Population Pharmacokinetic and Exposure-Response Analyses of Alectinib and Its Metabolite M4 to Support Dose Selection in Patients with Resected Stage IB - IIIA ALK-Positive Non-Small Cell Lung Cancer
Authors: Mai Tu , Sutaria Dhruvitkumar , Chan Phyllis , Ruf Thorsten , Petric Patricia , Cardona Andres , Xu TingTing , Archer Venice , Dang Steve , Miles Dale , Hsu Joy 
Published: February 2025

Background: Alectinib (Alecensa) is a tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK) by inhibiting intracellular signaling pathways involved in tumor cell proliferation and survival. Alectinib was previously approved globally for the treatment of metastatic ALK-positive non-small-cell lung cancer (NSCLC). On April 18, 2024, alectinib was approved in the United States as adjuvant treatment in adult patients following tumor resection of ALK-positive NSCLC (tumors ≥ 4 cm or node positive) based on the results of the ALINA study: a Phase 3, global, multicenter, open-label, randomized study comparing the efficacy and safety of alectinib versus platinum-based chemotherapy as adjuvant therapy in patients with completely resected Stage IB (tumors ≥ 4 cm)−Stage IIIA ALK-positive NSCLC (per AJCC 7th edition)1. Objectives: The objectives of the population pharmacokinetic (popPK) and exposure-response (efficacy and safety) analyses were to characterize the PK characteristics of alectinib and M4 and to evaluate the relationship between total exposure of alectinib + M4 and efficacy (disease-free survival [DFS]) and safety endpoints (serious adverse event [SAE] and adverse event [AE]) of grade 3 and above) in patients in ALINA study.Methods: Previously established popPK models for alectinib and its major metabolite M4 were used to assess the PK data in ALINA study, with parameters fixed to the final estimates from these models2 (MAXEVAL=0). Visual predictive check and diagnostic plots were used to evaluate the ability of these models to capture the PK data from ALINA patients. Once confirmed that the PK characteristics of ALINA patients were consistent with that of the previous patient population, individual exposure metrics for exposure-efficacy and exposure-safety analyses were derived using these popPK models. Cox-proportional hazards model was developed to quantify the relationship between total average concentration of alectinib+M4 at steady state (Cave,ss,total) and DFS. Logistic regression analyses were conducted to evaluate the relationship between Cave,ss,total and SAEs and AEs of grade 3+ in ALINA.Results: The concentration-time course for alectinib and M4 in 124 patients with completely resected Stage IB-IIIA ALK-positive NSCLC who received alectinib could be adequately described by the popPK models previously developed for alectinib and M4. Body weight was confirmed to be the only significant covariate contributing to the between-patient PK variabilities. Both exposure-efficacy analysis for DFS and exposure safety analyses for SAEs and AEs of grade 3+ did not show any significant exposure-response relationship between alectinib and M4 exposures at 600mg BID of alectinib and efficacy or safety endpoints. Conclusions: Results from popPK, exposure-efficacy and -safety analyses supported alectinib 600 mg BID dosing regimen in the completely resected Stage IB -Stage IIIA ALK-positive NSCLC patients.Citations: [1] Y Wu, R Dziadziuszko, JS Ahn, F Barlesi, M Nishio, DH Lee, JS Lee, W Zhong, …, B Solomon. Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer. N Engl J Med 2024;390:1265-1276. April 2024 [2] J Hsu, F Jaminion, E Guerini, B Balas, W Bordogna, P Morcos, and N Frey. Pharmacometric analyses of alectinib to facilitate approval of the optimal dose for the first-line treatment of anaplastic lymphoma kinase positive non-small cell lung cancer. CPT: 10(11):1357–1370, sep 2021.