Background
Randomized, controlled phase 3 trial (ECOG-ACRIN E4512) evaluating adjuvant crizotinib in surgically resected, early-stage ALK-positive NSCLC. Eligible patients had resected tumors ≥4 cm or node-positive, negative margins, no neoadjuvant therapy, ALK positivity, and ECOG PS 0–1. 166 of 168 planned patients enrolled (85 crizotinib, 81 observation); accrual was halted when the FDA approved adjuvant alectinib. 153 (92%) had centrally confirmed ALK positivity.
Results
Interventions and follow up: Arm A: crizotinib 250 mg PO twice daily for up to 2 years
Arm B: observation (initially double-blind placebo, later amended to observation)
Primary endpoint: disease-free survival (DFS) in the centrally-tested ALK-positive ITT population
mFollow up: 65.7 months
Results: DFS: median 74.6 (95% CI 71.2–NA) vs 106.2 (67.8–NA) months, HR 1.08 (90% CI 0.67–1.73; 95% CI 0.61–1.90), P=.80 — not met
Arm B: observation (initially double-blind placebo, later amended to observation)
Primary endpoint: disease-free survival (DFS) in the centrally-tested ALK-positive ITT population
mFollow up: 65.7 months
Results: DFS: median 74.6 (95% CI 71.2–NA) vs 106.2 (67.8–NA) months, HR 1.08 (90% CI 0.67–1.73; 95% CI 0.61–1.90), P=.80 — not met
Adverse events
Grade ≥3 (any attribution, crizotinib): 58% — diarrhea 10%, edema 5%, hypertension 5%
Serious AEs (crizotinib): 27% — dyspnea 4%, abdominal pain 3%
Deaths: 1 (not deemed treatment-related)
Serious AEs (crizotinib): 27% — dyspnea 4%, abdominal pain 3%
Deaths: 1 (not deemed treatment-related)
Conclusions
Adjuvant crizotinib did not improve DFS versus observation in resected early-stage ALK-positive NSCLC. The trial was underpowered because accrual stopped early after FDA approval of adjuvant alectinib, and the numerical DFS favored observation. The result does not support adjuvant crizotinib.
Key Limitations
Small sample (166 enrolled of 168 planned) and early closure severely limited power; the control arm was changed from double-blind placebo to open-label observation mid-trial; crizotinib is a first-generation ALK inhibitor now superseded by more potent CNS-penetrant agents; the long accrual window (2014–2024) spanned major shifts in ALK-directed therapy.
Clinical Context
Adjuvant alectinib (ALINA trial) is FDA-approved (April 2024) and is the NCCN-preferred adjuvant therapy for resected stage IB–IIIA ALK-positive NSCLC; crizotinib has no established adjuvant role. E4512 reinforces that first-generation crizotinib is not an appropriate adjuvant standard.