SUZHOU, China and ROCKVILLE,
Md., May 23, 2024 /PRNewswire/ -- 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 its four abstracts
selected for presentations at the 2024 American Society of Clinical
Oncology (ASCO) Annual Meeting are now available on ASCO's official
website. These abstracts report on the company's three lead drug
candidates, including 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.
Updated results from the four studies will be presented in Oral
Reports or Posters at the ASCO Annual Meeting taking place on
May 31 - June 4, 2024 in Chicago, IL. 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.
"It is our pleasure to present the latest data on our key drug
candidates at the ASCO Annual Meeting for the seventh consecutive
year," said Dr. Yifan Zhai, Chief
Medical Officer of Ascentage Pharma. "These encouraging results
once again highlight Ascentage Pharma's robust capabilities in
global innovation and clinical development. Going forward, we will
further expedite our clinical development programs globally in the
hope of benefitting more patients in China and 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
Candidates
|
Abstract
Title
|
Abstract#
|
Format
|
Olverembatinib
(HQP1351)
|
Updated efficacy
results of olverembatinib (HQP1351) in patients with tyrosine
kinase inhibitor (TKI)-resistant succinate dehydrogenase
(SDH)-deficient gastrointestinal stromal tumor (GIST) and
paraganglioma.
|
#11502
|
Oral
Report
|
Lisaftoclax
(APG-2575)
|
Safety and efficacy of
lisaftoclax, a novel BCL-2 inhibitor, in combination with
azacitidine in patients with treatment-naïve or relapsed or
refractory acute myeloid leukemia.
|
#6541
|
Poster
Presentation
|
Updated efficacy and
safety results of BCL-2 inhibitor lisaftoclax (APG-2575) alone or
combined with ibrutinib or rituximab in patients (pts) with
Waldenström macroglobulinemia (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 to second-generation
ALK inhibitors.
|
#3124
|
Poster
Presentation
|
The details of these abstracts are as follows:
Oral Report
Olverembatinib (HQP1351)
Updated efficacy results of olverembatinib (HQP1351) in
patients with tyrosine kinase inhibitor (TKI)-resistant succinate
dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST)
and paraganglioma
Abstract#: 11502
Session Title: Sarcoma
Date and Time: June 3, 2024, Monday, 3:00 PM – 6:00 PM (Central
Time)
First Author: Haibo Qiu, MD, PhD, Sun Yat-sen University Cancer Center,
Guangzhou, Guangdong, China.
Highlights:
Background: SDH-deficient GIST is a rare type of GIST, mainly
observed in the stomach of children, adolescents, and young adults
under 30 years of age. No active targeted therapies have been
identified in this subset of GIST. Olverembatinib, approved in
China for the treatment of
patients with chronic myeloid leukemia, has shown promising
clinical efficacy in SDH-deficient GIST. In this abstract, the
study reports updated efficacy data of olverembatinib in
SDH-deficient GIST and preliminary efficacy data in paraganglioma,
an SDH-deficient-related tumor.
Introduction: The aim of this study was to evaluate the safety
and efficacy (per RECIST v1.1) of olverembatinib in patients with
SDH-deficient GIST and other solid tumors. Olverembatinib was
administered orally once every other day (QOD) in 28-day
cycles.
Patient enrollment and methods: As of December 27, 2023, 26 patients with SDH-deficient
GIST (confirmed by immunohistochemistry [IHC] assay) had received
≥1 dose of olverembatinib (median [range] age, 30 [13-56] years),
and 25 of them had received 1-4 tyrosine kinase inhibitors
(TKIs; 42.3% of patients received ≥3 TKIs). Olverembatinib was
administered OQD in doses ranging from 30 to 50 mg (30 mg [n = 6];
40 mg [n = 14]; 50 mg [n = 6]). This study also enrolled 6 patients
with paraganglioma.
Efficacy results:
- In the 26 patients with SDH-deficient GIST, the median (range)
duration of treatment was 15.6 (1.8-42.3) months. 6 of those
patients achieved partial responses (PR); another 18 patients
achieved stable diseases (SD) lasting > 4 cycles. The clinical
benefit rate (CBR, complete response [CR] + PR + SD > 4 cycles)
was 92.3% (24/26) and the longest treatment duration was 40 months.
After a median (range) follow-up of 17.0 (4.1-57.5) months, the
median (range) progression-free survival (PFS) was 25.7 months
(12.1-not reached [NR]).
- Among the 6 patients with paraganglioma, 5 achieved SDs > 4
cycles, with a CBR of 83.3% and a median (range) PFS of 8.25
(1.87-NR) months.
Safety results: The adverse event profile was the same as
previously reported (Qiu H, et al, J Clin Oncol 41:11540), with no
newly emergent safety issues observed.
Conclusions: Olverembatinib was well tolerated. In patients with
SDH-deficient GIST, olverembatinib demonstrated a CBR exceeding 90%
and significantly prolonged the estimated median PFS, indicating
the potential benefit of this treatment and providing a benchmark
for future studies in this rare subtype of GIST.
