4315 - Efficacy of lorlatinib in patients (pts) with ROS1-positive advanced non-small cell lung cancer (NSCLC) and ROS1 kinase domain mutations

Background

Lorlatinib is a potent, brain-penetrant, 3^rd-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.

Methods

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).

Results

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.

Conclusions

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

Legal entity responsible for the study

Pfizer, Inc.

Funding

Pfizer.

Editorial Acknowledgement

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.

Disclosure

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.