Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-positive Advanced Non-small-cell Lung Cancer in the Global Phase III ALEX Study

Abstract Introduction At the prior data cut-off (February 9, 2017) the ALEX trial showed superior investigator-assessed progression-free survival (PFS) for alectinib versus crizotinib in untreated, anaplastic lymphoma kinase ( ALK) -positive, advanced non-small-cell lung cancer ( ALK + NSCLC) (hazard ratio [HR], 0.47, 95% confidence internal [CI], 0.34–0.65; p echinoderm microtubule-associated protein like 4-ALK ( EML4-ALK) variant may influence ALK inhibitor treatment benefit. We present updated analyses, including exploratory subgroup analysis by EML4-ALK variant, after an additional 10 months' follow-up (cut-off: December 1, 2017). Methods Patients were randomized to receive twice-daily alectinib 600 mg or crizotinib 250 mg until disease progression, toxicity, death, or withdrawal. PFS was determined by investigators. Baseline plasma and tissue biomarker samples were analyzed using hybrid-capture, next-generation sequencing to determine EML4-ALK variant. Results Baseline characteristics were balanced. Investigator-assessed PFS was prolonged with alectinib; stratified HR, 0.43 (95% CI, 0.32–0.58), median 34.8 months versus crizotinib 10.9 months. EML4-ALK fusions were detectable in 129 patients (plasma) and 124 (tissue); variants 1, 2 and 3/ab did not impact PFS, objective response rate or duration of response. Investigator-assessed PFS was longer for alectinib versus crizotinib across EML4-ALK variants 1, 2 and 3a/b in plasma and tissue. Despite longer treatment duration (alectinib 27.0 months versus crizotinib 10.8 months), safety of alectinib compared favorably with crizotinib. Conclusion Alectinib continues to demonstrate superior investigator-assessed PFS versus crizotinib in untreated ALK + NSCLC, irrespective of EML4-ALK variant.