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.