ALK-positive NSCLC is a type of lung cancer with a specific molecular profile characterized by the abnormal arrangement or the fusion of the ALK gene which occurs in approximately 3%-5% of all lung cancer cases. Most patients with ALK-positive NSCLC are relatively young, non-smoking or only have a light smoking history, and have a higher risk of brain metastasis.
Despite that multiple ALK-targeted therapies have already been approved, more than half of patients with NSCLC treated with second-generation ALK TKIs would develop acquired resistance, thus the Chinese Society of Clinical Oncology (CSCO) guidelines’ recommendation of platinum-based chemotherapies as a treatment option for patients who had failed on second-generation ALK-targeted therapies. It is widely acknowledged that chemotherapies are commonly associated with strong side effects and there is a growing general preference for chemotherapy-free regimens for the treatment of advanced tumors. Therefore, patients with resistance to second-generation ALK TKIs have an enormous unmet clinical need for new therapies that are effective and safe.
APG-2449, developed by Ascentage Pharma, is an orally-active small molecule FAK inhibitor and a third-generation ALK/ROS1 TKI, and the first FAK inhibitor cleared by the CDE to enter clinical study in China. In the first-in-human trial, APG-2449 demonstrated preliminary clinical benefit and favorable tolerability in patients with NSCLC who were either second-generation ALK TKI resistant or treatment-naïve. APG-2449 also showed potential inhibitory effect on brain metastases, with its ability to cross the blood-brain barrier confirmed through pharmacokinetics (PK) analysis on cerebrospinal fluid. Biomarker analysis found that the phosphorylated FAK (pFAK) expression in tumor tissues at baseline in patients with NSCLC who were second-generation ALK TKI-resistant, were positively correlated with the progress-free survival (PFS) after treatment with APG-2449, indicating that elevated phosphorylated FAK could be associated with drug resistance to second-generation ALK TKIs.
