Pilot RCT to study the effect of chronotherapy on gefitinib plasma concentrations and adherence in lung cancer patients.

Abstract

e15144 Background: Non-small cell lung cancer (NSCLC) represents the majority of lung cancer cases, with EGFR mutations driving targeted therapy using tyrosine kinase inhibitors (TKIs) like gefitinib. Preclinical evidence indicates chronopharmacokinetic variations in TKIs due to diurnal fluctuations in CYP3A4 activity, hepatic blood flow, and glucocorticoid-EGFR crosstalk, potentially affecting bioavailability and efficacy. Clinical data on gefitinib dosing time remains scarce, prompting this clinical trial to investigate the impact of gefitinib administration timing on plasma levels in non-small cell lung cancer (NSCLC) patients with EGFR mutations. Methods: EGFR-mutated NSCLC patients (age ≥18 years, ECOG ≤2, no CYP3A4 modulators/steroids) received gefitinib 250 mg once daily (morning Group A, n = 14; evening Group B, n = 16). Plasma trough levels of gefitinib and O-desmethyl gefitinib were measured at day 15 via LC-MS/MS. Serum EGFR was quantified at baseline and 3 months via ELISA. Adherence was assessed using the BAASIS questionnaire at 1 and 3 months. Statistical comparisons used t-tests/Wilcoxon tests (p < 0.05 significant). Results: The study enrolled 30 EGFR-sensitized NSCLC patients starting gefitinib 250 mg daily, randomized to morning (8-9 AM) or evening (4-5 PM) dosing. Of 30 enrolled, 18 completed (morning n = 10, evening n = 8). Trough gefitinib levels showed no significant inter-group difference (morning: 909±851 ng/mL; evening: 811±360 ng/mL; p = 0.53), similar for metabolite (p = 0.09). Serum EGFR decreased significantly overall (276±69 to 219±65 ng/mL, p = 0.005) and in morning group (p = 0.047), but not evening (p = 0.079). No correlation linked levels to response (PR/SD/PD). Adherence was poor (5.5% fully adherent); morning patients showed better compliance trends (e.g., fewer missed doses). Conclusions: Gefitinib plasma levels were comparable between morning and evening dosing, but morning administration associated with greater EGFR reduction, suggesting potential chrono efficacy advantages. Low adherence highlights need for interventions. Larger trials validate optimal timing to enhance outcomes. Clinical trial information: CTRI/2021/09/036915.