Pharmacometric analyses of alectinib to facilitate approval of the optimal dose for the first‐line treatment of anaplastic lymphoma kinase–positive non‐small cell lung cancer

Abstract

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK‐positive non‐small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib‐failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one‐compartment models with sequential zero/first‐order input and first‐order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment‐naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression‐free survival in treatment‐naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of treatment as a significant covariate, with an optimal response achieved for concentrations above 1040 nmol/L. With 600 mg twice daily (b.i.d.), 92% of global patients are above this threshold concentration, compared with only 43% of patients with 300 mg b.i.d. In Japan, where the body weight distribution is lower, the approved 300 mg b.i.d. dose brings about 70% of Japanese patients above this threshold. Logistic regression analyses found no significant relationship between the combined alectinib–M4 molar concentration and first occurrence of adverse events. These pharmacometric results were used to expedite and facilitate regulatory approvals of 600 mg b.i.d. for first‐line ALK‐positive NSCLC in the United States and European Union in 2017 and in China in 2018.

Therapeutic drug monitoring guided dosing versus standard dosing of alectinib in advanced ALK positive non-small cell lung cancer patients: Study protocol for an international, multicenter phase IV randomized controlled trial (ADAPT ALEC)

“…Another limitation is the fact that this study protocol is based on European standard dosing, while in Japan 300 mg BID is used ( 29 ). One hypothesis is that characteristics in the Japanese population (lower body weight and different metabolism) result in relatively higher levels and that they therefore have comparable exposure at a lower dose ( 30 , 31 ). We, therefore, expect that dosing based on levels in Japan will also be applicable.…”

Relative bioavailability and food effect study of an oral suspension of alectinib in healthy volunteers using venipuncture and capillary microsampling

“…dosing regimen in subsequent phase III clinical trials. 12,13 Given the well-established exposure-response relationship and Abbreviations: AUC 0-∞ , area under the concentration-time curve extrapolated to infinity; AUC 0-t , area under the concentration-time curve from time 0 to the last measurable concentration; CI, confidence interval; C max , maximum observed concentration; GLSM, geometric least squares mean; GMR, geometric mean ratio; PK, pharmacokinetic.…”

“…The exposure–response of combined alectinib + M4 was confirmed in the plateau at the 600 mg orally b.i.d. dosing regimen in subsequent phase III clinical trials 12,13 . Given the well‐established exposure–response relationship and approved alectinib dosing regimen of 600 mg b.i.d.…”

“…dosing regimen in subsequent phase III clinical trials. 12 , 13 Given the well‐established exposure–response relationship and approved alectinib dosing regimen of 600 mg b.i.d. orally administered with the capsule, the exposure following the suspension was adjusted to be in line with that of the capsule as a starting point for pediatric investigation.…”

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

“…Our analyses are described in our companion paper: 3 “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.…”