A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

Abstract

Lessons LearnedThis phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib.Background.Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100–200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC.Methods.Twenty-six patients with advanced NSCLC were treated at doses of 250–625 mg three times daily The EGFR mutation test was not mandatory in this study.Results.Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5–4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease.Conclusion.This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC.

Routine-Dose and High-Dose Icotinib in Patients with Advanced Non–Small Cell Lung Cancer Harboring EGFR Exon 21-L858R Mutation: the Randomized, Phase II, INCREASE Trial

“…Based on the safety, preliminary efficacy, and PK results, 125mg three times daily was selected as the recommended dose for the confirmative Phase III ICOGEN study which was conducted in 2009 [13]. Meanwhile, icotinib was safe and effective over a broad dose range from 100mg to 500mg thrice daily [20], allowing clinical application with increased dose.…”

Long-term safety of icotinib in patients with non-small cell lung cancer: a retrospective, real-world study

“…Icotinib is a first-generation, reversible, selective EGFR TKI, which is well-tolerated in a dose range of 100 to 500 mg according to its dose-escalating studies (14,15). The recommended dosage of icotinib (e.g., 125 mg thrice per day) was established by a phase 3 study, in which significantly lower incidence of adverse reactions (60.5% vs. 70.4%) was documented in the icotinib arm than the control arm, with no treatment-related deaths or serious adverse reactions like interstitial lung disease (ILD) reported (16).…”