ALK Mutation Status Before and After Alectinib Treatment in Locally Advanced or Metastatic ALK-positive NSCLC: Pooled Analysis of Two Prospective Trials

Abstract Background The effectiveness of ALK inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with non-small-cell lung cancer (NSCLC) and ALK point mutations using pooled data from two single-arm phase II studies. Methods Studies NP28673 and NP28761 enrolled adults with locally advanced/metastatic ALK-positive NSCLC who had progressed on crizotinib. ALK mutation analysis was conducted on cell-free DNA (cfDNA) from 187 patients post-crizotinib/pre-alectinib, and from 49 of these patients who subsequently progressed on alectinib. Results Baseline characteristics were generally balanced across patient subgroups. At baseline, 34 distinct ALK mutations were identified in 48/187 patients (25.7%). Median investigator-assessed progression-free survival was longer in patients without ALK single-nucleotide variants (n = 138) versus those with (n = 48): 10.2 months (95% confidence interval [CI], 8.1–14.3) versus 5.6 months (95% CI, 4.5–10.9), respectively. Sixteen out of 32 patients (50%) with ALK resistance mutations to crizotinib achieved an investigator-assessed response to alectinib (all partial responses); most of these ALK mutations were known to be sensitive to alectinib. Analysis of plasma samples taken post-progression on alectinib revealed that 26/49 (53%) samples harbored 16 distinct ALK mutations, with known alectinib-resistance mutations, I1171 T/N/S, G1202R, and V1180L, observed in 15/49 (31%) tumors. Conclusion Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cfDNA in plasma samples may be an alternative non-invasive method for monitoring resistance mutations during therapy.