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

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.

Keywords: ALK inhibitor; Alectinib; ER; Exposure response; NSCLC; Oncology; Pharmacokinetics.

Conflict of interest statement

Conflict of interest

Peter N. Morcos is an employee of, and holds stocks/shares in, F. Hoffmann-La Roche Ltd. Eveline Nueesch is an employee of, and holds stocks/shares in, F. Hoffmann-La Roche Ltd. Felix Jaminion is an employee of, and holds stocks/shares in, F. Hoffmann-La Roche Ltd. Elena Guerini is an employee of, and holds stocks/shares in, F. Hoffmann-La Roche Ltd. Joy C. Hsu is an employee of, and holds stocks/shares in, F. Hoffmann-La Roche Ltd. Walter Bordogna is an employee of, and holds stocks/shares in, F. Hoffmann-La Roche Ltd. Bogdana Balas is an employee of, and holds stocks/shares in, F. Hoffmann-La Roche Ltd. Francois Mercier is an employee of F. Hoffmann-La Roche Ltd.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the studies.

Figures

Fig. 1

Distribution of alectinib + M4 Ctrough,ss across all patients in exposure–response population. The black line in the center of the box represents the median value of the continuous Ctrough,ss. Boxes indicate the inter-quartile range (IQR). Whiskers represent 1.5*IQR. Outliers are marked outside of the whiskers by circles

Fig. 2

Diagnostic plots from the final Cox proportional hazards model. Top: Schoenfeld residuals from the final model. Solid lines represent locally smoothed fit to the Schoenfeld residuals, and the dash lines represent ± 2-standard-error around the fit. Bottom: Martingale residuals from the final model. The solid line represents locally smoothed fit to the martingale residuals. Martingale residuals should have a range between − ∞ and 1 and mean of zero, and should show no strong trends

Fig. 3

Overlay of the final Cox proportional hazards model (CPH) and associated 95% CIs and the nonparametric Kaplan–Meier analysis. The solid black line represents the observed OS from the nonparametric Kaplan–Meier analysis of the final pooled phase II OS data. The dashed lines represent the final CPH model estimate and associated 95% CIs

Fig. 4

Covariates from the final Cox proportional hazards model

Fig. 5

Exposure-safety analysis. Top: univariate logistic regression analysis for the assessment of the relationship between Ctrough,ss and SAEs (left) or Grade ≥ 3 AEs (right). The black points represent the individual exposures for patients reporting (1.0) or not reporting (0.0) the safety event. The solid black line represents the logistic regression fit along with the 95% CIs (blue shading) for the fit; Bottom: Boxplot distributions of Ctrough,ss by grades of SAEs (left) or Grade ≥ 3 AEs (right). Median values of Ctrough,ss are designated by black lines in the center of the boxes. Boxes indicate the inter-quartile range (IQR). Whiskers represent 1.5*IQR. Outliers are marked outside of the whiskers by circles