Ascentage Pharma Presents Updated Results from Multiple Clinical Studies at American Society of Clinical Oncology Annual Conference

SUZHOU,China,and ROCKVILLE,Md.,May 26,2023 -- Ascentage Pharma (6855.HK),a global biopharmaceutical company engaged in developing novel therapies for cancer,chronic hepatitis B (CHB),and age-related diseases,announced today that 4 of its abstracts were selected for presentations at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. These studies report on four of the company's lead drug candidates,including the first and only China-approved third-generation Bcr-Abl inhibitor,olverembatinib (HQP1351),Bcl-2 selective inhibitor,lisaftoclax (APG-2575),MDM2-p53 inhibitor,alrizomadlin (APG-115),and FAK/ALK/ROS1 inhibitor,APG-2449.

The ASCO 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. This year's ASCO Annual Meeting will take place both online and in-person at the McCormick Place,Chicago,IL,United States,on June 2–6,2023.

"We are pleased to have the opportunity to release the updated clinical results on four of our lead drug candidates and showcase our capabilities in global innovation and clinical development at the ASCO Annual Meeting,one of the most prominent medical congresses in the world," said Dr. Yifan Zhai,Chief Medical Officer of Ascentage Pharma. "Moving forward,we will continue to accelerate these clinical development programs globally in the hope of benefitting more patients around the world as soon as possible."

These four clinical studies to be presented at this year's ASCO Annual Meeting are as follows:

Drug Candidate

Abstract Title

Abstract #

Format

APG-2449

FAK inhibition with novel FAK/ALK inhibitor APG-2449 could overcome resistance in NSCLC patients who are resistant to second-generation ALK inhibitors.

#9015

Poster Discussion

Olverembatinib

(HQP1351)

Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor (TKI)- resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST).

#11540

Poster Presentation

APG-2575

(Lisaftoclax)

Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

#7569

Poster Presentation

APG-115

(Alrizomadlin)

A phase 2 study of alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic cutaneous melanoma that has failed immuno-oncologic (IO) drugs.

#9559

Poster

Presentation

Poster Discussion

APG-2449

FAK inhibition with novel FAK/ALK inhibitor APG-2449 could overcome resistance in NSCLC patients who are resistant to second-generation ALK inhibitors

Abstract#: 9015

Poster Board#: 3

Date and Time: June 4,2023,Sunday,4:30 PM - 6:00 PM (Central Time) / June 5,Monday,5:30 AM - 7:00 AM (Beijing Time)

Session Title: Lung Cancer—Non-Small Cell Metastatic

Highlights

This open-label,multicenter,Phase I dose-escalation and dose-expansion study was designed to evaluate the safety/tolerability,pharmacokinetics (PK),pharmacodynamics (PD),and efficacy of APG-2449 in patients with ALK/ROS1+ NSCLC or other solid tumors.

As of December 9,2022,130 patients were enrolled and treated with APG-2449 at doses ranging from 900 to1,500 mg. The median (range) age of these patients was 53 (21-78) years and 53.8% of them were female. After 1,200 mg daily (QD) was determined as the recommended Phase II dose (RP2D),patients with NSCLC were enrolled into 2 dose-expansion cohorts. Among them,Cohort 1 included patients who were resistant to second-generation ALK/ROS1+ tyrosine kinase inhibitors (TKIs),while Cohort 2 included those who were ALK/ROS1+ TKI-naïve.

Efficacy Results: 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.

Analysis of FAK Expressions: Among the 27 patients with ALK+ NSCLC that was resistant to second-generation ALK inhibitors,compared to baseline,those who experienced PR showed lower phosphorylated FAK (pFAK) levels in peripheral blood mononuclear cells (PBMCs) by Day 28 (24 hours after dosing on Day 28) than patients who experienced SD. Furthermore,patients with progressive disease showed an increase in PBMC pFAK levels on Day 28 compared to baseline,indicating that APG-2449 could inhibit FAK phosphorylation. Meanwhile,patients with higher pFAK expression in tumor tissues at baseline tended to achieve better clinical responses than those with lower pFAK expression after APG-2449 treatment.

