Final OS analysis from the phase III j-alex study of alectinib (ALC) versus crizotinib (CRZ) in Japanese ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC).

Abstract

9022 Background: The primary analysis of the J-ALEX (JapicCTI-132316) study for the ALK-inhibitor naïve ALK+ NSCLC demonstrated superior progression-free survival (PFS) in Japanese patients randomized to the ALC, compared with those assigned in the CRZ (HR 0.34, 99.7% CI 0.17–0.71, stratified log-rank p<0·0001) by the Independent Review Facility (IRF) (Hida et al., Lancet 2017). The final PFS and 2nd overall survival (OS) interim analysis (IA) data were subsequently reported (Nakagawa et al., Lung cancer 2020). Here, we report the final OS data. Methods: ALK+ NSCLC (by IHC and FISH or RT-PCR) patients were randomized 1:1 either to receive ALC (Japanese approved dose 300 mg BID, n = 103) or CRZ (250 mg BID, n = 104). Stratification factors included ECOG PS, treatment line, and clinical stage. The primary endpoint was PFS according to the blinded IRF. Secondary endpoints included OS, objective response rate, and safety. Results: After a median follow-up of 68.6 months in the ALC arm and 68.0 months in the CRZ arm, death events occurred in 40.8% and 39.4% in the ALC and the CRZ arms, respectively. Five-year survival rates for patients in the ALC and CRZ arm were 60.85% and 64.11%, respectively. The final OS HR was 1.03 (95%CI 0.67-1.58), however, median OS was not reached in either arm. Of note, patients in the CRZ arm tended to have their treatment switched earlier than those in the ALC arm (median time to treatment-switch: 12.3 months vs. NE). Most of the patients (78.8%) in the CRZ arm received ALC as a 1st subsequent therapy, whereas only 10.7% of patients in the ALC arm received CRZ. Conclusions: In this final J-ALEX OS analysis, prolongation of OS in the ALC arm was not observed compared to the CRZ arm. However, OS result may be substantially confounded since 78.8% of the patients in the CRZ arm received ALC as initial, subsequent therapy. Clinical trial information: 132316.

Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials

“…There is a lack of head-to-head comparative evidence between the novel-generation ALK-TIKs. Consistent with our findings, previous studies have associated alectinib and lorlatinib with favorable effectiveness [ 10 , 26 , 29 – 31 , 33 , 34 ]. The median PFS of alectinib was more than 30 months in two large phase 3 RCTs (ALEX and J-ALEX) [ 26 , 30 ], while that of brigatinib and ceritinib was 24 months and 16.6 months respectively [ 12 , 27 ].…”

“…The efficacy of crizotinib as the first-line treatment for patients with advanced ALK -rearranged NSCLC was proved in PROFILE 1014 [ 6 , 25 ], however, novel-generation ALK-TKIs in the first-line setting have shown improved PFS versus crizotinib [ 10 , 11 , 13 , 26 – 31 , 33 , 34 ]. This might be because of its poor brain penetrance and lower intracranial response [ 35 ].…”

“…Lastly, alectinib may increase overall survival because of the better control of the intracranial lesions. In contrast, the final OS analysis of J-ALEX indicated that OS HR was 1.03 (95%CI 0.67–1.58) and 5-year OS rate in the alectinib 300 mg and crizotinib arm were 60.85 and 64.11%, respectively [ 31 ]. Alectinib 300 mg did not demonstrate a significant overall survival benefit versus crizotinib.…”

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

“…Secondly, OS data might cause heterogeneity when taken as an endpoint to evaluate each treatment’s effect. Although we initially searched for the most updated OS HRs, data on OS had only 37% maturity in the ALEX trial ( 17 ) and 40.8% maturity in the J-ALEX trial ( 18 ); thus, it is still tempting for clinicians to consider an improvement in OS benefit for first-line ALK-TKIs compared with conventional chemotherapy. Therefore, we reported PFS as the primary outcome measure.…”

Targeting ALK Rearrangements in NSCLC: Current State of the Art

“…Alectinib was approved by the FDA for the first-line treatment of ALK+ NSCLC in 2017 based on the phase III ALEX trial with alectinib 600 mg twice daily ( 36 ). In a final analysis of the J-ALEX study, compared to crizotinib, alectinib did not achieve overall survival (OS) benefit ( 60 ), reflecting that the crossover to the post first-line treatment might greatly influence OS, especially in ALK+ NSCLC who could get significant benefit from all ALK TKIs. A prospective real-world study investigated the strategy of switching to alectinib in ALK+ NSCLC patients that did not experience disease progression with initial crizotinib ( 61 ).…”