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Clinical Trial
. 2025 Apr;20(4):513-520.
doi: 10.1016/j.jtho.2024.11.021. Epub 2024 Nov 22.

Final Overall Survival and Long-Term Safety of Lorlatinib in Patients With ALK-Positive NSCLC From the Pivotal Phase 2 Study: A Brief Report

Sai-Hong Ignatius Ou  1 , Benjamin J Solomon  2 , Benjamin Besse  3 , Alessandra Bearz  4 , Chia-Chi Lin  5 , Rita Chiari  6 , D Ross Camidge  7 , Jessica J Lin  8 , Antonello Abbattista  9 , Francesca Toffalorio  9 , Ross A Soo  10
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Free article
Clinical Trial

Final Overall Survival and Long-Term Safety of Lorlatinib in Patients With ALK-Positive NSCLC From the Pivotal Phase 2 Study: A Brief Report

Sai-Hong Ignatius Ou et al. J Thorac Oncol. 2025 Apr.
Free article

Abstract

Introduction: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases with broad coverage of ALK resistance mutations. We present the overall survival (OS) and long-term safety of lorlatinib in patients with advanced ALK-positive NSCLC from the final analyses of the pivotal phase 2 study.

Methods: Adults with ALK-positive NSCLC, enrolled in expansion cohorts (EXPs) on the basis of prior therapy (EXP1-5), received lorlatinib 100 mg orally once daily in continuous 21-day cycles. The primary endpoint was the objective response rate; secondary endpoints included OS and safety.

Results: Thirty patients were enrolled in EXP1 (treatment naïve), 59 in EXP2-3A (disease progression after crizotinib ± chemotherapy), 28 in EXP3B (disease progression after one second-generation ALK tyrosine kinase inhibitor [TKI] ± chemotherapy), 111 in EXP4-5 (disease progression after ≥2 ALK TKIs ± chemotherapy), and 139 in EXP3B-5 (disease progression after ≥1 ALK TKI ± chemotherapy). Median OS was not reached (NR) (95% confidence interval [CI]: NR-NR) in EXP1, NR (95% CI: 51.5-NR) in EXP2-3A, 37.4 months (95% CI: 12.3-NR) in EXP3B, 19.2 months (95% CI: 15.4-30.2) in EXP4-5, and 20.7 months (95% CI: 16.1-30.3) in EXP3B-5. All-cause adverse events leading to dose reduction were reported in 77 patients (28%), temporary treatment discontinuation in 158 patients (57%), and permanent discontinuation in 35 patients (13%).

Conclusions: After a minimum follow-up of five years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC.

Clinicaltrials: gov NCT01970865.

Keywords: ALK tyrosine kinase inhibitor; long-term safety; lorlatinib; non-small cell lung cancer; overall survival.

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Conflict of interest statement

Disclosure Dr. Ou received research grants or contracts from Pfizer; received consulting fees from AnHeart Therapeutics, Bristol Myers Squibb, Daiichi Sankyo, Janssen, J INTS BIO, and Pfizer; received speaker fees from Janssen and Pfizer; reports advisory role for Bristol Myers Squibb, Daiichi Sankyo, Elevation Oncology, Janssen, and Pfizer; and is a stockholder of BlossomHill Therapeutics, Inc., MBrace Therapeutics, and Nuvalent, Inc. Dr. Solomon received speaker fees from AstraZeneca, GSK, Merck, Roche, and Pfizer; reports advisory role for Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Janssen, MSD, Pfizer, Roche-Genentech, and Takeda; and declares holding a leadership role as board director of Cancer Council Victoria, International Association for the Study of Lung Cancer, and Thoracic Oncology Group of Australasia. Dr. Besse received consulting fees (to the institution) from AbbVie, Eli Lilly, Ellipses Pharma, F. Hoffmann-La Roche Ltd, Genmab A/S, Immunocore, Janssen, MSD, OSE Immunotherapeutics SA, Owkin, and Taiho Oncology, Inc.; received speaker fees (to the institution) from AbbVie, AstraZeneca, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo, Hedera Dx, Janssen, MSD, Roche, Sanofi-Aventis, and Springer Healthcare Ltd; reports participation on steering committee (to the institution) for AstraZeneca, BeiGene, Genmab A/S, GSK, Janssen, OSE Immunotherapeutics SA, PharmaMar, Roche-Genentech, Sanofi-Aventis, and Takeda; and reports participation on data safety monitoring board or advisory board for AbbVie, BioNTech SE, Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., CureVac AG, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, PharmaMar, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Turning Point Therapeutics, Inc. Dr. Bearz received speaker fees from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and Roche; reports advisory role for or consulting fees from MSD, Pfizer, Regeneron, Roche, and Takeda; and received a research grant from Pfizer. Dr. Lin received consulting fees from AbbVie, Anbogen Therapeutics, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, IMPACT Pharmaceutical Services, Merck KGaA, Novartis, and PharmaEngine, Inc.; received speaker fees from Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis, and Roche; received travel support from BeiGene, Daiichi Sankyo, IMPACT Pharmaceutical Services, and Eli Lilly; and reports advisory role for Bayer and Novartis. Dr. Chiari received speaker fees from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, and Roche; received travel support from Amgen and Roche; and reports participation on the data safety monitoring board or advisory board for Johnson & Johnson. Dr. Camidge received consulting fees from AnHeart Therapeutics, Roche, and Takeda. Dr. Lin received research funding (to the institution) from Bayer, Elevation Oncology, Hengrui Pharmaceuticals, Linnaeus Therapeutics, Neon Therapeutics, Novartis, Nuvalent, Inc., Pfizer, Relay Therapeutics, Roche, and Turning Point Therapeutics, Inc.; received consulting fees from AnHeart Therapeutics, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, C4 Therapeutics, Inc., CLaiM Therapeutics, Daiichi Sankyo, Elevation Oncology, Ellipses Pharma, Genentech, Hyku Biosciences, Merus, Mirati Therapeutics, Inc., Novartis, Nuvalent, Inc., Nuvation Bio, Pfizer, Regeneron, Takeda, Turning Point Therapeutics, Inc., and Yuhan Corporation; and travel support from Merus and Pfizer. Dr. Abbattista was an employee of Pfizer at the time of this study and holds stocks of Pfizer. Dr. Toffalorio is an employee of Pfizer and holds stocks of Pfizer. Dr. Soo reports participation on the advisory board for and consulting fees from AbbVie, Amgen, AnHeart Therapeutics, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GSK, J INTS BIO, Janssen, Eli Lilly, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Sanofi, Taiho, Takeda, Thermo Fisher Scientific Inc, and Yuhan Corporation; reports honorarium from Chugai; and received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer.

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