A Wainberg, Daniel V T Catenacci, Howard S Hochster, James Ford, Pamela Kunz, Fa-Chyi Lee, Howard Kallender, Fabiola Cecchi, Daniel C Rabe, Harold Keer, Anne-Marie Martin, Yuan Liu, Robert Gagnon, Peter Bonate, Li Liu, Tona Gilmer, Donald P Bottaro
Abstract
Purpose: The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma.
Patients and methods: Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ≥ 25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity.
Results: From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25-88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9-7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with foretinib treatment.
Conclusion: These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer.
Trial registration: ClinicalTrials.gov NCT00725712.
Conflict of interest statement
Competing Interests: Dr. Kallender, Dr. Martin, Dr. Y. Liu, Dr. Gagnon Dr. L. Liu, Dr. Gilmer are employees of, and have equity interest in GlaxoSmithKline. Dr. Keer is an employee of FivePrime Therapeutics Inc. with equity interest in Exelixis. Editorial support in the form of development of draft outline, development of manuscript first draft, assembling tables and figures, collating author comments, copyediting and referencing was provided by Ann Sherwood, PhD of CONNEXION Healthcare, Newtown, PA, and by MediTech Media, Manchester, UK, and was funded by GlaxoSmithKline. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
Figures
Source: PubMed