PMID- 35041775 OWN - NLM STAT- MEDLINE DCOM- 20220517 LR - 20220716 IS - 1752-8062 (Electronic) IS - 1752-8054 (Print) IS - 1752-8054 (Linking) VI - 15 IP - 5 DP - 2022 May TI - Population pharmacokinetic and exposure-response analyses from ALTA-1L: Model-based analyses supporting the brigatinib dose in ALK-positive NSCLC. PG - 1143-1154 LID - 10.1111/cts.13231 [doi] AB - The ALK in Lung Cancer Trial of brigAtinib in First Line (ALTA-1L) compared brigatinib versus crizotinib in anaplastic lymphoma kinase (ALK) inhibitor-naive patients with ALK+ non-small cell lung cancer (NSCLC). A population pharmacokinetic (PK) model was used to estimate brigatinib exposures for exposure-efficacy and exposure-safety analyses in ALTA-1L. A previously developed population PK model for brigatinib was applied to estimate brigatinib PK parameters. Relationships between static (time-independent) and dynamic (time-varying) exposure metrics and efficacy (progression-free survival [PFS], objective response rate [ORR], and intracranial ORR [iORR]) and safety outcomes (selected grade >/=2 and grade >/=3 adverse events [AEs]) were evaluated using logistic regression and time-to-event analyses. There were no meaningful differences in brigatinib PK in the first-line and second-line settings, supporting use of the previous population PK model for the first-line population. Exposure-response analyses showed no significant effect of time-varying brigatinib exposure on PFS. Brigatinib exposure was not significantly related to ORR, but higher exposure was associated with higher iORR (odds ratio: 1.13, 95% confidence interval: 1.01-1.28, p = 0.049). Across the observed median exposure (5th-95th percentile) at steady state for 180 mg once daily, the predicted probability of iORR was 0.83 (0.58-0.99). AEs significantly associated with higher exposure were elevated lipase (grade >/=3) and amylase (grade >/=2). Time to first brigatinib dose reduction was not related to exposure. These results support the benefit-risk profile of first-line brigatinib 180 mg once daily (7-day lead-in dose at 90 mg once daily) in patients with ALK+ NSCLC. CI - (c) 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. FAU - Gupta, Neeraj AU - Gupta N AUID- ORCID: 0000-0002-5500-5218 AD - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA. FAU - Reckamp, Karen L AU - Reckamp KL AD - Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. FAU - Camidge, David R AU - Camidge DR AD - University of Colorado Cancer Center, Aurora, Colorado, USA. FAU - Kleijn, Huub J AU - Kleijn HJ AD - Certara, Princeton, New Jersey, USA. FAU - Ouerdani, Aziz AU - Ouerdani A AD - Certara, Princeton, New Jersey, USA. FAU - Bellanti, Francesco AU - Bellanti F AD - Certara, Princeton, New Jersey, USA. FAU - Maringwa, John AU - Maringwa J AD - Certara, Princeton, New Jersey, USA. FAU - Hanley, Michael J AU - Hanley MJ AUID- ORCID: 0000-0001-9266-2797 AD - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA. FAU - Wang, Shining AU - Wang S AD - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA. FAU - Zhang, Pingkuan AU - Zhang P AD - Takeda Development Center Americas, Inc., Lexington, Massachusetts, USA. FAU - Venkatakrishnan, Karthik AU - Venkatakrishnan K AUID- ORCID: 0000-0003-4039-9813 AD - Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts, USA. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220208 PL - United States TA - Clin Transl Sci JT - Clinical and translational science JID - 101474067 RN - 0 (Organophosphorus Compounds) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - HYW8DB273J (brigatinib) SB - IM MH - Anaplastic Lymphoma Kinase MH - *Carcinoma, Non-Small-Cell Lung/drug therapy MH - Humans MH - *Lung Neoplasms/drug therapy/pathology MH - Organophosphorus Compounds MH - Protein Kinase Inhibitors/adverse effects MH - Pyrimidines/adverse effects PMC - PMC9099121 COIS- Neeraj Gupta: Employment (Takeda). Karen L Reckamp: Consultant/honoraria (to self) (Calithera, Euclises, Guardant, Precision Health, Amgen, AstraZeneca, Blueprint, Boehringer Ingelheim, Daiichi Sankyo, EMD Serono, Genentech, Janssen, Lilly, Merck KGaA, Seattle Genetics, Takeda, Tesaro; grant/research support (AbbVie, ACEA, Adaptimmune, Guardant, Molecular Partners, Seattle Genetics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Janssen, Loxo Oncology, Spectrum, Takeda, Xcovery, Zeno, Calithera, Daiichi Sankyo, Elevation Oncology). D. Ross Camidge: Honoraria (AstraZeneca, Takeda, Arrys/Kyn, Genoptix, G1 Therapeutics (DSMB), Mersana Therapeutics, Roche/Genentech, Ignyta, Daiichi Sankyo (ILD adjudication committee), Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med, Orion, Clovis, Celgene, Novartis); research funding: Ariad/Takeda). Huub Jan Kleijn: Consultant (Certara). Aziz Ouerdani: Consultant (Certara). Francesco Bellanti: Consultant (Certara). John Maringwa: Consultant (Certara). Michael J. Hanley: Employment (Takeda). Shining Wang: Employment (Takeda). Pingkuan Zhang: Employment (Takeda). Karthik Venkatakrishnan: Former employee (Takeda); current employee (EMD Serono Research & Development Institute, Inc.). EDAT- 2022/01/19 06:00 MHDA- 2022/05/18 06:00 PMCR- 2022/05/01 CRDT- 2022/01/18 17:28 PHST- 2021/12/02 00:00 [revised] PHST- 2021/08/24 00:00 [received] PHST- 2021/12/24 00:00 [accepted] PHST- 2022/01/19 06:00 [pubmed] PHST- 2022/05/18 06:00 [medline] PHST- 2022/01/18 17:28 [entrez] PHST- 2022/05/01 00:00 [pmc-release] AID - CTS13231 [pii] AID - 10.1111/cts.13231 [doi] PST - ppublish SO - Clin Transl Sci. 2022 May;15(5):1143-1154. doi: 10.1111/cts.13231. Epub 2022 Feb 8.