Ascentage Pharma's APG-2449, a tyrosine kinase inhibitor targeting FAK, ALK, and ROS1, has received clearance from China's Center for Drug Evaluation (CDE) to proceed with two Phase III registrational studies. These trials will evaluate APG-2449 in patients with non-small cell lung cancer (NSCLC). The advancement marks a significant step in addressing unmet needs in NSCLC treatment, particularly for those with resistance to existing therapies.
Phase III Trial Designs
The two pivotal, multicenter, open-label, randomized Phase III studies are designed to assess APG-2449 in distinct NSCLC patient populations.
One trial will compare the efficacy and safety of APG-2449 against platinum-based chemotherapies in patients with NSCLC who have developed resistance to or are intolerant of second-generation ALK TKIs. This is particularly relevant as over half of NSCLC patients treated with these second-generation inhibitors develop acquired resistance, leading to a need for alternative treatments.
The second study will evaluate APG-2449 versus crizotinib as a first-line therapy for treatment-naïve patients with ALK-positive advanced or locally advanced NSCLC. This aims to establish APG-2449 as a potential initial treatment option for this specific molecular subtype of lung cancer.
Addressing Unmet Needs in ALK-Positive NSCLC
ALK-positive NSCLC, characterized by abnormal ALK gene arrangements, affects approximately 3-5% of all lung cancer cases. These patients are often younger, non-smokers, and have a higher propensity for brain metastasis. While several ALK-targeted therapies are available, resistance to second-generation ALK TKIs remains a significant challenge. Current guidelines from the Chinese Society of Clinical Oncology (CSCO) recommend platinum-based chemotherapies for these patients, but these are associated with significant side effects, driving the need for chemotherapy-free regimens.
APG-2449: A Novel Multi-Targeted Inhibitor
APG-2449 is an orally-active small molecule that inhibits FAK and acts as a third-generation ALK/ROS1 TKI. It is the first FAK inhibitor cleared by the CDE for clinical study in China. Early clinical trials have demonstrated preliminary benefits and favorable tolerability in NSCLC patients, including those resistant to second-generation ALK TKIs and treatment-naïve individuals. Pharmacokinetic analysis has confirmed its ability to cross the blood-brain barrier, suggesting potential in treating brain metastases.
Biomarker analysis has indicated that phosphorylated FAK (pFAK) expression in tumor tissues of patients resistant to second-generation ALK TKIs is positively correlated with progression-free survival (PFS) after APG-2449 treatment. This suggests that elevated pFAK may contribute to drug resistance, and APG-2449's multi-targeted inhibition could offer a new strategy.
Expert Commentary
Professor Li Zhang from Sun Yat-sen University Cancer Center, the principal investigator of the Phase III studies, noted, "APG-2449 is an effective multitargeted inhibitor that acts on FAK/ALK/ROS1... We are particularly encouraged by the preliminary efficacy observed in patients with resistance to second-generation ALK TKIs, as it suggests that multitargeted inhibition on FAK and ALK may offer a new strategy for the management of patients with NSCLC resistant to second-generation ALK TKIs."
Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, added, "The CDE's approvals for the two registrational Phase III studies of APG-2449 are very encouraging as they mark a major milestone in the drug candidate's clinical development."
