Biomarker Analysis and Final Efficacy of Lorlatinib in Patients With ALK-Positive Advanced Non-Small Cell Lung Cancer

Document Type

Conference Proceeding

Publication Date

10-1-2025

Publication Title

J Thorac Oncol

Keywords

anaplastic lymphoma kinase, biological marker, circulating tumor DNA, crizotinib, lorlatinib, adult, clinical outcome, cohort analysis, conference abstract, controlled study, drug therapy, female, follow up, high throughput sequencing, human, human tissue, major clinical study, male, non small cell lung cancer, overall survival, phase 2 clinical trial, survival rate

Abstract

Introduction: Lorlatinib is a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinase inhibitor (TKI) approved for patients with ALK-positive advanced non-small cell lung cancer (NSCLC) in the first line as well as in those previously treated with a second-generation ALK TKI. In patients treated with lorlatinib after failure of a second-generation ALK TKI, ALK mutations were identified as a potential marker of response. To identify other correlates, we evaluated ALK fusion subtypes and comutations to predict clinical outcomes with lorlatinib and identify potential resis- tance mechanisms. Methods: Plasma samples were prospectively collected at baseline and end of treatment from patients enrolled in the following expansion cohorts (EXPs) in the global phase 2 study (NCT01970865): EXP1 (treatment naive), EXP2-3A (prior crizotinib ± chemotherapy), and EXP3B-5 (>1 prior ALK TKI ± chemotherapy). Circulating tumor DNA (ctDNA) was analyzed using Guardant360. ALK fusion subtypes and mutation and TP53 mutation status were corre- lated with clinical outcomes. Tumor tissue samples collected at baseline were also analyzed by next-generation sequencing. Results: Thirty patients were enrolled in EXP1, 59 in EXP2-3A, and 139 in EXP3B-5. Baseline ctDNA samples were available for 28 patients in EXP1, 55 in EXP2-3A, and 129 in EXP3B-5. In EXP2-3A cohort, patients with short EML4-ALK fusion variant 3 (v3) had shorter overall survival (OS) or lower survival probability at 72 months than those with long variants (v1 and v2), while similar OS benefit was observed regardless of the variant type in EXP1 and EXP3B-5 (Table). Presence of TP53 mutation led to shorter OS or lower survival probability at 72 months in EXP1, EXP2-3A, and EXP3B-5 cohorts. Confirmation of these results in tumor tissue is ongoing. In patients with matched paired ctDNA samples, none had acquired ALK single or compound mutations in EXP1; however, these mutations were detected in patients in EXP2-3A and EXP3B-5 cohorts. Conclusions: After a minimum follow-up of 5 years, final analyses from this phase 2 study confirmed substantial activity and prolonged OS with lorlatinib in treatment-naive and previously treated patients with ALK-positive advanced NSCLC, regardless of the ctDNA-based biomarker groups. Resistance mecha- nisms in treatment-naive patients did not include emergence of ALK mutations, while new single and compound mutations emerged in a small number of patients who previously received an ALK TKI.

Volume

20

Issue

10

First Page

S473

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