Alectinib Versus Crizotinib in Treatment-Naive Advanced ALK Positive Non-Small Cell Lung Cancer (NSCLC): Primary Results of the Global Phase III ALEX Study

BACKGROUND: Alectinib, a TKI targeting ALK, has shown robust eficacy in crizotinib‐naïve/resistant ALK+ NSCLC. J‐ALEX showed superiority of alectinib 300mg BID vs crizotinib in Japanese pts with crizotinib‐naïve ALK+ NSCLC (progression‐free survival [PFS] HR 0.34, p<0.0001). We report primary results from the ALEX study of drstline alectinib 600mg BID vs crizotinib in advanced ALK+ NSCLC (NCT02075840). METHODS: This open‐label randomized multicenter phase III study enrolled pts with stage IIIB/IV ALK+ NSCLC, determined by central IHC testing. Eligible pts had ECOG PS 0‐2 and no prior systemic therapy for advanced NSCLC. Pts with asymptomatic CNS metastases were allowed. Pts (n=303) were randomized 1:1 to receive alectinib 600mg or crizotinib 250mg BID. Primary endpoint: Investigator (Inv)‐assessed PFS (RECIST v1.1), with systematic CNS imaging in all pts. Secondary endpoints included independent review committee (IRC)‐ assessed PFS, IRC‐assessed time to CNS progression (TTP), objective response rate (ORR), overall survival (OS) and safety. RESULTS: At the primary data cut‐off (9 Feb 2017), alectinib demonstrated statistically signidcant superiority vs crizotinib, reducing risk of progression/death by 53% (HR 0.47, 95% CI 0.34‐0.65, p<0.0001); alectinib median PFS was not reached (95% CI 17.7‐NE) vs crizotinib 11.1 months (95% CI 9.1‐13.1). Key secondary endpoints showed superiority for alectinib vs crizotinib, respectively: IRC PFS, HR 0.50 (95% CI 0.36‐0.70; p<0.0001); median PFS 25.7 months (95% CI 19.9‐NE) vs 10.4 months (95% CI 7.7‐14.6); CNS TTP, cause‐specidc HR of CNS progression 0.16 (95% CI 0.10‐0.28; p<0.0001); ORR (Inv) 83% (95% CI 76‐89) vs 76% (95% CI 68‐82), p=0.09; OS, based on 25% events, HR 0.76 (95% CI 0.48‐1.20; p=0.24). Grade 3/4 AEs were less frequent with alectinib, 41%, vs 50% with crizotinib; fatal AEs occurred in 3% vs 5%, respectively. Rates of AEs leading to discontinuation, dose reduction and interruption were lower with alectinib. CONCLUSIONS: Alectinib showed superior eficacy and favorable tolerability compared with crizotinib. ALEX results support alectinib as a new standard of care for treatment‐naïve ALK+ NSCLC.