CPT Pharmacometrics Syst Pharmacol. 2020 Nov 12. doi: 10.1002/psp4.12569. Online ahead of print.
Brigatinib is a kinase inhibitor indicated for patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer who progressed on or are intolerant to crizotinib. Approval was based on results from a randomized, dose-ranging phase 2 study (ALTA). Despite an apparent dose-response relationship for efficacy in ALTA, an exposure-response relationship was not discernable using static models driven by time-averaged exposure. However, exposure-response modelling using daily
time-varying area under the concentration curve as the predictor in time-to-event models predicted that increasing the dose of brigatinib (range: 30 mg qd to 240 mg qd) would result in clinically meaningful improvements in progression-free survival (PFS), intracranial PFS, and overall survival. Grade ≥2 rash and amylase elevation were predicted to significantly increase with brigatinib exposure. These results provided support for a favorable benefit-risk profile with the approved dosing regimen (180 mg qd with 7-day lead-in at 90 mg) versus 90 mg qd.