WCLC 2025 - Posters & ePosters-EP.12.52 A High-Fat Meal Optimizes the Pharmacokinetic Profile of DO-2, a Novel MET-Kinase Inhibitor for NSCLC

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This study investigates the pharmacokinetics of DO-2, a novel selective MET-kinase inhibitor for non-small cell lung cancer (NSCLC) patients with MET exon-14 skipping or MET amplification mutations. DO-2 is a deuterated derivative of JNJ-38877605 designed to reduce insoluble metabolite formation and currently undergoing phase 1 trials.<br /><br />Preclinical data suggest optimal MET kinase inhibition requires maintaining plasma concentrations over 160 ng/mL for 8-10 hours (time over threshold, ToT), while avoiding creatinine-related adverse events linked to levels above 500 ng/mL. This food interaction study, conducted in 12 healthy volunteers using a randomized crossover design, assessed the pharmacokinetics of a 40 mg DO-2 dose under fasted conditions, with a high-fat (English breakfast) meal, and a low-fat (continental) meal.<br /><br />Key findings include:<br />- A high-fat meal significantly prolonged ToT (10.9 hrs) compared to fasting (8.2 hrs, p=0.035); the low-fat meal showed a similar effect (10.5 hrs, p=0.60 vs. high fat).<br />- Time to maximum concentration (Tmax) increased from 1.6 hours (fasted) to about 5 hours with food.<br />- Maximum plasma concentration (Cmax) decreased by about 16% with food intake.<br />- Total drug exposure (area under the curve, AUC0-24h) was similar between fed and fasted states.<br />- Similar pharmacokinetic patterns were observed for active and inactive DO-2 metabolites.<br /><br />The prolongation of ToT and reduced Cmax with food are attributed to delayed gastric emptying and increased gastric pH, effects that enhance DO-2 solubility and absorption without changing overall exposure. Type of meal fat content did not alter these benefits.<br /><br />In conclusion, co-administration of DO-2 with food optimizes its pharmacokinetic profile by prolonging therapeutic exposure while limiting peak concentrations, potentially improving clinical efficacy and safety. This dosing strategy will be evaluated further in ongoing patient studies.

Asset Subtitle

Daan Lanser

Meta Tag

Speaker Daan Lanser

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

DO-2

MET-kinase inhibitor

non-small cell lung cancer

NSCLC

MET exon-14 skipping

MET amplification

pharmacokinetics

food interaction

high-fat meal

deuterated derivative