Safety, pharmacokinetic, pharmacodynamic, and efficacy properties of orally administered APG-2449 in patients with advanced <i>ALK</i> ^<i>+</i> and <i>ROS1</i> ^<i>+</i> non-small-cell lung cancer: a multicentre, open-label, single-arm phase 1 trial.

Abstract

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). 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 <i>ALK</i>-positive or <i>ROS1</i>-positive NSCLC regardless of previous TKI treatment were enrolled during the dose escalation. After RP2D was determined, patients with second-generation TKI-treated <i>ALK</i> ^<i>+</i> NSCLC, TKI-naïve <i>ALK</i> ^<i>+</i> , and TKI-naïve or TKI-treated <i>ROS1</i> ^<i>+</i> 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. 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 <i>ALK</i>-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%). 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. Ascentage Pharma Group Corp Ltd. (Hong Kong).