Envonalkib Versus Crizotinib in Treatment‐Naive ALK ‐Positive Non‐Small Cell Lung Cancer: Final Efficacy and Biomarker Analyses of the Randomized Phase III Study

ABSTRACT This study reports efficacy and biomarker results from a multicenter, randomized, open‐label Phase III study (NCT04009317). Treatment‐naive anaplastic lymphoma kinase ( ALK )‐positive non‐small cell lung cancer (NSCLC) patients were centrally randomized 1:1 to envonalkib or crizotinib, stratified by brain metastases and chemotherapy lines. The primary endpoint was progression‐free survival (PFS) assessed by independent review committee. This analysis updated investigator‐assessed PFS. A total of 264 patients were randomized (envonalkib: 131, crizotinib: 133). Median follow‐up was 46.5 and 46.8 months for envonalkib and crizotinib, respectively. Envonalkib significantly improved PFS over crizotinib (median PFS: 30.4 vs. 12.0 months, p < 0.0001; hazard ratio [HR] = 0.48, 95% CI: 0.35–0.65). Overall survival (OS) data remained immature. In the envonalkib group, circulating tumor DNA (ctDNA) analysis revealed poor prognosis for patients with co‐mutations in p53 pathway genes ( TP53 , CDKN2A , MDM2 , MDM4 ) or other concurrent oncogenic drivers (median PFS: 15.7 and 8.3 months). Among 52 patients with post‐progression ctDNA data, putative resistance mechanisms were identified in 14 (26.9%), including secondary ALK mutations ( n = 9) and/or bypass pathway activations ( n = 9). Final follow‐up confirms the robust benefit of envonalkib over crizotinib, supporting its role as a first‐line option for ALK ‐positive NSCLC. Biomarker analyses validate the prognostic impact of genomic co‐alterations and delineate resistance mechanisms.