Abstract
BACKGROUND: APG-2449 is a focal adhesion kinase (FAK) inhibitor and a third-generation anaplastic lymphoma kinase (ALK)-proto-oncogene receptor tyrosine kinase ROS (ROS1) tyrosine kinase inhibitor (TKI). The aim of this first-in-human study was to evaluate safety and efficacy of APG-2449 in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: This single-arm, multicentre, phase 1 clinical trial included a dose escalation to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), followed by a dose-expansion stage at RP2D to evaluate safety. Secondary endpoints included pharmacokinetics, pharmacodynamics, and preliminary efficacy. APG-2449 was administered once daily in 28-day cycles through a 3 + 3 dose escalation. Eligible patients were aged 18 years or older and had advanced ALK or ROS1 fusion gene-positive NSCLC and other solid tumours (during the dose escalation). Patients with ALK-positive or ROS1-positive NSCLC regardless of previous TKI treatment were enrolled during the dose escalation. After RP2D was determined, patients with second-generation TKI-treated ALK (+) NSCLC, TKI-naïve ALK (+) , and TKI-naïve or TKI-treated ROS1 (+) NSCLC were enrolled in dose expansion. Eligible patients also had: (1) an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 1 or less; (2) adequate bone marrow reserve and organ function; and (3) no or stable brain metastases. This study was registered with ClinicalTrials.gov (NCT03917043). Recruitment is ongoing. FINDINGS: 144 patients were enrolled from May 27, 2019, to April 2, 2024, and received APG-2449 (150-1500 mg/day). MTD was not reached, and RP2D was 1200 mg. The most common grade ≥3 treatment-emergent adverse events (TEAE) were anaemia [6 (4.2%)], alanine aminotransferase (ALT) increased [6 (4.2%)], electrocardiogram QT prolonged [5 (3.5%)], and pneumonia [5 (3.5%)]. The most common grade ≥3 treatment-related adverse events (TRAEs) were ALT increased [5 (3.5%)], QT prolonged [5 (3.5%)], and vomiting [2 (1.4%)]. There were no treatment-related deaths. Pharmacokinetic analyses indicated a dose-proportional increase in plasma exposure, and that APG-2449 penetrated the blood-brain barrier (cerebrospinal fluid [CSF]-to-free plasma ratio 0.65-1.66). Of patients with ALK-positive, TKI-naïve NSCLC (n = 14) treated at RP2D, the objective response rate (ORR) was 78.6% (11/14), and median progression-free survival (mPFS) was not reached. Of 22 patients with NSCLC resistant to second-generation ALK inhibitors (without ALK compound mutations or activation of bypass or downstream signalling pathways), 10 (45.5%) achieved partial response, with a mPFS of 13.6 months. Intracranial partial response occurred in 9/12 patients at the RP2D (intracranial ORR: 75.0%). INTERPRETATION: APG-2449 demonstrated favourable preliminary safety, pharmacokinetics, and efficacy in TKI-untreated or second-generation ALK-resistant NSCLC. Higher baseline tumour phosphorylated FAK levels were associated with greater APG-2449 treatment benefit. Targeting FAK signalling may provide a feasible strategy for overcoming second-generation ALK TKI resistance. FUNDING: Ascentage Pharma Group Corp Ltd. (Hong Kong).