Treatment with Next-Generation ALK Inhibitors Fuels Plasma <i>ALK</i> Mutation Diversity.

Abstract

Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary <i>ALK</i> mutations. Here, we investigated utility of plasma genotyping for identifying <i>ALK</i> resistance mutations at relapse on next-generation ALK TKIs. We analyzed 106 plasma specimens from 84 patients with advanced <i>ALK</i>-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify <i>ALK</i> mutations. By genotyping plasma, we detected an <i>ALK</i> mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of <i>ALK</i> mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 <i>ALK</i> mutations (24% vs. 2%, <i>P</i> = 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an <i>ALK</i> mutation in 22 (76%), including 14 (48%) with ≥2 <i>ALK</i> mutations. The most frequent combinations of <i>ALK</i> mutations were G1202R/L1196M and D1203N/1171N. Detection of ≥2 <i>ALK</i> mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, <i>P</i> = 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired ≥1 new <i>ALK</i> mutations on lorlatinib. <i>ALK</i> resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of <i>ALK</i> resistance mutations leading to treatment-refractory compound <i>ALK</i> mutations.