Simon E Koele1, Stijn W van Beek1, Anthonie J van der Wekken2, Berber Piet3, Michel M van den Heuvel3, Rob ter Heine1
1 Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands 2 Department of Pulmonology and Tuberculosis, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. 3 Department of Pulmonology, Radboud University Medical Center, Nijmegen, the Netherlands.
Introduction: Brigatinib is a recently approved drug for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK+ NSCLC). It was approved through the Federal Drug Administration’s fast-track based on the pivotal phase II trial in which brigatinib showed higher progression-free survival and objective response rate with increasing exposure compared to crizotinib(1). Based on the phase II and III trials, brigatinib can be prescribed both in the first and second line of ALK+ NSCLC treatment(2). Recommended dosing consists of a seven-day lead-in period of 90 mg QD, followed by a maintenance phase of 180 mg QD(3). A pharmacokinetic-pharmacodynamic model of brigatinib has been developed, based on the dose-finding studies(4). Time-averaged brigatinib exposure was shown to predict the efficacy: progression-free survival (PFS) as well as the safety: probability of developing a grade ≥2 rash, and grade ≥2 amylase increase. This enables research into alternative dosing strategies.
Objectives: Develop a pharmacokinetically-guided individualized dosing strategy to improve the efficacy of brigatinib with a minimal impact on safety.
Methods: An in silico study of four different dosing strategies was performed in a virtual population of 10.000 ALK+ NSCLC patients using a previously published pharmacokinetic-pharmacodynamic model(4). The population characteristics were defined in the PK model with mean albumin concentrations set to 35g/L and baseline target lesions to 3.7 mm. Two fixed dosing strategies were explored: The currently approved dosing regimen (A): 90 mg QD for seven days followed by 180 mg QD, and the highest clinically proven tolerable dose (B): 90 mg QD for seven days followed by 240 mg QD(1). For the two pharmacokinetically-guided dosing strategies, serum trough concentration measurements were simulated on day fourteen of the treatment and were used to determine the new maintenance dose. Included pharmacokinetically-guided dosing strategies were: (C): 90 mg QD for seven days, followed by a dose adaptation to 180 mg QD for seven days, whereafter a pharmacokinetically-guided dose adaptation was made to reach the median plasma trough concentration associated with the 180 mg QD dosing regimen during the maintenance phase, and (D): 90 mg QD for seven days, followed by a dose adaptation to 240 mg QD for seven days, whereafter a pharmacokinetically-guided dose adaptation was made to reach the median plasma trough concentration associated with the 240 mg QD dosing regimen during the maintenance phase. We predicted the median PFS, and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Pharmacokinetic and –dynamic simulations were performed in R v3.4.3 using RStudio v1.3 as an interface(5, 6).
Results: Predicted median PFS, for the currently approved fixed-dose regimen of 180 mg QD (A) was 14.6 months and increased to 14.9 months after implementation of the precision dosing strategy (C). The predicted median PFS for the fixed dose 240 mg QD (B) regimen was 15.8 months and increased to 16.2 months with the implementation of the precision dosing strategy was implemented (D). The predicted probability to develop a grade ≥ 2 rash and grade ≥ 2 amylase increase were 8.7% and 7.5% for strategy A, 8.8% and 7.6% for strategy C 10.3% and 8.8% for strategy B and 10.5% and 8.9% for strategy D respectively.
Conclusion: Using pharmacokinetically guided dosing, we predict that favorable brigatinib exposures can be achieved without a relevant impact on safety in ALK+ NSCLC patients. Individual doses can be titrated to reach exposures corresponding to the median trough concentration of 240 mg QD and thereby the efficacy is predicted to increase significantly compared to the currently approved fixed-dose regimen. Clinical trials using a pharmacokinetically-guided precision dosing approach should be performed before implementation in clinical practice.
References:
[1] Camidge DR, Kim DW, Tiseo M, Langer CJ, Ahn MJ, Shaw AT, et al. Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials. J Clin Oncol. 2018;36(26):2693-701.
[2] Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, et al. Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial. J Clin Oncol. 2020;38(31):3592-603.
[3] European Medicine Agengy. Alunbrig Assessment report. 2018.
[4] Gupta N, Wang X, Offman E, Rich B, Kerstein D, Hanley M, et al. Brigatinib Dose Rationale in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Exposure-Response Analyses of Pivotal ALTA Study. CPT Pharmacometrics Syst Pharmacol. 2020;9(12):718-30.
[5] RStudioTeam. RStudio: Intergrated Development for R.: PBC, Boston, MA.; 2020.
[6] R Core Team. A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna Austria2019.
Reference: PAGE 29 (2021) Abstr 9845 [www.page-meeting.org/?abstract=9845]
Poster: Clinical Applications