On June 7, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that it has released the results from its Phase I first-in-human (FIH) study of the company’s novel FAK inhibitor and third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) APG-2449 in patients with second-generation TKI-resistant ALK/ROS1+ non-small-cell lung cancer (NSCLC) or mesothelioma in a Poster Presentation at the 58th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Ascentage Pharma, JUN 7, 2022, View Source;ascentage-pharma-releases-for-the-first-time-results-of-its-fakalkros1-inhibitor-apg-2449-demonstrating-safety-and-efficacy-in-patients-with-advanced-nsclc-301563283.html [SID1234615727]). APG-2449 is the first China-developed third-generation ALK inhibitor entering clinical studies.

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Entering the fifth consecutive year in which its abstracts were selected for presentations by the ASCO (Free ASCO Whitepaper) Annual Meeting, Ascentage Pharma showcased results from multiple clinical trials of its five drug candidates, including the first-time results of APG-2449 highlighting the company’s promising pipeline in solid tumors. APG-2449 demonstrated preliminary efficacy in TKI-naïve patients or those whose disease was resistant to second-generation TKIs, with 4 partial responses (PRs) observed in the 14 patients with second-generation-TKI resistant and ALK-positive NSCLC. In the 10 TKI-naïve ALK/ROS1+ patients, the objective response rate (ORR) was 80%, and the disease control rate (DCR) was 100%.

Discovered and developed by Ascentage Pharma, APG-2449 is a novel, orally-available FAK/ALK/ROS1 inhibitor and the first China-developed third-generation ALK inhibitor entering clinical studies.

Prof. Hongyun Zhao of Sun Yat-sen University Cancer Center, who is the principal investigator of this study, said, "APG-2449 is a potent FAK/ALK/ROS1 inhibitor that can address drug resistance to second-generation ALK TKIs. In this FIH study, APG-2449 demonstrated favorable safety and antitumor activity in patients with advanced NSCLC, and showed on-target pharmacodynamic effects. Building on results from this Phase I study, we look forward to further evaluate APG-2449’s efficacy in advanced NSCLC patients resistant to second-generation ALK inhibitor.

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, commented, "APG-2449 is one of our key drug candidates, outside our pipeline of apoptosis-targeting assets. The data presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting demonstrated APG-2449’s therapeutic potential in patients with advanced NSCLC and are indicative of our progress in the field of solid tumors. We will continue to take firm steps to advance this clinical development program. Furthermore, we are proud to be able to present clinical development progress for a number of Ascentage Pharma’s drug candidates at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting, which highlight our capabilities in global innovation. Honoring our mission of addressing unmet clinical needs in China and around the world, we are now accelerating our clinical programs to bring more safe and effective therapeutics to patients in need."

The highlights of this abstract on APG-2449 are as follows:

First-in-human phase I results of APG-2449, a novel FAK and third-generation ALK/ ROS1 tyrosine kinase inhibitor (TKI), in patients (pts) with second-generation TKI-resistant ALK/ROS1 non-small-cell lung cancer (NSCLC) or mesothelioma.

Abstract: #9071

This dose-escalation and dose-expansion study was designed to assess the safety, tolerability, recommended Phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of APG-2449 in patients with second-generation TKI-resistant ALK/ROS1+ NSCLC or mesothelioma.
As of December 30, 2021, 84 Chinese patients with NSCLC or mesothelioma enrolled were treated with APG-2449 at doses ranging from 150 to 1,500 mg. APG-2449 was administered orally once daily on a 28-day cycle using a "3+3" dose escalation design.
4 PRs were observed in 14 ALK+ patients resistant to second-generation TKIs treated at the RP2D. Among 8 patients with brain metastases, 1 complete response (CR) and 3 PRs were observed intracranially. In 10 TKI-naïve patients, the ORR was 80% (ALK+, 6/8; ROS1+, 2/2) and the DCR was 100%.
In addition, AGP-2449 demonstrated a favorable safety profile. The preliminary biomarker data showed decreased FAK phosphorylation in peripheral blood mononuclear cells and increased IFN-γ levels in serum after multiple doses of APG-2449.
Conclusions: APG-2449 has a favorable safety and PK profile. Preliminary efficacy was observed in patients whose disease was resistant to second-generation or TKI-naïve. Biomarker data indicated potential target engagement on FAK and the immunomodulatory effects of APG-2449.