APG-2449 / Ascentage Pharma - LARVOL DELTA

APG-2449, a novel focal adhesion kinase (FAK) inhibitor, enhances the antitumor activity of chemotherapy in preclinical models of small-cell lung cancer (SCLC) with activated FAK (AACR 2025) - "Novel FAK inhibitor APG-2449 demonstrated a synergistic enhancement when combined with first- and second-line chemotherapies in SCLC, significantly increasing antitumor activity. These encouraging findings support further clinical development of APG-2449 for the treatment of patients with SCLC."

IO biomarker • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

FAK inhibitor APG-2449 induces immunogenic cell death and enhances anti-tumor immunity in cervical cancer through the PERK-eIF2α pathway (AACR 2025) - "These observations underscore that APG-2449 elicits a robust immunogenic response, suggesting that inhibition of FAK/ALK/ROS1 could be a promising therapeutic approach for enhancing anti-tumor immunity in cervical cancer.These results highlight the potential of APG-2449 as an innovative therapeutic agent capable of modifying the tumor microenvironment to foster an effective anti-tumor immune response via the FAK/PERK-eIF2α axis. Future studies are needed to determine the clinical efficacy of APG-2449, particularly in combination with other immunotherapies."

Immunogenic cell death • Cervical Cancer • Oncology • Solid Tumor • CALR • CD8 • ROS1

Ascentage Pharma to Present Five Preclinical Studies from Innovative Pipeline at American Association of Cancer Research (AACR) Annual Meeting 2025 (GlobeNewswire) - "Ascentage Pharma...announced that five abstracts highlighting the latest preclinical results from its pipeline programs have been selected for presentations at the 2025 American Association of Cancer Research Annual Meeting (AACR)....The data to be presented encompasses five of the company’s novel drug candidates: BCR-ABL tyrosine kinase inhibitor olverembatinib (HQP1351), Bcl-2 inhibitor lisaftoclax (APG-2575), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, EED inhibitor APG-5918, and IAP antagonist AS03157."

Preclinical • Acute Myelogenous Leukemia • Prostate Cancer • Small Cell Lung Cancer • T Acute Lymphoblastic Leukemia

APG-2449 Monotherapy or in Combination With PLD in Patients With Platinum-resistant Recurrent OC or Advanced ST (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • Oncology • Ovarian Cancer • Solid Tumor

APG-2449 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: Ascentage Pharma Group Inc. | Trial completion date: Feb 2025 ➔ Jan 2028 | Trial primary completion date: Jan 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Esophageal Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pleural Mesothelioma • Solid Tumor • ALK • ROS1

APG-2449, a Novel Focal Adhesion Kinase (FAK) Inhibitor, Exhibits Antileukemic Activity and Enhances Lisaftoclax (APG-2575)-Induced Apoptosis in Acute Myeloid Leukemia (AML) (ASH 2024) - "This novel combination showed antileukemic activity in both BCL-2 inhibitor-sensitive and -insensitive AML cells in vitro and in xenograft models. Overall, these promising results provide a novel approach in the clinical development of lisaftoclax for treatment of patients with AML."

IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • ALK • ANXA5 • BCL2L1 • MCL1 • STAT3

APG-2449 Monotherapy or in Combination With PLD in Patients With Platinum-resistant Recurrent OC or Advanced ST (clinicaltrials.gov) - P1 | N=50 | Not yet recruiting | Sponsor: Ascentage Pharma Group Inc.

New P1 trial • Oncology • Ovarian Cancer • Solid Tumor

ASH 2024 | Results From Three Clinical Studies of Ascentage Pharma’s Bcl-2 Inhibitor Lisaftoclax Selected for Presentations, Including an Oral Report (PRNewswire) - "Ascentage Pharma...today announced that the latest results from three clinical studies of one of the company's key drug candidate, lisaftoclax (APG-2575), have been selected for presentations, including an Oral Report, at the 66th American Society of Hematology (ASH) Annual Meeting. This is the third consecutive year in which clinical results on lisaftoclax have been selected by the ASH Annual Meeting. In 2024, results from multiple clinical and preclinical studies on four of the company's investigational drug candidates...have been selected for presentations...At this year's ASH Annual Meeting, Ascentage Pharma will present an Oral Report featuring the latest results from a Phase I/II study of lisaftoclax in patients with relapsed/refractory multiple myeloma (R/R MM) or immunoglobulin light-chain (AL) amyloidosis. Furthermore, the latest data of lisaftoclax combinations in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and myelodysplastic..."