Safety Results: A total of 117 (90%) patients experienced treatment-related adverse events (TRAEs) with the most frequent TRAEs being elevated blood creatinine (43.8%),elevated alanine aminotransferase (ALT) (40.8%),and aspartate aminotransferase (AST) (33.1%),as well as gastrointestinal disorders that included nausea (25.4%),vomiting (21.5%),and diarrhea (21.5%). A total of 17 (13.1%) TRAEs were grade≥3.

Conclusions: APG-2449 showed a favourable preliminary safety profile and antitumor efficacy in patients with NSCLC. Preliminary efficacy was observed in patients who were TKI-naïve and resistant to second-generation ALK inhibitors. FAK inhibition could be a novel approach to overcome ALK resistance in patients with NSCLC that is resistant to second-generation ALK inhibitors.

Poster Presentation

HQP1351 (Olverembatinib)

Antitumor activity of olverembatinib (HQP1351) in patients (pts) with tyrosine kinase inhibitor- (TKI)- resistant succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST)

Abstract#: 11540

Poster Board#: 474

Date and Time: June 3,Saturday,1:15 PM – 4:15 PM (Central Time) / June 4,2:15 AM – 5:15 AM (Beijing Time)

Session Title: Sarcoma

Highlights

This open-label,multicenter Phase Ib/II study in China was designed to evaluate the safety,tolerability,PK,and antitumor activity of olverembatinib in patients with TKI-resistant locally advanced or metastatic GIST.

As of January 15,a total of 20 patients with SDH-deficient GIST were enrolled in the study. The median (range) age of these patients was 30 (14-56) years. Olverembatinib,at doses ranging from 20 to 50 mg (50 mg cohort [n=6]; 40 mg cohort [n=8]; 30 mg cohort [n=6]),was administered once every other day (QOD) in 28-day cycles.

Efficacy Results: The median duration of treatment in the 20 patients with SDH-deficient GIST was 7.8 (1.81-42.3) months. A total of 5 of these patients experienced PRs. Of the 16 evaluable patients who were treated with olverembatinib for 16 weeks or more,the clinical benefit rate (CBR=CR+PR+SD > 16 weeks) was 93.8% (15/16) and the longest treatment duration was 42 months.

Safety Results: All patients experienced at least one treatment-emergent adverse event (TEAE),most of which were grade 1 or 2; 2 patients experienced grade 3 AEs; and the only hematologic AE with an incidence rate≥20% was anemia (55%). A total of 15 (75%) patients experienced TRAEs,including 1 patient who experienced a grade 3 TRAE (neutropenia). No serious TRAEs were reported during the study.

Conclusions: Olverembatinib was well-tolerated up to 50 mg QOD and showed antitumor activity in patients with TKI-resistant SDH-deficient GIST. A total of 5 (25%) PRs were reported among 20 evaluable patients; the 16 patients treated for ≥16 weeks achieved a CBR of 93.8%. These promising findings warrant further investigation.

Lisaftoclax (APG-2575)

Preliminary data of a phase 1b/2 study of BCL-2 inhibitor lisaftoclax (APG-2575) alone or combined with ibrutinib or rituximab in patients (pts) with Waldenström macroglobulinemia (WM).

Abstract#: 7569

Poster Board#: 120

Date and Time: June 5,8:00 AM (Central Time) / June 5,9:00 PM (Beijing Time)

Session Title: Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia

Highlights：

This open-label,global Phase Ib/II study was designed to evaluate the safety,efficacy,and PK of the orally administered high-selective novel Bcl-2 inhibitor lisaftoclax as monotherapy or in combination with ibrutinib or rituximab in patients with WM.

