Final Biomarker and Efficacy Analyses of Lorlatinib in Patients With ALK-Positive Advanced Non-Small Cell Lung Cancer in a Phase 2 Study
- Author(s)
- Bauer, TM; Martini, JF; Besse, B; Lin, CC; Soo, RA; Riely, GJ; Wang, IM; Toffalorio, F; Shepard, DA; Usari, T; Hamilton, P; Camidge, DR; Kao, S; Chiari, R; Gadgeel, S; Felip, E; Shaw, AT; Solomon, BJ;
- Journal Title
- Journal of Thoracic Oncology
- Publication Type
- Online publication before print
- Abstract
- INTRODUCTION: In patients treated with lorlatinib after failure of a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), ALK mutations were identified as a potential marker of response. To identify other correlates, we evaluated ALK fusion subtypes and co-mutations to predict clinical outcomes with lorlatinib and identify potential resistance mechanisms. METHODS: Plasma samples were prospectively collected at baseline and end of treatment from patients enrolled in the global phase 2 study: EXP1 (treatment-naive), EXP2-3A (prior crizotinib ± chemotherapy), and EXP3B-5 (≥1 prior second-generation ALK TKI ± chemotherapy). Circulating tumor DNA (ctDNA) and tumor tissue samples were analyzed using next-generation sequencing, and baseline results were correlated with clinical outcomes. RESULTS: In the EXP2-3A cohort, patients with EML4::ALK fusion variant 3 detected by ctDNA had shorter overall survival (OS) than those with variants 1 or 2; similar OS benefit was observed regardless of variant type in EXP1 and EXP3B-5. Presence of a TP53 mutation was associated with shorter OS in all cohorts. These observations were further supported by tumor tissue analysis results. In patients with matched paired ctDNA samples (EXP1, n=8; EXP2-3A, n=17; EXP3B-5, n=64), acquired ALK mutations were detected in the EXP2-3A and EXP3B-5 cohorts but not in the EXP1 cohort. CONCLUSIONS: After 5 years of follow-up, final analyses from this phase 2 study further supported substantial activity and prolonged OS with lorlatinib in treatment-naive and previously treated patients with ALK-positive advanced NSCLC, regardless of the biomarker subgroups. Resistance mechanisms in treatment-naive patients did not include emergence of ALK mutations.
- Keywords
- ALK tyrosine kinase inhibitor; lorlatinib; non-small cell lung cancer; overall survival
- Department(s)
- Medical Oncology
- Publisher's Version
- https://doi.org/10.1016/j.jtho.2026.104202
- Open Access at Publisher's Site
https://doi.org/10.1016/j.jtho.2026.104202- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-10-12 05:40:41
Last Modified: 2026-10-12 05:41:16