1280P - Effects of semaglutide on the exposure of alectinib in patients with NSCLC

Background

Alectinib serves as a preferred first-line treatment for advanced anaplastic lymphoma kinase–positive (ALK+) non-small cell lung cancer (NSCLC), offering durable efficacy. Nonetheless, its side effect of substantial weight gain poses serious health risks for patients. Semaglutide, a highly effective glucagon-like peptide 1 receptor agonist (GLP-1RA) for treating obesity, shows potential for mitigating alectinib-induced weight gain. However, its mechanism may also impact alectinib absorption, warranting investigation into a potential drug-drug interaction, given alectinib's exposure-response relationship (Groenland et al., Clin Pharmacol Ther 2021).

Methods

In this prospective crossover study, patients with ALK+ NSCLC receiving alectinib as standard of care, were sequentially treated with alectinib alone and alectinib combined with a single subcutaneous dose of semaglutide (2.0 mg) for both seven days. Plasma samples were collected for pharmacokinetic analysis after each week, while toxicity was also assessed. The primary endpoint was the alectinib exposure (area under the curve; AUC_0-10h), with secondary endpoints including the minimum concentration (C_trough), maximum concentration (C_max), and toxicity.

Results

In 10 patients, co-administration of semaglutide significantly reduced alectinib AUC_0-10h by 32% (95% confidence interval (CI): -45% to -15%; p = 0.004) compared to alectinib monotherapy. Semaglutide also decreased C_trough and C_max by 25% (95% CI: -46% to 3%; p = 0.072) and 36% (95% CI: -48% to -20%; p = 0.001) respectively, with fewer patients maintaining efficacy threshold levels (i.e. 435 ng/mL; 60% vs 100%). Additionally, combination therapy resulted in more overall toxicity (5 versus 25 events), predominantly grade 1 or 2 gastrointestinal side effects.

Conclusions

Our study reveals a clinically relevant and significant decrease in alectinib exposure with semaglutide co-administration, emphasizing the importance of caution due to a potential negative impact on alectinib effectiveness. Consequently, monitoring alectinib plasma concentrations in patients receiving semaglutide is crucial to ensure optimal exposure and treatment outcomes. Potentially, other GLP-1RAs may have a similar effect on alectinib exposure.

Clinical trial identification

NL9702 (Dutch trial register).

Editorial acknowledgement

Legal entity responsible for the study

Erasmus Medical University Centre, Rotterdam.

Funding

Has not received any funding.

Disclosure

A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Amgen, Bayer, AstraZeneca, Boehringer Ingelheim, Jansen, Mirati; Financial Interests, Institutional, Invited Speaker: Lilly, Jansen; Financial Interests, Institutional, Other, IDMC: Roche; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Local PI: Lilly, Amgen, Daiichi Sankyo, JNJ, Mirati; Financial Interests, Institutional, Coordinating PI: Roche; Financial Interests, Institutional, Steering Committee Member: Roche; Non-Financial Interests, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Member: IASCL, ASCO, AACR. R.H. Mathijssen: Financial Interests, Institutional, Invited Speaker: Bayer, Novartis; Financial Interests, Institutional, Advisory Board: Servier, NaDeNo Nanoscience; Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pfizer, Roche, Sanofi, Servier, Boehringer-Ingelheim, Novartis, Nordic Pharma; Financial Interests, Institutional, Coordinating PI: Pamgene; Financial Interests, Institutional, Funding: Echo Pharmaceuticals, Deuter Oncology. All other authors have declared no conflicts of interest.