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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 1/2018

Open Access 01-07-2018 | Original Article

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

Authors: Peter N. Morcos, Eveline Nueesch, Felix Jaminion, Elena Guerini, Joy C. Hsu, Walter Bordogna, Bogdana Balas, Francois Mercier

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2018

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Abstract

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.
Appendix
Available only for authorised users
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Metadata
Title
Exposure–response analysis of alectinib in crizotinib-resistant ALK-positive non-small cell lung cancer
Authors
Peter N. Morcos
Eveline Nueesch
Felix Jaminion
Elena Guerini
Joy C. Hsu
Walter Bordogna
Bogdana Balas
Francois Mercier
Publication date
01-07-2018
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 1/2018
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3597-5

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