Clinical data • Preclinical • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Small Lymphocytic Lymphoma

Registrational Phase III Studies of APG-2449 Cleared by China CDE for the Treatment of Patients with NSCLC (PRNewswire) - "Ascentage Pharma...announced that APG-2449...has been cleared by the Center for Drug Evaluation (CDE) of China's...NMPA to enter two registrational Phase III studies that will separately evaluate APG-2449 in patients with non-small cell lung cancer (NSCLC) who are resistant to or intolerant of second-generation anaplastic lymphoma kinase (ALK) TKIs; and treatment-naïve patients with ALK-positive advanced or locally advanced NSCLC. These two pivotal studies will be multicenter, open-label, randomized, registrational Phase III studies: first one is to evaluate the efficacy and safety of APG-2449 versus platinum-based chemotherapies in patients with NSCLC who are resistant to or intolerant of second-generation ALK TKIs. The second registrational Phase III study is designed to evaluate the efficacy and safety of APG-2449 versus crizotinib as frontline therapies for treatment-naïve patients with ALK-positive advanced or locally advanced NSCLC."

New P3 trial • Non Small Cell Lung Cancer

Latest data on the novel FAK/ALK/ROS1 inhibitor APG-2449 in patients with non-small cell lung cancer (NSCLC) resistant to second-generation ALK inhibitors (CSCO 2024) - No abstract available

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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. (ASCO 2024) - P1 | "APG-2449 demonstrated preliminary efficacy in pts with NSCLC whose disease was TKI naïve and resistant to 2G ALK inhibitors, especially in brain metastases. High pFAK expression levels in baseline tumor tissue correlated with improved APG-2449 treatment responses in pts with NSCLC resistant to 2G ALK inhibitors. Internal study identifier: APG2449XC101."

Clinical • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • BRAF • KRAS • ROS1

Live from ASCO 2024 | Ascentage Pharma Releases Updated Data of FAK/ALK/ROS1 Inhibitor APG-2449 in Patients with NSCLC (PRNewswire) - P1 | N=150 | NCT03917043 | Sponsor: Ascentage Pharma Group Inc. | "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%....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."

P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

ASCO 2024 | Ascentage Pharma to Present Four Studies, Including an Oral Report Featuring the Latest Data of Olverembatinib in SDH-Deficient GIST (PRNewswire) - "Ascentage Pharma...announced today that results from four clinical studies of the company's three key drug candidates have been selected for presentations, including an Oral Report, at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. The three drugs are olverembatinib (HQP1351), the first and only China-approved third-generation BCR-ABL inhibitor; lisaftoclax (APG-2575), a Bcl-2-selective inhibitor; and APG-2449, a FAK/ALK/ROS1 inhibitor....'Our presentations this year include an Oral Report featuring updated data of olverembatinib in patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST), an indication that currently has no effective treatment. Furthermore, we will release detailed data of lisaftoclax in patients with acute myeloid leukemia (AML) and in patients with Waldenstrom macroglobulinemia (WM), as well as those of APG-2449 in patients with non-small cell lung cancer (NSCLC).'"

Clinical data • Acute Myelogenous Leukemia • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Waldenstrom Macroglobulinemia

APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC) (AACR 2024) - "Standard-of-care therapy is surgery followed by platinum and paclitaxel; however, most patients who initially respond to therapy eventually relapse after developing metastatic disease and chemoresistance. The combination regimen can also prolong ascites-free and survival times, as shown in the ID8-Luc peritoneal syngeneic model. These promising results support future clinical development of this combination treatment for ovarian cancer."

Clinical • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • PTK2

AACR 2024 | Ascentage Pharma Presents Results from Three Studies at 2024 American Association of Cancer Research Annual Meeting (PRNewswire) - "APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant and platinum-sensitive ovarian cancer cell lines. FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells in a dose-dependent manner. APG-2449 in combination with PLD showed enhanced antitumor activity in platinum-resistant OVCAR-3 ovarian cancer CDX model. The combination regimen prolonged ascites-free and survival times in the ID8-Luc peritoneal syngeneic model."

Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

A Phase Ib/II Study of APG-2449 in Combination with Doxorubicin Hydrochloride Liposome in Patients with Ovarian Cancer (ANZCTR) - P1 | N=40 | Recruiting | Sponsor: Ascentage Pharma Pty Ltd | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Neutropenia • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor

AACR 2024 | Ascentage Pharma to Present Three Preclinical Studies at 2024 American Association of Cancer Research Annual Meeting (PRNewswire) - "Abstract#: 4569:...Results from this preclinical study show that the novel FAK inhibitor APG-2449 can reduce the metastasis of tumor cells and achieve synergistic antitumor effects with PLD in xenograft mouse models of ovarian cancer. These results support the future clinical development of APG-2449 in combination with PLD for the treatment of ovarian cancer."

