Impact of the EML4-ALK variant on the efficacy of alectinib (ALC) in untreated ALK+ advanced NSCLC (aNSCLC) in the global phase III ALEX study

Abstract

Background: The ALEX study (NCT02075840) showed superior investigator (INV)‐ assessed PFS with ALC vs crizotinib (CZ) (stratified HR 0.47, 95% CI 0.34‐0.65, p<0.001): median PFS not estimable ALC vs 11.1 months [m] CZ. Follow‐up analysis (cut‐off Dec 1 2017) indicated a median PFS of 34.8m ALC vs 10.9m CZ (stratified HR 0.43, 95% CI 0.32‐0.58) [Camidge et al. ASCO 2018]. We report efficacy data from ALEX by EML4‐ALK variant group. Methods: Patients (pts) with stage IIIB/IV ALK+NSCLC (by central IHC) and no prior systemic therapy for aNSCLC were enrolled (asymptomatic CNS metastases allowed) and randomized 1:1 to receive ALC 600mg BID (n=152) or CZ 250mg BID (n=151). ALK rearrangement was assessed in baseline samples by next generation sequencing (NGS; FoundationOne® [tissue] and Foundation ACT [plasma]) using the primary data cut‐off (Feb 9 2017). PFS (INV‐assessed, RECIST v1.1), objective response rate (ORR) and duration of response (DoR) were assessed by EML4‐ALK variant. Results: Baseline demographics/PFS were comparable between the biomarker evaluable populations (BEP; n=203 tissue, n=222 plasma) and the ITT population (n=303). ALK rearrangement was detected by NGS in 136/203 (67%; tissue) and 145/ 222 (65%; plasma) pts. EML4‐ALK variants 1, 2 and 3a/b accounted for ≈90% of variants (variant 2 was least prevalent). In the primary data set analysis, no significant difference was observed in INV‐assessed PFS or ORR between the EML4‐ALK variant groups in both tissue and plasma BEPs for ALC‐ and CZ‐treated pts (Table). Median DoR was similar for EML4‐ALK variants 1, 2 and 3 in the ALC arm but not in the CZ arm. Efficacy data by independent review were comparable. Conclusions: These exploratory post‐hoc analyses from the ALEX study show that the greater efficacy benefit of ALC vs CZ in ALK+ aNSCLC appeared independent of the EML4‐ALK variant.