Discussion
NSCLC, intracranial disease, ALK-positive NSCLC, TRAEs
DISEASE PROGRESSION, BRAIN METASTASIS, BRAIN METASTASES, NSCLC, CNS METASTASES
In the present randomized phase III trial, envonalkib significantly improved PFS compared with crizotinib (median, 24.87 vs. 11.60 months; HR = 0.47, 95% CI, 0.34–0.64). Moreover, envonalkib had superior efficacy over crizotinib against intracranial disease. In participants with brain target lesions at baseline, IRC-assessed CNS-ORRs were 78.95% and 23.81% in the envonalkib and crizotinib groups, respectively. Envonalkib significantly delayed disease progression in participants with baseline brain metastases and starkly reduced the risk of brain metastasis in participants without baseline brain metastasis. The incidence of TRAEs resulting in permanent discontinuation of envonalkib was low (6.11%), and no new safety signals were observed.CNS metastases are protected from most systemic anticancer treatments due to the blood-brain barrier. Even small-molecule drugs can have a low diffusion rate through the barrier. As its lower capability of penetrating the brain-blood barrier, the activity against brain metastases of crizotinib is limited.Previous phase III trials showed that second-generation ALK inhibitors, e.g., brigatinib, alectinib, and ensartinib, could significantly improve PFS in advanced ALK-positive NSCLC participants with no prior treatment with ALK inhibitors compared with crizotinib, with median PFS ranging from 25.8 to 34.8 months and HR values ranging from 0.43 to 0.51.Older age and poorer performance status are prognostic factors in NSCLC.The safety profile of envonalkib from this phase III trial was generally consistent with that from the previous phase I study, with no new safety signal observed.The EML4-ALK fusion gene has variants that may have an impact on the treatment efficacy of ALK-TKIs.This study had limitations. Only Chinese participants were enrolled, indicating limited generalizability of the results. Because of the ethnic differences in the epidemiology and management of NSCLC,In conclusion, envonalkib is effective and with a manageably safe profile in advanced ALK-positive NSCLC patients who have previously received no ALK inhibitors, significantly improving PFS compared with crizotinib, as well as reducing the risk of progression or development of brain metastases. Envonalkib might be a new option for first-line treatment of advanced ALK-positive NSCLC.