Background
Phase III, open-label RCT (ALEX). N=303. Untreated advanced ALK-positive NSCLC. First-line alectinib vs crizotinib.
Interventions and follow up
Arm A: Alectinib 600 mg PO BID
Arm B: Crizotinib 250 mg PO BID
Primary endpoint: Investigator-assessed PFS
mFollow up: 18.6 mo (alectinib), 17.6 mo (crizotinib) at primary; 48.2 mo (alectinib), 23.3 mo (crizotinib) at final OS analysis
Arm B: Crizotinib 250 mg PO BID
Primary endpoint: Investigator-assessed PFS
mFollow up: 18.6 mo (alectinib), 17.6 mo (crizotinib) at primary; 48.2 mo (alectinib), 23.3 mo (crizotinib) at final OS analysis
Results
IRC PFS: 25.7 mo vs 10.4 mo, HR 0.50 (95% CI 0.36–0.70; P<.001)
Final mPFS: 34.8 mo vs 10.9 mo
mOS: not reached vs 57.4 mo, HR 0.67 (95% CI 0.46–0.98)
5-yr OS: 62.5% vs 45.5%
OS, CNS mets subgroup: HR 0.58 (95% CI 0.34–1.00)
12-mo survival rate: 84.3% vs 82.5%
Final mPFS: 34.8 mo vs 10.9 mo
mOS: not reached vs 57.4 mo, HR 0.67 (95% CI 0.46–0.98)
5-yr OS: 62.5% vs 45.5%
OS, CNS mets subgroup: HR 0.58 (95% CI 0.34–1.00)
12-mo survival rate: 84.3% vs 82.5%
Adverse events
Overall: Grade 3–5 AEs 41% (alectinib) vs 50% (crizotinib)
Lab changes: ALT increased 15% vs 5%, AST increased 11% vs 5%
GI: Nausea 3% vs 1%, vomiting 3% vs 0%, diarrhea 2% vs 0%
Lab changes: ALT increased 15% vs 5%, AST increased 11% vs 5%
GI: Nausea 3% vs 1%, vomiting 3% vs 0%, diarrhea 2% vs 0%
Conclusions
Alectinib had superior efficacy and lower toxicity vs crizotinib in untreated advanced ALK-positive NSCLC, establishing it as a first-line standard.
Key Limitations
Open-label design. Crizotinib comparator now superseded as preferred 1L. No head-to-head vs lorlatinib (CROWN). Confirmatory parallel trials (J-ALEX, Japanese 300 mg BID dose; ALESIA, Asian) used different doses/populations.
Clinical Context
FDA approved alectinib 1L ALK+ NSCLC (2017). ALEX, J-ALEX, and ALESIA together established alectinib over crizotinib as a 1L standard; lorlatinib (CROWN) now preferred in fit patients. ESMO recommends a 2nd/3rd-generation ALK TKI 1L.