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Final Biomarker and Efficacy Analyses of Lorlatinib in Patients With ALK-Positive Advanced Non-Small Cell Lung Cancer
Todd M Bauer1, Jean-François Martini2, Benjamin Besse3
1Greco-Hainsworth Centers for Research, Tennessee Oncology, PLLC, 2004 Hayes St, Nashville, TN 37203, USA.
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.