Crizotinib versus observation or placebo for surgically resected early-stage ALK-positive non-small-cell lung cancer (Eastern Cooperative Oncology Group-American College of Radiology Imaging Network E4512): a phase 3 trial.

backgroundCrizotinib is an established first-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of advanced ALK-positive non-small-cell lung cancer (NSCLC). E4512 aimed to evaluate the effect of adjuvant crizotinib on disease-free survival (DFS) in patients with resected, early-stage ALK-positive NSCLC.

methodsIn this randomised, controlled, phase 3 trial conducted in 1618 sites across the USA, Guam, and Puerto Rico, patients were randomly assigned 1:1 by computer-generated sequence to receive crizotinib 250 mg orally twice daily or observation (changed from initial double-blind placebo) for up 2 years. Eligible patients had resected NSCLC tumours that were 4 cm or larger in diameter or lymph node-positive, negative surgical margins, no neoadjuvant therapy, ALK positivity by local or central testing, and an Eastern Cooperative Oncology Group performance status of 0-1. Adjuvant chemotherapy was allowed but not required. Stratification factors were stage, previous radiation therapy, and sex. The primary endpoint was disease-free survival (DFS) in the centrally tested ALK-positive intention-to-treat population and presented as hazard ratio with 90% and 95% CI. The trial was registered at ClinicalTrials.gov (NCT02201992) and is completed. Safety was assessed in all patients whose tumours tested ALK-positive and who received the study drug.

findingsBetween Aug 18, 2014, and May 10, 2024, 166 patients (of 168 planned) were enrolled (85 to crizotinib and 81 to observation). Accrual was stopped when the US Food and Drug Administration approved adjuvant alectinib for resected ALK-positive NSCLC. Overall, 153 (92%) patients had centrally confirmed ALK-positive tumours. Among these 153 individuals, 99 (65%) were female, 54 (35%) were male, and 121 (79%) were White. After a median follow-up of 65·7 months (IQR 37·5-85·6), median DFS was 74·6 (95% CI 71·2 to not assessable) months in the crizotinib group and 106·2 (67·8 to NA) months in the observation group (HR 1·08 [90% CI 0·67-1·73; 95% CI 0·61-1·90; p=0·80). In the crizotinib group, 46 (58%) patients had grade 3 or higher adverse events of any attribution (most commonly diarrhoea, in eight [10%] patients; oedema, in four [5%] patients; and hypertension, in four [5%] patients), including one death that was not deemed treatment-related. 21 (27%) patients had serious adverse events, most commonly dyspnoea (three [4%] patients), abdominal pain (two [3%] patients), thromboembolic event (two [3%] patients), diarrhoea (two [3%] patients), dehydration (two [3%] patients), and hypertension (two [3%] patients).

interpretationAdjuvant crizotinib does not prolong DFS in patients with surgically resected ALK-positive NSCLC. These findings suggest that crizotinib should not be recommended as an adjuvant therapy for patients with resected ALK-positive NSCLC.

fundingNational Cancer Institute of the US National Institutes of Health.