Impact of tumor-intrinsic molecular features on survival and acquired tyrosine kinase inhibitor resistance in ALK-positive NSCLC.

While tyrosine kinase inhibitors (TKIs) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n=309). This was paired with a large-scale genomic cohort of ALK-positive NSCLC patients who underwent liquid biopsies (n=1118). Somatic co-mutations in TP53 and loss of function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (OS; HR 2.58; 95% CI 1.62-4.09 and HR 1.93; 95% CI 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR 4.11; p<0.001 and 2.94 p=0.026, respectively), and had inferior progression free survival (PFS) on first-line TKI (HR 1.52; 95% CI 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR 4.63; p<0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. V3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy.