ALK Variants Associated With Resistance to Therapy in ALK-Positive NSCLC


Specific anaplastic lymphoma kinase (ALK) variants may be linked to the development of ALK resistance mutations and poor clinical outcomes in patients with non-small cell lung cancer (NSCLC), according to a study published in the Journal of Clinical Oncology (online January 26, 2018; doi:10.1200/JCO.2017.76.2294).

ALK tyrosine kinase inhibitors (TKIs) have been shown to effectively treat advanced ALK fusion-positive NSCLC. However, clinical outcomes in these patients may vary, and the benefit of TKIs is dependent on acquired resistance. Recent data suggest that the ALK fusion variant may affect clinical outcomes, but the molecular basis for this association is in need of further research.

Jessica J Lin, MD, Massachusetts General Hospital, and colleagues conducted a study to better understand the molecular drivers of ALK fusion-positive NSCLC resistance to TKIs. Researchers sampled 129 patients with ALK-positive NSCLC with known ALK variants. Resistance mutations and clinical outcomes on ALK TKIs were evaluated retrospectively according to ALK variant.

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A separate Foundation Medicine data set of 577 patients with ALK-positive NSCLC were also evaluated.

Researchers noted that the most frequent ALK variants were EML4-ALK variant 1 (43%; n = 55 patients) and variant 3 (40%; n = 51 patients).

After analyzing 77 tumor biopsy specimens from patients with variants 1 and 3 who progressed on an ALK TKI, resistance mutations were significantly more common in variant 3 than in variant 1 (57% vs 30%, respectively; P = .023). The most common ALK resistance mutation in variant 3 was ALK G1202R (32%; P < .001).


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Analysis of the Foundation Medicine database revealed similar outcomes; there was a notable association of variant 3 with ALK resistance mutation and with G1202R (P = .010 and .015, respectively).

Furthermore, researcher reported that among the patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival compared with variant 1 (HR, 0.31; 95% CI, 0.12-0.79; P = .001).

Dr Lin and colleagues concluded that these results provide a molecular link between ALK variant and clinical outcomes in NSCLC. “ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors,” they wrote.—Zachary Bessette