1142P - The influence of food with different fat concentrations on alectinib exposure: A randomized cross-over pharmacokinetic trial

Background

Alectinib is the keystone treatment in anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). An exposure-response threshold of 435 ng/mL has been established, above which the survival was prolonged significantly. However, 37% of patients did not reach this threshold. Since alectinib is orally administered twice daily and its absorption is largely influenced by food, further investigation into this relationship is needed to improve treatment efficacy.

Methods

A randomized three-period cross-over clinical trial was set up to compare alectinib exposure in ALK+ NSCLC patients with three different diets. Every 7 days, the first dose of alectinib was taken with A; a standardized continental breakfast at 8 AM, B; a 250 gram low-fat yoghurt at 8 AM, or C; a self-chosen lunch at 12 PM. The second dose was taken with self-chosen dinner at 7 PM. Pharmacokinetic sampling for alectinib exposure (C_trough) was performed at day 8 of each period prior to alectinib intake. A linear mixed model was used to calculate the relative difference in C_trough levels 12 hours after last intake. For multiple testing, Bonferroni correction was applied. Toxicity was assessed during all study periods.

Results

Eighteen patients were evaluable. C_trough decreased with 16% (-24 to -8%; 95% CI, p=0.002) and 20% (-26 to -14%; 95% CI, p<0.001) when taken with low-fat yoghurt compared to continental breakfast and self-chosen lunch respectively. Exposure with self-chosen lunch, however, did not change the exposure compared to a continental breakfast (+5%, -4 to +14%; 95% CI, p>0.6). In addition, in the low-fat yoghurt period, 39% of the patients did not reach the efficacy threshold of 435 ng/mL, versus 6% during the other diets (p<0.01). No differences in toxicities were observed.

Conclusions

Alectinib intake with low-fat yoghurt resulted in a clinically relevant decrease in alectinib exposure, that could impair treatment efficacy. Patients and physicians should be warned for this potentially dangerous food-drug interaction. Compared to a continental breakfast, alectinib intake with a self-chosen lunch did not significantly alter drug exposure. Hence, this could be a safe and patient-friendly alternative for a continental breakfast.

Clinical trial identification

Netherlands Trial Register: NL9702.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M.G.D. Veerman: Financial Interests, Personal, Advisory Board: Lilly. S.L. Koolen: Financial Interests, Personal, Invited Speaker: Promise Proteomics. A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Sanofi, Amgen, Bayer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker: Takeda, Lilly, Jansen, Pfizer, AstraZeneca, Lilly, Amgen, Daiichi, Roche, Roche, JNJ, Mirati; Financial Interests, Institutional, Research Grant: Amgen; Non-Financial Interests, Other, Chair lung cancer group; EORTC; Non-Financial Interests, Member: IASCL, ASCO, AACR. R.H. Mathijssen: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Other, Patent pending: Pamgene; Financial Interests, Institutional, Research Grant: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Roche, Servier. All other authors have declared no conflicts of interest.