Exposure-response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer

Cancer Chemotherapy and Pharmacology
Peter N MorcosFrancois Mercier

Abstract

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. 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). 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....Continue Reading

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Jul 21, 2020·Clinical Pharmacology and Therapeutics·Stefanie L GroenlandNeeltje Steeghs
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Nov 10, 2020·European Journal of Clinical Pharmacology·Anna Mueller-SchoellCharlotte Kloft

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Clinical Trials Mentioned

NCT01801111
NCT01871805
NCT02075840

Software Mentioned

R

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