Poster Presentations
Lisaftoclax (APG-2575)
Safety and efficacy of lisaftoclax, a novel BCL-2 inhibitor,
in combination with azacitidine in patients with treatment-naïve or
relapsed or refractory acute myeloid leukemia
Abstract#: 6541
Session Title: Hematologic Malignancies—Leukemia,
Myelodysplastic Syndromes, and Allotransplant
Date and Time: June 3, 2024, Monday, 9:00 AM – 12:00 PM
(Central Time)
First Author: Huafeng Wang, MD, PhD, The First
Affiliated Hospital, Zhejiang University School of Medicine,
Hangzhou, Zhejiang, China.
Highlights:
Background and introduction: Early studies showed that
lisaftoclax in combination with various agents can synergistically
induce apoptosis in acute myeloid leukemia (AML). This poster
presents follow-up safety and efficacy data from a Phase Ib/II
study of lisaftoclax combined with azacitidine (AZA) in adults with
AML.
Patient enrollment and methods:
- This study enrolled elderly (≥75 years)/unfit treatment-naïve
(TN) patients with AML who were intolerant of standard
induction chemotherapies and patients (≥18 years) with
relapsed/refractory (R/R) AML. Lisaftoclax (400/600/800 mg) was
administered orally once daily in 28-day cycles. In the first
treatment cycle, a daily ramp up schedule was used to prevent tumor
lysis syndrome (TLS). AZA was administered once daily on D1-D7 at
75 mg/m2.
- As of January 25, 2024, 76
patients with AML were enrolled, including 37 patients with
R/R AML and 39 elderly/unfit patients with TN AML who were
intolerant of standard induction chemotherapies. The median (range)
age was 66 (20-81) years, and 61.8% of the patients were male.
Efficacy results:
- In patients with R/R AML treated with lisaftoclax combined
with AZA, the overall response rate ([ORR]=CR + CRi + morphologic
leukemia-free state [MLFS] + PR) was 72.7%, the composite complete
remission rate (CRc = CR + CRi) was 45.5%. In the 600 mg cohort
(n=30), the median duration of treatment was 3.8 months, the ORR
was 76.7%, the CRc was 50.0%, the median time to CRc was 2.5
months, the median PFS was 10.2 months, and the median overall
survival (OS) was 14.7 months.
- Among patients with TN AML treated with lisaftoclax
combined with AZA, the ORR was 64.1%, the CRc was 51.3%. In the 600
mg cohort (n=29), the median duration of treatment was 3.3 months,
the median time to CRc was 1.9 months. The median PFS was not
reached.
- 600 mg lisaftoclax combined with AZA was established as
the recommended Phase II dose (RP2D).
Safety results: All patients treated with lisaftoclax combined
with AZA reported treatment-emergent adverse events (TEAEs), with
89.5% experiencing Grade 3/4 TEAEs and 43.4% experiencing serious
adverse events (SAEs). Common TEAEs included neutropenia (60.5%),
thrombocytopenia (60.5%), diarrhea (42.1%), hypokalemia (40.8%),
pyrexia (35.5%), and vomiting (30.3%). Grade ≥ 3 TEAEs reported in
≥ 10% of patients included neutropenia (57.9%), thrombocytopenia
(50.0%), anemia (27.6%), pneumonia (17.1%), and febrile neutropenia
(10.5%). No TLS was reported. The 30-/60-day mortality rates were
1.3% and 3.9%, respectively.
Conclusions: These data support a promising role for the new
Bcl-2 inhibitor lisaftoclax combined with AZA for the treatment of
elderly/unfit TN patients with AML intolerant of standard induction
chemotherapies and patients with R/R AML, especially given a
potentially favorable safety profile in terms of TLS, the incidence
of neutropenic fever, and low early mortality. A Phase III
randomized, double-blind study is being conducted to determine
whether lisaftoclax combined with AZA improves the survival of
elderly/unfit TN patients with AML intolerant of standard induction
chemotherapies.
Updated efficacy and safety results of BCL-2 inhibitor
lisaftoclax (APG-2575) alone or combined with ibrutinib or
rituximab in patients (pts) with Waldenström macroglobulinemia
(WM)
Abstract#: 7078
Session Title: Hematologic Malignancies—Lymphoma and
Chronic Lymphocytic Leukemia
Date and Time: June 3, 2024, Monday, 9:00 AM–
12:00 PM (Central Time)
First Author: Masa Lasica, MBBS, FRACP, FRCPA, St
Vincent's Hospital, Melbourne,
Victoria, Australia.
Highlights:
Background: Lisaftoclax is a novel, oral, highly selective,
potent Bcl-2 inhibitor. Lisaftoclax can overcome resistance to
ibrutinib in ibrutinib-insensitive RPCI-WM1 models. In other
non-Hodgkin lymphoma (NHL) models (including DOHH2 follicular
lymphoma models and OCI-LY1 diffuse large B-cell lymphoma [DLBCL]
models), lisaftoclax combined with ibrutinib has a strong
synergistic antitumor effect.
