The Phase 3 E4512 clinical trial has definitively shown that crizotinib does not provide disease-free survival benefits when used as adjuvant therapy in patients with resected early-stage ALK-positive non-small cell lung cancer (NSCLC). The results, presented at the 2025 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in Barcelona, represent a significant finding for thoracic oncology practice.
Trial Design and Patient Population
The ALCHEMIST E4512 trial enrolled 166 evaluable patients with surgically resected stage IIA through IIIB ALK-positive NSCLC over nearly ten years, from August 2014 to May 2024. Patients were required to have negative surgical margins, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no prior exposure to ALK-targeted therapy. ALK-positive status was confirmed through fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or next-generation sequencing (NGS).
Participants were randomized to receive either crizotinib at 250 mg twice daily for up to two years or active surveillance. The trial was powered to detect a 40% reduction in the hazard of disease-free survival, with an expected median DFS of 70 months with crizotinib versus 42 months with observation.
The median age was 63 years in the crizotinib group and 61 years in the observation group. Females comprised 68% and 62% of patients in the respective groups. The majority of patients were White (80% vs 77%), and most had never smoked (53% vs 64%). Stage II disease was present in 36% vs 37% of patients, while stage III disease affected 41% vs 47% in the crizotinib and observation groups, respectively.
Primary Efficacy Results
After a median follow-up of 58.3 months, the trial failed to meet its primary endpoint. Patients receiving crizotinib exhibited a median disease-free survival of 72.8 months, compared to 75.1 months in the observation group, resulting in a hazard ratio of 1.06 (90% CI: 0.63-1.77; P = 0.86). This finding demonstrated no statistically significant difference between the treatment arms.
"Adjuvant crizotinib did not prolong DFS compared with observation nor OS—although these data are not mature—in resected ALK-positive NSCLC," stated lead study author David Gerber, MD, of UT Southwestern Medical Center during his presentation.
Overall survival data remain immature, with median OS not reached in either arm at the time of reporting. While the hazard ratio for OS numerically favored crizotinib (HR 0.49; 90% CI: 0.18-1.37), this finding did not achieve statistical significance (P = 0.26).
Safety and Tolerability Profile
The safety profile of adjuvant crizotinib reflected known toxicities from previous metastatic NSCLC studies. Grade 3 or higher treatment-related adverse effects occurred in 43% of patients receiving crizotinib. The most common severe toxicities included diarrhea (8%) and peripheral edema (5%). Eye disorders, abdominal pain, elevated alanine aminotransferase levels, and decreased neutrophil count each occurred in 3% of patients. One patient experienced a treatment-related grade 4 stroke.
The median duration of crizotinib therapy was 13.5 months. Treatment discontinuation occurred in 77 patients, with adverse effects leading to permanent discontinuation in 27% of cases. Additional reasons for discontinuation included completion per protocol (40%), patient withdrawal or refusal (14%), disease recurrence (5%), and initiation of other treatment (4%).
Clinical Implications and Study Termination
The trial was terminated in April 2025 following recommendations from the Data and Safety Monitoring Committee, partly due to the FDA's approval of alectinib as adjuvant therapy for resected ALK-positive NSCLC, which became the new standard of care and impacted the clinical equipoise necessary for continuation of the study.
These findings have significant implications for clinical practice, as they demonstrate that crizotinib's pharmacodynamic and pharmacokinetic properties may be inadequate to eradicate micrometastatic disease post-surgery. The lack of disease-free survival benefit, combined with meaningful toxicity leading to treatment discontinuation in 25% of patients, supports the current preference for second-generation ALK inhibitors like alectinib in the adjuvant setting.
The results emphasize the evolving paradigm in ALK-positive NSCLC management, where newer-generation ALK inhibitors with superior CNS activity and more favorable efficacy profiles have established themselves as the preferred adjuvant agents. The study's rigorous methodology, including randomized design and comprehensive follow-up, exemplifies the gold standard for biomarker-driven trials in personalized thoracic oncology.
