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

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 + 200 mg 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 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. 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.

FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy

“…33,34 In this regard, a recent phase I trial testing the safety of erlotinib combined with the FGFR unselective inhibitor dovitinib in patients with NSCLC was terminated because of unacceptable toxicity. 35 In the present work, however, we have proposed combining EGFR inhibitors with a more selective FGFR1 inhibitor, hoping to result in a more favorable tolerability profile.…”

Detection of Known and Novel FGFR Fusions in Non–Small Cell Lung Cancer by Comprehensive Genomic Profiling

“…However, in a phase I study (NCT0151969), the combination of an EGFR TKI (erlotinib) with dovitinib (a multireceptor TKI with activity against FGFR1 and FGFR3) led to intolerable toxicity. 28 Therefore, it may be more feasible to consider combining EGFR inhibitors with more selective FGFR inhibitors currently in clinical development. Whether serial administration of these agents (i.e., an EGFR Figure 2.…”

In Vitro Screening of Six Protein Kinase Inhibitors for Time‐Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug–Drug Interactions

“…Hence, predictions were based on its reversible IC 50 value only and suggested minor interactions with CYP3A4 substrates (≤1.3‐fold increases in AUC). Dovitinib is a strong CYP1A inducer and has markedly (by >90%) reduced the plasma exposures to the CYP1A marker substrate caffeine and to erlotinib, a CYP1A and CYP3A4 substrate, in human beings . No other interaction studies have hitherto been reported.…”