WCLC 2021 | Mini Oral - Ascentage Pharma Announces Latest Data of Its Investigational Bcl-2/Bcl-xL Inhibitor Pelcitoclax (APG-1252) Combined with Osimertinib in Patients with EGFR TKI-Resistant Non-Small Cell Lung Cancer

SUZHOU,China,and ROCKVILLE,MD.,Sept 9,2021 --Ascentage Pharma (6855.HK),a global biopharmaceutical company engaged in developing novel therapies for cancers,chronic hepatitis B (CHB),and age-related diseases,today reported the Phase Ib results of the dual Bcl-2/Bcl-xL inhibitor,APG-1252 (pelcitoclax),in combination with osimertinib in patients with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistant non-small cell lung cancer (NSCLC),during a Mini Oral Session at the 2021 World Conference on Lung Cancer (WCLC). The data was presented by Prof. Li Zhang,the principal investigator of the study from Sun-Yat Sen University Cancer Center.

Organized by the International Association for the Study of Lung Cancer (IASLC),the World Conference on Lung Cancer (WCLC) is the world's largest multidisciplinary oncology event dedicated to lung cancer and other thoracic cancers,with a focus on the most cutting-edge research and clinical advances in the field. Results presented by Ascentage Pharma at this year's WCLC are from a single-arm,multicenter Phase Ib dose-escalation and dose-expansion study designed to evaluate the pharmacokinetics (PK),safety and preliminary efficacy of pelcitoclax in combination with osimertinib in patients with advanced EGFR-mutant NSCLC.

Being developed by Ascentage Pharma,pelcitoclax is a novel small-molecule drug candidate that restores apoptosis by selectively inhibiting Bcl-2 and Bcl-xL proteins simultaneously. In preclinical studies,pelcitoclax in combination osimertinib has demonstrated synergistic anti-tumor effects in animal models of EGFR-mutant NSCLC that were sensitive or resistant to osimertinib. Therefore,pelcitoclax in combination with osimertinib has the potential of offering a new treatment option.

Highlights of the data presented during a Mini Oral Session at this year's WCLC:

Phase 1b Study of Pelcitoclax (APG-1252) in Combination With Osimertinib in Patients With EGFR TKI-Resistant NSCLC

Abstract: MA02.06

Track: Novel Therapeutics and Targeted Therapies

Time: 10:05 – 10:10,September 8,2021,Mountain Time / 00:05 – 00:10,September 9,Beijing Time

This single-arm,multicenter Phase Ib study of pelcitoclax in combination with osimertinib in patients with advanced EGFR-mutant NSCLC,comprised a dose-escalation phase and a dose-expansion phase. Pelcitoclax was administered at 160 mg or 240 mg by IV infusion once a week,and osimertinib was administered orally at 80 mg daily (QD). The dose-escalation primarily evaluated the safety and tolerability of the combination regimen in patients progressed on prior EGFR TKI treatments,and determined the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of pelcitoclax. The dose-expansion comprised two arms: 1) Patients with third-generation EGFR TKI-resistant NSCLC; 2) Patients with osimertinib-naïve NSCLC. Each arm planned to enroll 20 patients.

As of June 24,56 patients were enrolled in the study. 33 of them were enrolled in the dose-escalation and dose-expansion arm 1. Those patients had received a median of 4 (range: 1-10) lines of prior treatment,87.9% had received chemotherapies,75.8% had been treated with osimertinib,and 63.6% had brain metastasis at the time of enrollment. The 23 patients enrolled in arm 2 had received a median of 0 (range: 0-2) lines of prior treatment,8.7% had received chemotherapies,17.4% had been treated with first-generation tyrosine kinase inhibitors (TKIs),and 30.4% had brain metastasis at the time of enrollment.

