Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive 
non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine 
kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and 
the benefit of TKIs is limited as a result of acquired resistance. Emerging data 
suggest that the ALK fusion variant may affect clinical outcome, but the 
molecular basis for this association is unknown. Patients and Methods We 
identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK 
resistance mutations and clinical outcomes on ALK TKIs were retrospectively 
evaluated according to ALK variant. A Foundation Medicine data set of 577 
patients with ALK-positive NSCLC was also examined. Results The most frequent 
ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 
patients (40%). We analyzed 77 tumor biopsy specimens from patients with 
variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were 
significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). 
In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 
0%; P < .001). Analysis of the Foundation Medicine database revealed similar 
associations of variant 3 with ALK resistance mutation and with G1202R ( P = 
.010 and .015, respectively). Among patients treated with the third-generation 
ALK TKI lorlatinib, variant 3 was associated with a significantly longer 
progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 
0.79; P = .011). Conclusion Specific ALK variants may be associated with the 
development of ALK resistance mutations, particularly G1202R, and provide a 
molecular link between variant and clinical outcome. ALK variant thus represents 
a potentially important factor in the selection of next-generation ALK 
inhibitors.