Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction.

Article Details

Citation

Copy to clipboard

Das M, Padda SK, Frymoyer A, Zhou L, Riess JW, Neal JW, Wakelee HA

Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction.

Lung Cancer. 2015 Sep;89(3):280-6. doi: 10.1016/j.lungcan.2015.06.011. Epub 2015 Jun 22.

PubMed ID

26149476 [ View in PubMed

]

Abstract

INTRODUCTION: Erlotinib 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. METHODS: Escalating 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+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure. RESULTS: Two 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 ngxh/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. CONCLUSIONS: This 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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Dovitinib	Cytochrome P450 1A2	Protein	Humans	Unknown	Inducer	Details