Optimized Alectinib Dose Regimen for Treatment of Patients With ALK-Positive Non-Small Cell Lung Cancer Based on Robust Pharmacometric Analyses and Clinical Evidence.

Funding

F. Hoffmann‐La Roche Ltd.

Conflict of Interest

B.B., E.G., N.F., T.R., V.A., and W.B. are employees of, and hold stocks/shares in, F. Hoffmann‐La Roche Ltd.

Groenland and colleagues report alectinib exposure–response analyses of a real‐life patient cohort (n = 52) with ALK‐positive non‐small cell lung cancer (NSCLC) receiving alectinib 600 mg (n = 31), 450 mg (n = 9) or 300 mg (n = 12), twice daily (b.i.d.). Based on a significant difference in median progression‐free survival (PFS) between patients with steady‐state alectinib concentrations below (n = 19) or above (n = 33) 435 ng/mL, the authors recommend therapeutic drug monitoring as part of routine clinical management of alectinib. Therapeutic drug monitoring could be an efficient method of optimizing individual clinical outcomes when an established, efficacious, and safe exposure range cannot be maintained in the majority of patients with a unique dosing regimen.

In clinical practice, this would lead to approximately one‐third of patients receiving an alectinib dose exceeding the globally approved 600 mg b.i.d., potentially up to 900 mg b.i.d., which exhibited limiting toxicity effects (grade 3 headache/neutropenia) in a phase I/II study. Lack of tolerability contributed to the decision to select 600 mg b.i.d. for subsequent studies. This was validated by results from phase III studies and our exposure–response analyses, which established that exposures generated by alectinib 600 mg b.i.d. maximize PFS in the global first‐line ALK‐positive NSCLC population while maintaining an acceptable safety profile.

Our analyses are described in our companion paper: “Pharmacometric Analyses of Alectinib to Facilitate Approval of the Optimal Dose for the First‐Line Treatment of ALK‐Positive Non‐Small Cell Lung Cancer.” Our conclusions contradict those of Groenland et al., whose analyses have four main limitations:

The methodology is at high risk of immortal time bias, known to result in misleading apparent exposure–response relationships. Such bias happens when information observed after patients enroll, e.g., exposure, are used in time‐to‐event analyses. We conducted a landmark analysis to avoid this. The landmark is a prespecified timepoint following study entry; only events occurring after this landmark are considered. We used a 6‐week landmark, and time‐to‐event analyses were based on the average concentration of alectinib and its equipotent active metabolite, M4, up to this timepoint.

The contribution of M4 exposure, which is weakly correlated to alectinib exposure, was not investigated.

The important effect of tumor size at baseline on PFS was not taken into account.

The sample size was small.

Our clinical efficacy and safety experience together with our exposure–response analysis do not support deviation from the recommended 600 mg b.i.d. alectinib dose, as this could result in suboptimal dosing and introduce unacceptable risks to patients.