Final Biomarker and Efficacy Analyses of Lorlatinib in Patients With ALK-Positive Advanced NSCLC in a Phase 2 Study

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.

Plasma samples were prospectively collected at baseline and at the end of treatment from patients enrolled in the global phase 2 study, who were divided into three expansion cohorts (EXPs): EXP1 (treatment-naive), EXP2-3A (prior crizotinib ± chemotherapy), and EXP3B-5 (one or more prior second-generation ALK TKI ± chemotherapy). Circulating tumor DNA (ctDNA) and tumor tissue samples were analyzed using next-generation sequencing, and the baseline results were correlated with clinical outcomes.

In the EXP2-3A cohort, patients with EML4::ALK fusion variant 3 detected by ctDNA analysis had shorter overall survival (OS) than those with variants 1 or 2; a similar OS benefit was observed regardless of variant type in EXP1 and EXP3B-5 cohorts. The 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.

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. The resistance mechanisms in treatment-naive patients did not include the emergence of ALK mutations.

NCT01970865.