In dose-escalation,1 partial response (PR) was observed in the 11 evaluable patients. In arm 1 of the dose-expansion phase,3 PRs (2 were osimertinib-resistant) and 13 stable diseases (SDs) were observed in the 20 evaluable patients,at an objective response rate (ORR) of 15% and a disease control rate (DCR) of 80%. In arm 2 of the dose-expansion phase,13 PRs and 8 SDs were observed in the 22 evaluable patients,including 3 patients harboring EGFR Exon 20 insertion,at an ORR of 59.1% and a DCR of 95.5%.

In dose-escalation,one case of dose-limiting toxicity (DLT) of grade 4 thrombocytopenia was observed at 240 mg; while no grade 3 or higher thrombocytopenia was observed at 160 mg,and the increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) also occurred at much lower rate than 240 mg. Thus,pelcitoclax 160 mg per week plus osimertinib 80 mg QD was selected as the RP2D. The most common treatment-related adverse events (TRAEs) included transient thrombocytopenia,increased AST,increased ALT,increased amylase,increased blood creatinine,decreased leukocytes,anemia,and rash.

Conclusion: Pelcitoclax in combination with osimertinib was safe and well-tolerated. Preliminary synergistic anti-tumor effects were observed in some patients with osimertinib-resistant NSCLC. In patients who received osimertinib for the first time,pelcitoclax has demonstrated preliminary synergistic anti-tumor effects with osimertinib similar to that of navitoclax.

Prof. Li Zhang,the principal investigator of the study from Sun-Yat Sen University Cancer Center,said: "Although osimertinib is currently the preferred first-line treatment for patients with EGFR-mutant NSCLC,there are still no effective treatments for patients who are resistant to osimertinib. Our data presented at this year's WCLC has demonstrated synergistic anti-tumor effects of pelcitoclax plus osimertinib in some osimertinib-resistant patients,thus indicating the potential as a new clinical strategy that could address this unmet medical need. In the next step,we will carry out additional analysis of biomarkers in an effort to enrich the patient population responding to this regimen."

Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma,commented: "There is currently an enormous unmet medical need in patients with NSCLC,especially in the EGFR TKI-resistant subgroup that is in desperate need of effective treatment options. These results reported at the WCLC this year showed the therapeutic potential of pelcitoclax plus osimertinib in patients with EGFR TKI-resistant NSCLC,therefore provided rationale for the continued clinical investigations. We will press forward with this clinical development program which hopefully will offer a new treatment option to patients in need."

About Ascentage Pharma

Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers,chronic hepatitis B,and age-related diseases. On October 28,2019,Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 6855.HK.

Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis,or programmed cell death. The company has built a pipeline of eight clinical drug candidates,including novel,highly potent Bcl-2,and dual Bcl-2/Bcl-xL inhibitors,as well as candidates aimed at IAP and MDM2-p53 pathways,and next-generation tyrosine kinase inhibitors (TKIs). Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials in the US,Australia,Europe,and China. Ascentage Pharma has been designated for multiple Major National R&D Projects,including five Major New Drug Projects,one New Drug Incubator status,four Innovative Drug Programs,and one Major Project for the Prevention and Treatment of Infectious Diseases. HQP1351,the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML),has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA. A New Drug Application (NDA) for HQP1351 has been submitted and subsequently granted Priority Review status and a Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) in China. To date,Ascentage Pharma has obtained a total of 12 ODDs from the US FDA for 4 of the company's investigational drug candidates.

Leveraging its robust R&D capabilities,Ascentage Pharma has built a portfolio of global intellectual property rights,and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology,MD Anderson Cancer Center,Mayo Clinic,Dana-Farber Cancer Institute,MSD,and AstraZeneca. The company has built a talented team with global experience in the discovery and development of innovative drugs,and is setting up its world-class commercial manufacturing and Sales & Marketing teams. Ascentage Pharma aims to continuously strengthen its R&D capabilities and accelerate its clinical development programs to fulfil its mission of 'addressing unmet clinical needs in China and around the world' for the benefit of more patients.

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