Lorlatinib is a potent, brain-penetrant, 3rd-generation ALK/ROS1 TKI active against most known resistance mutations (mut). In a Ph I/II study, lorlatinib showed robust clinical activity in ALK+ or ROS1+ NSCLC pts, most of whom had CNS metastases and were heavily pre-treated. Efficacy and molecular profiling based on tumor tissue were explored based on prior TKI treatment.
Pts with ROS1+ NSCLC (N = 59) were enrolled from the ongoing Ph I/II study (NCT01970865); samples were collected for molecular profiling. DNA was extracted from tumor tissues (archival or de novo samples) and analyzed with a ROS1 mut-focused next generation sequencing (NGS) panel (Molecular MD, Portland, OR, USA).
Based on the tumor tissue analysis set, 51 tumor samples (13 were ROS1 TKI-naïve [7 had de novo tissue evaluated in this analysis, 6 had archival tissue]; 38 were TKI-pre-exposed [21 de novo, 17 archival]) were collected from Ph I/II ROS1+ pts; 35 (68.6%) had no detectable ROS1 mut while 7 (13.7%) harbored ≥1 ROS1 mut; 9 (17.6%) samples were not analyzable. Four unique ROS1 mut were detected, with G2032R being the most frequent (57.1%). Among 13 ROS1 TKI-naïve pts, none had a detectable ROS1 mut; objective response rate (ORR) was 76.9%. In pts previously treated with crizotinib ± chemotherapy, 21 out of 34 (61.8%) had no ROS1 mut detected, 6 (17.6%) harbored a mut and 7 were not analyzable. Overall ORR was 29.4%, 23.8% for pts with no detectable ROS1 mut and 33.3% for pts with a mut. Finally, in 4 pts (all with de novo samples) treated with 1 non-crizotinib TKI or ≥ 2 TKIs (which could include crizotinib), only 1 (25%) harbored a ROS1 mut and no responses were observed. Of 4 pts with the G2032R mut, all had stable disease (SD) (duration 2.0 to 9.6 months); 3 pts with other ROS1 mut had a partial response (DOR 11.1 and 14.9+ months [+ denotes pts still on study with ongoing responses]) or SD. Plasma DNA analysis will be reported.
Lorlatinib evoked responses in treatment-naive pts or those resistant to prior ROS1 TKIs. Lorlatinib also exhibited activity against some ROS resistance mut, and provided some disease control for tumors harboring the difficult-to-treat G2032R mut with BOR of SD.
Clinical trial identification
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Editorial support was provided by Jade Drummond and Brian Szente of inScience Communications, Springer Healthcare (Chester, UK and Philadelphia, PA, US), and was funded by Pfizer.
B.J. Solomon: Honoraria: Bristol-Myers Squibb, AstraZeneca; Royalty, IP Rights/Patent Holder: Veristrat (Biodesix); Travel, accommodations, expenses: AstraZeneca, Roche, Merck, Bristol-Myers Squibb, Novartis; Institutional: Speakers or advisory board: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche/Genentech, Novartis; Research funding: Pfizer. J.-F. Martini: Employee and Stock: Pfizer. S-H.I. Ou: Consulting or advisory role: Pfizer, Roche/Genentech, Novartis, AstraZeneca, Takeda, Foundation Medicine; Speakers' bureau: Genentech, AstraZeneca, Takeda; Honoraria: Pfizer, Roche Pharma AG, Genentech/Roche, Ariad/Takeda, Novartis, AstraZeneca, Foundation Medicine; Institutional, Research funding: Pfizer, Roche Pharma AG, AstraZeneca/MedImmune, AstraZeneca, Clovis Oncology, Ariad, Ignyta, Peregrine Pharmaceuticals, GlaxoSmithKline, Astellas Pharma, Chugai Pharma. R.A. Soo: Consulting or advisory role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Taiho Pharmaceutical; Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech; Research funding: AstraZeneca. A. Bearz: Speakers’ Bureau: MSD, Roche, BMS, Pfizer, Takeda, Eli-Lilly, Novartis; Consultant: MSD, Roche, BMS, Pfizer, Takeda, Eli-Lilly, Novartis. S. Li: Employment: Pfizer. H. Thurm: Employment and stock: Pfizer. G.J. Riely: Consultant: Genentech; Travel, accommodations, expenses: Merck Sharp & Dohme. Institutional: Research funding: Novartis, Roche/Genentech, Millennium, GlaxoSmithKline, Pfizer, Infinity Pharmaceuticals, Ariad. T.M. Bauer: Employment: Tennessee Oncology, Sarah Cannon Research Institute; Consulting or advisory role: Ignyta, Guardant Health, Loxo, Pfizer, Moderna Therapeutics; Institutional: Research funding: Daiichi Sankyo, Medpacto, Inc., Incyte, Mirati Therapeutics, MedImmune, Abbvie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Principa Biopharma, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Principa Biopharma, Peleton, Immunocore, Roche, Aileron Therapeutics, Bristol-Myers Squibb, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma. A.T. Shaw: Speaker or advisory board: Pfizer, Novartis, Genentech, Roche, Ariad, Takeda, Ignyta, Blueprint Medicines, Loxo, Daiichi Sankyo, EMD Serono, Taiho Pharmaceutical, KSQ Therapeutics, Natera; Honoraria: Pfizer, Novartis, Roche/Genentech, Foundation Medicine, Takeda; Research funding: Pfizer, Novartis, Roche/Genentech. All other authors have declared no conflicts of interest.