Envonalkib

Anaplastic lymphoma kinase (ALK) fusion gene is one of the most common driver genes in non-small cell lung cancer (NSCLC). ALK-tyrosine kinase inhibitors (TKIs) have become the standard treatment option for patients with advanced ALK gene fusion positive NSCLC. Currently, the China National Medical Products Administration (NMPA) has approved ten ALK-TKIs, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, iruplinalkib, envonalkib, dirozalkib and conteltinib. Iruplinalkib is a novel ALK-TKI independently developed in China. On June 27, 2023, the NMPA approved iruplinalkib for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC who had progressed on or were intolerant to crizotinib. On January 16, 2024, the NMPA approved iruplinalkib for first-line treatment of patients with locally advanced or metastatic ALK-positive NSCLC patients. To help clinicians better understand the efficacy and safety of iruplinalkib and to facilitate its more rational clinical application, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists organized experts to develop the "Expert consensus on iruplinalkib for the treatment of ALK-positive non-small cell lung cancer (2026 edition)". This consensus provides systematic and comprehensive update of clinical research data on iruplinalkib published before June 25, 2026, based on the 2024 edition. It covers common clinical issues and provides corresponding recommendations for the use of iruplinalkib in the treatment of ALK-positive NSCLC.

In metastatic ALK-positive non-small cell lung cancer (mNSCLC), ALK tyrosine kinase inhibitors (ALKi) represent the established standard of care. While second- and third-generation ALKi (including alectinib, brigatinib, ensartinib, envonalkib, and lorlatinib) have demonstrated superior efficacy compared with the first-generation inhibitor crizotinib in randomized trials, the absence of direct head-to-head comparisons limits the definition of their relative clinical benefit. We performed an updated indirect comparison of next-generation ALKi using data from pivotal randomized controlled trials. Seven first-line trials in ALK-positive mNSCLC were identified, and individual patient data were reconstructed from published Kaplan-Meier curves to estimate treatment effects using Cox proportional hazards models and restricted mean survival time (RMST) analyses, with crizotinib as a common comparator. All next-generation ALKi demonstrated significant progression-free survival (PFS) benefit versus crizotinib. In indirect comparisons, lorlatinib showed superior PFS compared with alectinib [hazard ratio (HR) 0.61; 95% confidence interval (CI): 0.43-0.85], brigatinib (HR 0.48; 95% CI: 0.33-0.71), ensartinib (HR 0.60; 95% CI: 0.40-0.90), and envonalkib (HR 0.42; 95% CI: 0.28-0.62). RMST analyses indicated increasing separation between lorlatinib and alectinib over time, suggesting a more sustained PFS benefit with lorlatinib. Among patients with baseline brain metastases (BMs), lorlatinib showed the strongest PFS effect compared with alectinib, brigatinib, ensartinib, and envonalkib. For overall survival (OS), alectinib demonstrated a statistically significant benefit versus crizotinib, while no significant differences were observed among next-generation ALKi. This indirect comparison indicates that lorlatinib provides the most durable PFS and the strongest intracranial disease control, although ALKis are characterized by distinct toxicity profiles. In the absence of clear OS differences at present, first-line treatment selection should integrate efficacy, intracranial activity, tolerability, and emerging molecular features within a personalized therapeutic framework.