Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug–drug interaction |
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| Institution: | 1. Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA;2. VA Palo Alto Health Care System, Palo Alto, CA;3. Department of Pediatrics, Stanford University, Stanford, CA;4. Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis School of Medicine, Sacramento, CA;1. Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States;2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States;3. Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan;4. Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States;5. Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, United States;6. Institute of Clinical Medicine; National Yang-Ming University, Taipei, Taiwan;1. Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada;2. Division of Medical Oncology Department of Medicine, University of Ottawa and the Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada;3. NCIC Clinical Trials Group and Queen’s University, 10 Stuart Street, Kingston, Ontario K7L 3N6, Canada;4. Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre University Health Network, and the University of Toronto, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada;1. Thoraxoncologie, Nederlands Kanker Instituut, Amsterdam, The Netherlands;2. Thoraxoncologie, Universitair Ziekenhuis Antwerpen, Belgium;1. Respiratory Function and Sleep Laboratory, S. Luigi Hospital, Orbassano, Italy;2. Department of Oncology, University of Torino, Torino, Italy;1. Division of Hematology-Oncology, Department of Medicine, Chao Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA;2. Divsion of Hematology-Oncology, Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA 92307, USA;3. Comprehensive Cancer Centers of Nevada, Las Vegas, NV 89169, USA;4. University Cancer and Blood Center, Athens, GA 30607, USA;5. Foundation Medicine Inc., Cambridge, MA 02141, USA;6. Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, USA |
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| Abstract: | IntroductionErlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.MethodsEscalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150 mg erlotinib + 300 mg dovitinib) and cohort -1 (150 mg erlotinib + 200 mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.ResultsTwo of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308 ± 698 ng/ml and AUC 0–24 41,030 ± 15,577 ng × h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0–24 decreased significantly by 93% (p = 0.02) and 97% (p < 0.01), respectively, during dovitinib co-administration.ConclusionsThis small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued. |
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| Keywords: | Dovitinib Erlotinib TKI 258 NSCLC Epidermal growth factor receptor (EGFR) |
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