Brigatinib Dose Rationale in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Exposure-Response Analyses of Pivotal ALTA Study.

Abstract

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 II study (ALK in Lung Cancer Trial of AP26113 (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 modeling 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 once daily (q.d.) to 240 mg q.d.) 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 q.d. with 7-day lead-in at 90 mg) versus 90 mg q.d.

• Authors: Neeraj Gupta, Xiaohui Wang, Elliot Offman, Benjamin Rich, David Kerstein, Michael Hanley, Paul M Diderichsen, Pingkuan Zhang, Karthik Venkatakrishnan
• Journal: CPT: pharmacometrics & systems pharmacology (CPT Pharmacometrics Syst Pharmacol) Vol. 9 Issue 12 Pg. 718-730 (12 2020) ISSN: 2163-8306 [Electronic] United States
• PMID: 33185028 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Takeda Pharmaceuticals. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Organophosphorus Compounds
• Protein Kinase Inhibitors
• Pyrimidines
• Crizotinib
• Anaplastic Lymphoma Kinase
• brigatinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Anaplastic Lymphoma Kinase (antagonists & inhibitors)
• Area Under Curve
• Brain Neoplasms (drug therapy)
• Carcinoma, Non-Small-Cell Lung (diagnosis, drug therapy, metabolism)
• Crizotinib (administration & dosage, adverse effects, pharmacology)
• Dose-Response Relationship, Drug
• Exanthema (chemically induced, epidemiology)
• Female
• Humans
• Hyperamylasemia (chemically induced, epidemiology)
• Lung Neoplasms (pathology)
• Male
• Middle Aged
• Organophosphorus Compounds (administration & dosage, adverse effects, pharmacology)
• Predictive Value of Tests
• Progression-Free Survival
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacology)
• Pyrimidines (administration & dosage, adverse effects, pharmacology)
• Safety
• Treatment Outcome