This phase 2 study evaluated biomarker correlates (ALK fusion subtypes, co-mutations, ctDNA) of clinical outcomes with lorlatinib across treatment-naive (EXP1), prior crizotinib (EXP2-3A), and prior second-generation ALK TKI (EXP3B-5) cohorts in ALK-positive advanced NSCLC, with 5 years of follow-up.
EML4::ALK variant 3 (by ctDNA) was associated with shorter OS in the EXP2-3A cohort but not in EXP1 or EXP3B-5; TP53 co-mutation was linked to shorter OS across all cohorts; acquired ALK resistance mutations emerged in EXP2-3A and EXP3B-5 but not in treatment-naive patients (EXP1, n=8).
Matched paired ctDNA sample sizes were small (EXP1 n=8, EXP2-3A n=17), limiting biomarker subgroup analyses; ctDNA detection rates may not fully capture tumor heterogeneity; findings are from a single-arm phase 2 study without a comparator arm.
TP53 co-mutation and EML4::ALK variant 3 (in post-crizotinib patients) identify higher-risk subgroups, but lorlatinib still showed substantial activity and prolonged OS across all biomarker subgroups. Treatment-naive patients treated with lorlatinib do not appear to develop ALK resistance mutations, suggesting non-ALK mechanisms drive resistance in that setting.
