Population Pharmacokinetics (Poppk) And Exposure-Response (Er) Analyses To Confirm Alectinib 600 Mg Bid Dose Selection In A Crizotinib-Progressed Or Intolerant Population.

e20598Background: Alectinib, a potent and selective CNS-active ALK inhibitor, which has received FDA accelerated approval for treatment of patients with ALK+ NSCLC who have progressed on, or are intolerant to, crizotinib. This analysis evaluated the popPK and ER relationships for alectinib efficacy and safety to confirm the recommended Phase 2 dose. Methods: A popPK model for alectinib and its major, similarly active metabolite, M4, was developed in NONMEM 7.2 software using plasma concentrations collected from patients receiving alectinib 300–900 mg BID. Covariates (demographics, laboratory values, disease status) were evaluated to determine their potential influence on the between-patient variability in the PK of alectinib and M4. Graphical analyses were explored for ER relationships for alectinib-associated antitumor activity across alectinib 300–900 mg BID dose escalation. Logistic regression and Cox proportional hazards analyses were conducted for evaluation of alectinib ER for BOR and PFS following ...