{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T01:03:22Z","timestamp":1793754202902,"version":"4.6.1"},"reference-count":24,"publisher":"American Medical Association (AMA)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"\n Importance<\/jats:title>\n \n ROS1<\/jats:italic>\n rearrangement is rare but is an attractive therapeutic target in advanced non\u2212small cell lung cancer (NSCLC). Crizotinib, entrectinib, and repotrectinib have been approved by the US Food and Drug Administration for treatment of\n ROS1<\/jats:italic>\n -positive NSCLC. Lorlatinib, a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI), targets\n ROS1<\/jats:italic>\n and\n ALK<\/jats:italic>\n ; however, its efficacy and safety for patients with advanced\n ROS1<\/jats:italic>\n -positive remains unknown.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To evaluate the efficacy and safety of lorlatinib for patients with advanced\n ROS1<\/jats:italic>\n -positive NSCLC never treated with any TKI.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n This multicenter phase 2 nonrandomized clinical trial enrolled patients with advanced\n ROS1<\/jats:italic>\n -positive NSCLC who were TKI-naive with an Eastern Cooperative Oncology Group performance status of 2 or less, and 1 or no prior platinum-based chemotherapy. Participants were recruited from June 2019 to April 2023 and followed up through August 2024. Data analysis was performed from April 5 to August 30, 2025.\n <\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Lorlatinib, 100 mg daily, was administered until disease progression, toxic effects, consent withdrawal, or death.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, and safety.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n The analysis included 32 patients (mean [IQR] age, 59 [11] years; 20 female [63%] and 12 male [37%] individuals), all of whom had adenocarcinoma histologic findings. There were 21 patients (66%) who were treatment-naive, and 11 (34%) who had prior chemotherapy. The median (SD) follow-up duration was 22.1 (15.4-46.8) months; ORR was 73% (95% CI, 56%-86%; 22 of 30 patients), and disease control rate was 90% (95% CI, 74%-97%; 27 of 30 patients). Median (IQR) PFS was 53.6 (95% CI, 27.8-79.5) months, and overall survival was not reached. For treatment-naive vs previously treated patients, the ORR was 90% vs 60%, and PFS was not reached vs 35.8 months. Grade 3 to 4 adverse effects were hypertriglyceridemia (5 patients [16%]) and hypercholesterolemia (8 patients [25%]). No treatment-related deaths occurred.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this nonrandomized clinical trial, lorlatinib demonstrated durable efficacy and manageable safety in TKI-naive advanced\n ROS1<\/jats:italic>\n -positive NSCLC, supporting the potential for using lorlatinib in earlier treatment settings.\n <\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT03612154<\/jats:ext-link>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaoncol.2025.5097","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T13:00:20Z","timestamp":1764680420000},"page":"84","source":"Crossref","is-referenced-by-count":7,"title":["Lorlatinib in Tyrosine Kinase Inhibitor\u2212Naive Advanced\n ROS1<\/i>\n -Positive Non\u2212Small Cell Lung Cancer"],"prefix":"10.1001","volume":"12","author":[{"given":"Beung Chul","family":"Ahn","sequence":"first","affiliation":[{"name":"Center for Lung Cancer, Division of Hematology and Oncology, Department of Internal Medicine, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Jung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngjoo","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Lung Cancer, Division of Hematology and Oncology, Department of Internal Medicine, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koung Jin","family":"Suh","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Wan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Min","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Hyeong","family":"Lee","sequence":"additional","affiliation":[{"name":"Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Youn","family":"Han","sequence":"additional","affiliation":[{"name":"Center for Lung Cancer, Division of Hematology and Oncology, Department of Internal Medicine, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"3","key":"coi250073r1","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/nm.2658","article-title":"RET, ROS1 and ALK fusions in lung cancer.","volume":"18","author":"Takeuchi","year":"2012","journal-title":"Nat Med"},{"issue":"11","key":"coi250073r2","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1097\/JTO.0b013e3182a4dd6e","article-title":"Clinicopathologic analysis of 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