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

Abstract

PurposeAlectinib 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.MethodsA 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).ResultsOverall, 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.ConclusionAlectinib 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 materialThe online version of this article (10.1007/s00280-018-3597-5) contains supplementary material, which is available to authorized users.

Model‐Informed Drug Development Approach to Expedite Approval: Case of Alectinib in First‐Line Anaplastic Lymphoma Kinase + Non‐Small Cell Lung Cancer

“…dosing regimen provided systemic alectinib exposures, which maximize the PFS benefit in the majority of patients. In addition, the pooled analysis revealed a larger distribution of baseline tumor size in the global population and identified baseline tumor size as a negative prognostic factor for PFS, consistent with analyses in the crizotinib‐resistant population . Overall, these consistent follow‐on analyses provided further confidence in the earlier qCP outcomes ( Figure ).…”

“…Previous analyses confirmed no significant ER relationship for safety with the alectinib 600 mg b.i.d. dosing regimen in a large global population, supporting an acceptable safety profile . Applicability of foreign data to the US population was demonstrated by data showing that the median PFS in the crizotinib control arm in J‐ALEX performed consistently with the global crizotinib phase III trial, PROFILE 1014, of 10.9 months, confirming lack of ethnic/racial effect on response to ALK‐inhibitor treatment.…”

“…in standard of care, crizotinib‐resistant, ALK‐positive NSCLC, supporting its initial approval (Alecensa, USPI, Roche, Basel, Switzerland). During its development, the MIDD approach was judiciously implemented to derive the alectinib clinical dosing regimen in the crizotinib‐resistant population and support dosing with concomitant medications . Alectinib is now listed in the US National Comprehensive Cancer Network Guideline 2018 as a preferred treatment option for first‐line (1L) ALK‐positive NSCLC based on results from a Japanese phase III trial, J‐ALEX (JapicCTI‐132316), using alectinib 300 mg b.i.d.…”

Exposure–Response Analyses of Anaplastic Lymphoma Kinase Inhibitors Crizotinib and Alectinib in Non‐Small Cell Lung Cancer Patients

“…In a previously performed exposure-response analysis in patients treated with alectinib (n = 207), no association has been identified between median C min of alectinib and its active metabolite M4 and overall survival. 18 Although overall survival is regarded In case of (calculated) C min below the TDM target of 235 ng/mL for crizotinib or 435 ng/mL for alectinib and manageable toxicity, the dose will be increased by one dose level (after checking treatment adherence and drug-drug interactions). Maximum dose levels are based on data from phase I dose finding studies.…”

Alectinib in the treatment of ALK-positive non-small cell lung cancer: an update on its properties, efficacy, safety and place in therapy

“…Evaluating results particularly from the J-ALEX and ALEX trials, a specific consideration should be directed to dose selection, which has a critical role in maximizing the potential for efficacy, while minimizing the potential for safety risks in a target patient population. 50 Mok and colleagues, at European Society for Medical Oncology Asia 2017, presented data of Asian versus non-Asian pretreated ALK-positive patients from the global phase III ALEX study of alectinib (600 mg twice daily) versus crizotinib (250 mg twice daily) in first-line advanced ALK-positive NSCLC. Overall, 303 patients were randomized: alectinib n = 152 ( n = 69 Asian, n = 83 non-Asian), crizotinib n = 151 ( n = 69 Asian, n = 82 non-Asian).…”