Preclinical • Ovarian Cancer

Roles and inhibitors of FAK in cancer: current advances and future directions. (PubMed, Front Pharmacol) - "To date, numerous FAK inhibitors, including IN10018, defactinib, GSK2256098, conteltinib, and APG-2449, have been developed, which have demonstrated positive anti-tumor effects in preclinical studies and are undergoing clinical trials for several types of tumors. This review aims to clarify FAK's role in cancer, offering a comprehensive overview of the current status and future prospects of FAK-targeted therapy and combination approaches. The goal is to provide valuable insights for advancing anti-cancer treatment strategies."

Journal • Review • Oncology

APG-2449 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: Ascentage Pharma Group Inc.

Metastases • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastrointestinal Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • ALK • ROS1

FAK inhibition with novel FAK/ALK inhibitor APG-2449 could overcome resistance in NSCLC patients who are resistant to second-generation ALK inhibitors. (ASCO 2023) - P1 | "APG-2449 showed a favorable preliminary safety profile and antitumor efficacy in pts with NSCLC. Preliminary efficacy was observed in those whose disease was TKI naïve and resistant to second-generation ALK inhibitors. FAK inhibition could be a novel approach to overcome ALK resistance in pts with NSCLC who are resistant to second-generation ALK inhibitors."

Clinical • Gastroenterology • Gastrointestinal Disorder • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

Live from ASCO 2023 | Ascentage Pharma Releases Updated Data Showing APG-2449’s Potential as a New Treatment for Drug-Resistant NSCLC (PRNewswire) - P1 | N=150 | NCT03917043 | Sponsor: Ascentage Pharma | "Ascentage Pharma...announced today that for the second consecutive year, it has released updated data of APG-2449, a novel FAK/ALK/ROS1 tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma, in patients with...(NSCLC), in a Poster Discussion session at the 59th American Society of Clinical Oncology (ASCO) Annual Meeting....Showcasing progress in clinical development at the ASCO Annual Meeting for six consecutive years, Ascentage Pharma had clinical results from four clinical studies of four of the company's lead drug candidates selected for presentations in 2023....the updated clinical data of APG-2449 showed the potential as a new treatment option that can effectively overcome drug resistance through the targeted inhibition of FAK. These data indicated efficacy and safety of APG-2449 in patients with NSCLC, with 8 partial responses (PRs) in the 28 patients who had failed treatment with the second-generation ALK TKIs."

P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

"APG-2449 (ALK/ROS1 and FAK TKI) #ASCO23 #LCSM" (@Tony_Calles)

Lung Cancer • ROS1

Ascentage Pharma Presents Updated Results from Multiple Clinical Studies at American Society of Clinical Oncology Annual Conference (PRNewswire) - P1 | N=150 | NCT03917043 | Sponsor: Ascentage Pharma Group Inc. | "Ascentage Pharma...announced today that 4 of its abstracts were selected for presentations at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting....As of December 9, 2022, 130 patients were enrolled and treated with APG-2449 at doses ranging from 900 to1,500 mg.... In the subgroup of patients with TKI-naïve NSCLC (n = 33; 31 were efficacy evaluable), the overall response rate (ORR) and disease control rate (DCR = complete response [CR] rate + partial response [PR] rate + stable diseases [SD] rate) were 70.6% (12/17) and 88.2% (15/17), respectively, in ROS1+ treatment-naïve patients; and were 78.6% (11/14) and 100% (14/14) in ALK+ treatment-naïve patients. Among the 27 patients with ALK+ NSCLC that was resistant to second-generation ALK inhibitors, 7 achieved PR (7/27; 25.9%) when treated with APG-2449 at the RP2D."

P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

ALK inhibitors downregulate the expression of death receptor 4 in ALK-mutant lung cancer cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. (PubMed, Neoplasia) - "Three tested ALK-TKIs including APG-2449, brigatinib and alectinib effectively and preferentially inhibited Akt/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation of the biological significance of DR4 downregulation in ALK-targeted cancer therapy."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • FRA1 • JUN • TNFRSF10A

ASCO 2023 | Ascentage Pharma to Present Results from 4 Studies Highlighting Extended Therapeutic Potential of Lead Drug Candidates (PRNewswire) - "Ascentage Pharma...announced that results from four clinical studies of the company's key assets, including the first China-approved third-generation BCR-ABL tyrosine kinase inhibitor (TKI) olverembatinib (HQP1351), Bcl-2 selective inhibitor lisaftoclax (APG-2575), MDM2-p53 inhibitor alrizomadlin (APG-115), and FAK/ALK/ROS1 inhibitor (APG-2449), have been selected for presentations at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting."

Clinical data • P1/2 data • P2 data • Breast Cancer • Cutaneous Melanoma • Gastrointestinal Stromal Tumor • Hematological Malignancies • Lung Cancer • Lymphoma • Lymphoplasmacytic Lymphoma • Melanoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Sarcoma • Skin Cancer • Soft Tissue Sarcoma • Solid Tumor • Thoracic Cancer • Waldenstrom Macroglobulinemia