As of January 25,a total of 46 patients were enrolled in the study and later enrolled into 3 arms as follows:

Arm A: lisaftoclax monotherapy in patients with WM resistant/intolerant to Bruton tyrosine kinase inhibitors (BTKi) (n=14)

Arm B: lisaftoclax plus ibrutinib in treatment-naïve patients (n=24)

Arm C: lisaftoclax plus rituximab in ibrutinib and other BTKi-naïve relapsed/refractory patients (n=8)

The dose of lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval-2 (mTPI-2) design. Doses in Arms A,B,and C were escalated to up to 1,000 mg,1,200 mg,and 800 mg,respectively.

Efficacy Results: The ORR (PR and deeper responses) and median time to response (MTTR) for Arms A,and C were 25%,90.9%,and 37.5%; and 4.3,1.9,and 4.4 months,respectively. The study did not observe any significant difference between patients with and without the CXCR4 mutation.

Safety Results: At 1,1 grade 3 dose-limiting toxicity (DLT) (grade 3 tumor lysis syndrome [TLS]) due to pre-existing renal impairment was observed in Arm B. At 1,1 grade 3 laboratory TLS occurred in Arm B because of dehydration and active symptomatic recurrence. Abnormal electrolytes in this patient was resolved after 1 day of drug intervention and the AE did not recur. Grade≥3 lisaftoclax-related AEs included neutropenia (13%),leukocytopenia (4.3%),anemia (2.2%),weight loss (2.2%),and septic shock (2.2%). Ventricular arrhythmias were not observed. The PK data indicated no drug- drug interaction (DDI) between lisaftoclax and ibrutinib.

Conclusions: Lisaftoclax alone or combined with ibrutinib/rituximab demonstrated measurable effects in patients with treatment-naïve or BTKi-refractory WM.

Alrizomadlin (APG-115)

A phase 2 study of alrizomadlin (APG-115) in combination with pembrolizumab in patients with unresectable or metastatic cutaneous melanoma that has failed immuno-oncologic (IO) drugs.

Abstract#: 9559

Poster Board#: 322

Date and Time: June 3,2:15 AM – 5:15 AM (Beijing Time)

Session Title: Melanoma/Skin Cancers

Highlights

This open-label,multicenter Phase Ib/II study conducted in the U.S. and Australia was designed to evaluate the safety,and antitumor activity of alrizomadlin plus pembrolizumab in patients with unresectable or metastatic cutaneous melanoma or advanced solid tumors. At the meeting,the latest Phase II efficacy and safety results from the cutaneous melanoma subgroup were released.

As of December 12,a total of 31 patients with cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy were enrolled in the study. The median (range) age of these patients was 65 (27-84) years,21 （67.7%）of the patients were male,and 10 (32.3%) were female. Alrizomadlin 150 mg was administered QOD for 2 consecutive weeks,with 1 week off,in 21-day cycles. Pembrolizumab 200 mg was administered intravenously on day 1 of the treatment cycles.

Efficacy Results: In 26 efficacy-evaluable patients,2 achieved CR and,4 achieved PR,resulting in a confirmed ORR (ORR=CR+PR) of 23.1%. The initial analysis indicated that the ORR observed in patients whose disease had failed IO treatment was primarily attributable to the alrizomadlin plus pembrolizumab regimen,not the delayed effect of prior immunotherapy.

Safety Results: A total of 30 (96.8%) patients reported TRAEs,the most frequent (>10%) being nausea (71%),vomiting (38.7%),fatigue (35.5%),thrombocytopenia (32.3%),diarrhea (25.8%),neutropenia (19.4%),decreased appetite (16.1%),and decreased leukocyte count (12.9%). 4 (12.9%) patients reported serious TRAEs,including anemia,thrombocytopenia,deep vein,thrombosis,joint effusion,pulmonary embolism,and vomiting.

Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and demonstrates clinical efficacy in patients with cutaneous melanoma that had progressed on PD-1/PD-L1 immunotherapy.