Population pharmacokinetics (popPK) and exposure-response (ER) analyses bridge J-ALEX to the global population with an alectinib (ALC) 600mg bid dosing regimen.

Abstract

e20616 Background: J-ALEX showed superiority of ALC 300mg BID vs crizotinib (CRIZ) in Japanese ALK inhibitor naïve ALK-positive NSCLC patients (pts). PopPK and ER analyses were used to bridge J-ALEX data to the global population to confirm the appropriateness of ALC 600mg BID dose, used in global trials. Methods: The previous popPK analysis (Hsu et al, ASCO 2016) was updated to include PK data from J-ALEX and the ongoing global ALEX study to confirm any significant covariates influencing PK of ALC and major metabolite, M4, using Bayesian feedback analysis. ER analyses from J-ALEX (n=96) investigated the relationship between ALC and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis and key safety events using logistic regression. Results: The popPK models previously developed for pts who have progressed on, or are intolerant to CRIZ were able to adequately predict ALC and M4 PK in J-ALEX and ALEX. Body weight remained the only significant covariate influencing ALC and M4 PK. Administration of ALC 600mg BID in the global population ensures that ALC and M4 exposures across the body weight range are not inferior to those seen in Japanese pts receiving ALC 300mg BID, while lower doses would result in lower exposures. CPH analysis demonstrated a statistically significant relationship between ALC exposure and PFS in J-ALEX such that one third of pts in J-ALEX may benefit from a higher exposure of ALC (Table). ALC 600mg BID ensures the distribution of achieved exposures maximize the expected PFS benefit while lower ALC exposures could result in reduced efficacy. No significant exposure-safety relationships were identified in J-ALEX consistent with previous analyses conducted following ALC 600mg BID. Conclusions: ALC 600mg BID is the appropriate dose in the global ALK inhibitor naïve population. Clinical trial information: JapicCTI-132316. [Table: see text]