On June 1, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that it has released updated data of its novel drug candidate AGP-2449, a FAK/ALK/ROS1 tyrosine kinase inhibitor (TKI), in patients with non-small-cell lung cancer (NSCLC) in a poster presentation at the 60th American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, IL (Press release, Ascentage Pharma, JUN 1, 2024, View Source;ascentage-pharma-releases-updated-data-of-fakalkros1-inhibitor-apg-2449-in-patients-with-nsclc-302161192.html [SID1234643948]). This is the third consecutive year in which clinical data from this study of APG-2449 were selected for presentations at the ASCO (Free ASCO Whitepaper) Annual Meeting.
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The ASCO (Free ASCO Whitepaper) Annual Meeting showcases the most cutting-edge research in clinical oncology and state-of-the-art advanced cancer therapies and is the world’s most influential and prominent scientific gathering of the clinical oncology community. Presenting clinical development progress at the ASCO (Free ASCO Whitepaper) Annual Meeting for the seventh consecutive year, Ascentage had four clinical studies of three of the company’s proprietary drug candidates selected for presentations, including an oral report, at ASCO (Free ASCO Whitepaper) 2024.
Results presented this year reaffirmed the therapeutic potential of APG-2449 in NSCLC, with data demonstrating preliminary efficacy in patients with NSCLC who were TKI naïve and resistant to second-generation ALK TKIs, as well as early antitumor activity in brain metastases. Biomarker analysis showed that, in patients with NSCLC resistant to second-generation ALK TKIs, phosphorylated FAK (pFAK) expression levels in tumor tissue at baseline and reduction in pFAK levels in peripheral blood mononuclear cells (PBMCs) were correlated with responses to APG-2449.
"APG-2449 is an effective multitargeted inhibitor that acts on FAK/ALK/ROS1. Compared to the data released at last year’s ASCO (Free ASCO Whitepaper) Annual Meeting, the latest results presented this year continued to show manageable safety and favorable antitumor activity in patients with NSCLC," said Prof. Li Zhang, the principal investigator of this study from Sun Yat-sen University Cancer Center. "We are very 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. We hope that Ascentage Pharma will conduct further studies on APG-2449 and allow more patients to benefit from this novel therapeutic agent as soon as possible."
"These data of APG-2449 in patients with NSCLC revealed a connection between resistance to ALK inhibitors and the FAK pathway, thus suggesting that the multitargeted FAK/ALK/ROS1 TKI APG-2449 may bring renewed hope to patients with NSCLC who are resistant to second-generation ALK inhibitors. This finding is indeed very encouraging," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Remaining committed to the mission of addressing unmet clinical needs in China and around the world, we will press forward with this clinical development program in order to bring a safe and effective new treatment option to patients in need."
Highlights of these data presented at ASCO (Free ASCO Whitepaper) 2024 are as follows:
Updated study results of novel FAK/ALK/ROS1 inhibitor APG-2449 in patients (pts) with non-small-cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors.
Abstract#: 3124
Session Title: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Date and Time: June 1, 2024, Saturday, 9:00 AM – 12:00 PM (Central Time)
First Author: Yuxiang Ma, MD, PhD, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Highlights:
Background: ALK inhibitors increase FAK pathway gene expression in ALK+ NSCLC cell lines, with the highest induced expression in drug-tolerant persister cells. This suggests that FAK pathway activation is involved in the mechanism that leads to ALK TKI resistance in ALK+ NSCLC. APG-2449 is an orally active FAK inhibitor and a third-generation ALK/ROS1 TKI that has shown potent antitumor activity in preclinical models. This poster reports further safety and efficacy data of APG-2449.
Patient enrollment and methods:
This study comprises dose-escalation and dose-expansion portions. 1,200 mg daily (QD) was determined as the RP2D. There were two cohorts in the dose-expansion portion: Cohort 1 included patients with NSCLC who were resistant to second-generation ALK TKIs; Cohort 2 included patients with NSCLC who were ALK or ROS1 TKI naïve.
As of April 2, 2024, a total of 144 patients with NSCLC, mesothelioma, or ovarian cancer were treated with APG-2449 at doses ranging from 150 – 1,500 mg. The median (range) age of patients was 53 (21-78) years, and 53.5% were female.
Efficacy results:
The ORRs of APG-2449 in patients with ROS1+ and ALK+ TKI-naïve NSCLC (n=36) were 68.2% (15/22) and 78.6% (11/14), respectively. Of the 22 patients with NSCLC resistant to second-generation ALK inhibitors and without targetable bypass gene mutations (e.g., KRAS G12C, BRAF V600E), 10 achieved PRs (10/22; 45.5%). Among the patients treated at RP2D, 12 had brain metastasis at baseline, 9 of whom achieved intracranial PR, resulting in an intracranial ORR of 75.0%.
Biomarker analysis found that, in patients with NSCLC that was resistant to second-generation ALK TKIs, responses to APG-2449 were correlated with pFAK levels in tumor tissues at baseline and reductions in pFAK levels in PBMCs.
Safety results: A total of 129 (89.6%) patients had treatment‑related adverse events (TRAEs), the most frequent (≥10%) of which were elevated serum creatinine (49.3%), increase in alanine aminotransferase (42.4%), increase in aspartate aminotransferase (36.1%); nausea (28.5%); vomiting (23.6%); diarrhea (22.9%); decreased leukocyte count (22.2%), decreased neutrophil count (17.4%) and rash (13.2%). In all, 20 (13.9%) TRAEs were grade ≥ 3.
Conclusions: APG-2449 demonstrated preliminary efficacy in patients with NSCLC whose disease was TKI naïve and resistant to second-generation ALK inhibitors, especially in brain metastases. Biomarker analysis showed that, in patients with NSCLC resistant to second-generation ALK TKIs, responses to APG-2449 PFS were correlated with pFAK levels in tumor tissues at baseline and reductions in pFAK levels in PBMCs.
*APG-2449 is an investigational drug that has not been approved in any country and region.
Appendix: The four clinical studies of Ascentage Pharma’s three drug candidates, including lisaftoclax, presented at this year’s ASCO (Free ASCO Whitepaper) Annual Meeting.
Drug Candidates
Abstract Title
Abstract #
Format
Olverembatinib
(HQP1351)
Updated efficacy results of
olverembatinib (HQP1351) in patients
withtyrosinekinase inhibitor (TKI)-
resistantsuccinatedehydrogenas
e (SDH)-deficientgastrointestinal
stromal tumor (GIST)and
paraganglioma
#11502
Oral
Report
Lisaftoclax
(APG-2575）
Safety and efficacy of lisaftoclax, a
novel BCL-2 inhibitor, in combination
withazacitidine in patients with
treatment-naïve or relapsed
or refractory acute myeloid leukemia
#6541
Poster
Presentation
Updated efficacy and safety results of
BCL-2 inhibitorlisaftoclax (APG-2575)
alone or combinedwithibrutinibor
rituximab in patients (pts)with
Waldenströmmacroglobulinemia
(WM)
#7078
Poster
Presentation
APG-2449
Updated study results of novel
FAK/ALK/ROS1 inhibitor APG-2449 in
patients (pts) with non-small-cell lung
cancer (NSCLC) resistant tosecond-
generationALK inhibitors
#3124
Poster
Presentation