In a study reported in the Journal of Clinical Oncology, Lin et al found that specific ALK variants may be associated with the development of resistance mutations to ALK tyrosine kinase inhibitors (TKIs) in ALK-positive non–small cell lung cancer (NSCLC).
The study involved 129 patients with ALK-positive NSCLC and known ALK variants from the Massachusetts General Hospital (n = 113) and University of California, Irvine (n = 16). A separate group of 577 patients with ALK-positive NSCLC and known ALK variants was identified during routine clinical care using next-generation sequencing at Foundation Medicine. ALK resistance mutations and clinical outcomes on ALK TKIs were assessed according to ALK variant.
Frequency of Variants and Outcomes
In the first cohort, 123 patients (95%) had an EML4-ALK fusion, with the most frequent ALK variants being EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). Analysis of 77 tumor biopsy specimens from patients with variants 1 and 3 whose disease had progressed on ALK TKI treatment showed that ALK resistance mutations were significantly more common in variant 3 vs variant 1 (57% vs 30%, P = .023), including greater frequency of the ALK G1202R mutation (32% vs 0%, P < .001). Analysis of the Foundation Medicine database showed similar associations of variant 3 with ALK resistance mutation (P = .010) and with the G1202R mutation (P = .015).
In the first cohort, progression-free survival did not differ between patients with variant 1 vs variant 3 who received crizotinib (Xalkori) as first TKI or first-line treatment or second-generation TKIs after crizotinib. However, in an exploratory analysis, among patients treated with the third-generation TKI lorlatinib, variant 3 was associated with significantly longer progression-free survival vs variant 1 (hazard ratio = 0.31, P = .011).
The investigators concluded: “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.”
The study was supported by the National Cancer Institute, National Foundation for Cancer Research, Be a Piece of the Solution, and Targeting a Cure for Lung Cancer Research Fund at Massachusetts General Hospital.
Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
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