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Purpose Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3–39.0) for alectinib 600 mg twice daily (BID). We investigated exposure–response relationships from final pooled phase II OS and safety data to assess alectinib dose selection. Methods A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3). Results Overall, 92% of patients (n = 207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs. Conclusion Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC. Electronic supplementary material The online version of this article (10.1007/s00280-018-3597-5) contains supplementary material, which is available to authorized users.