Introduction: This is an open-label, multicenter, global Phase
Ib/II study designed to evaluate the efficacy, safety,
tolerability, and pharmacokinetics (PK) of lisaftoclax monotherapy
or in combinations with agents such as ibrutinib/rituximab in
patients with WM.
Patient enrollment and methods:
- In this study, patients with WM were enrolled in 3 arms,
including Arm A: lisaftoclax monotherapy in patients resistant or
intolerant to prior treatment with Bruton's tyrosine kinase
inhibitors (BTKis); Arm B: lisaftoclax combined with ibrutinib in
treatment-naïve patients with WM; and Arm C: lisaftoclax combined
with rituximab in BTKi-naïve patients with relapsed/refractory
WM.
- Lisaftoclax was orally administered once daily in 28-day
cycles. Lisaftoclax was gradually escalated from the starting dose
of 400 mg to 1,200 mg. As of January 25,
2024, a total of 46 patients were enrolled in the study (Arm
A [n=14] at doses of up to 1,000 mg; Arm B [n=24] at doses of up to
1,200 mg; Arm C [n=8] at doses of up to 800 mg).
Efficacy results:
- The median (range) durations of treatment were 11 (1-28),
23.5 (1-34), and 11.5 (5-33) months for Arms A, B, and C,
respectively.
- The objective response rates (ORRs; PR, very good partial
response [VGPR], CR) were 41.7%, 90.9%, and 37.5% for Arms A, B,
and C, respectively.
- In Arm A, patients with wild-type CXCR4 (n =7) had
better overall response to lisaftoclax than the
CXCR4mut group (n = 3).
- In Arms B and C, no significant differences
between patients with/without CXCR4mut
were observed.
Safety results:
- In Arm B, 1 dose-limiting toxicity (DLT, grade 3 clinical TLS),
attributed to pre-existing renal impairment, occurred at 1,200 mg;
and 1 grade 3 laboratory TLS, primarily attributed to dehydration
and concomitant symptomatic therapies, occurred at 1,000 mg.
Abnormal electrolytes was resolved without recurrence after 1 day
of drug interruption.
- Grade ≥ 3 lisaftoclax-related adverse events
(AEs) included neutropenia
(15.2%), thrombocytopenia (4.3%), decreased
leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight
loss (2.2%), and septic shock (2.2%).
- Ventricular arrhythmia was not observed.
- One patient required dose reduction because
of neutropenia.
- The maximum-tolerated dose (MTD) was not
reached.
- Lisaftoclax combined with ibrutinib showed
a PK exposure comparable to lisaftoclax
or ibrutinib alone, indicating no potential
drug-drug interactions (DDIs).
Conclusions: Lisaftoclax alone and combined with ibrutinib or
rituximab was well tolerated and demonstrated measurable effects in
patients with treatment-naïve or BTKi-treatment-failed WM.
APG-2449
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 and clinical
studies. This poster reports further safety and efficacy data of
APG-2449.
Patient enrollment and methods:
- This study comprises a dose-escalation portion and a
dose-expansion portion. 1,200 mg daily (QD) was determined as the
RP2D. There are 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 December 9, 2023, 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), 9 achieved
PRs (9/22; 40.9%). Among the patients treated with 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, PFS was correlated
with phosphorylated FAK (pFAK) levels in the tumor tissue,
suggesting that patients with higher pFAK levels were more likely
to benefit from APG-2449.
Safety results: A total of 129 (89.6%) patients had
treatment‑related adverse events (TRAEs), the most frequent 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%); and
decreased leukocyte count (22.2%). 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 high pFAK expression levels in
baseline tumor tissue correlated with improved APG-2449 treatment
responses in patients with NSCLC resistant to second-generation ALK
TKIs.
*Olverembatinib is an investigational drug that has not been
approved for any indication outside the Chinese mainland.
*Lisaftoclax and APG-2449 are investigational drugs that have
not been approved in any country and region.
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 9 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, including 5 global registrational phase III
studies, 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.
Olverembatinib, the company's core drug candidate developed for
the treatment of drug-resistant chronic myeloid leukemia (CML) and
the company's first approved product in China, has been granted Priority Review
Designations and Breakthrough Therapy Designations by the Center
for Drug Evaluation (CDE) of China National Medical Products
Administration (NMPA). To date, the drug had been included into the
China 2022 National Reimbursement
Drug List (NRDL). Furthermore, olverembatinib has been granted an
Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by
the US FDA, and an Orphan Designation by the EMA of the EU. To
date, Ascentage Pharma has obtained a total of 16 ODDs from the US
FDA and 1 Orphan Designation from the EMA of the EU 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. One pivotal aim of Ascentage Pharma is to continuously
strengthen its R&D capabilities and accelerate its clinical
development programs, in order to fulfil its mission of addressing
unmet clinical needs in China and
around the world for the benefit of more patients.
Forward-Looking Statements
The forward-looking statements made in this article relate only
to the events or information as of the date on which the statements
are made in this article. Except as required by law, Ascentage
Pharma undertakes no obligation to update or revise publicly any
forward-looking statements, whether as a result of new information,
future events, or otherwise, after the date on which the statements
are made or to reflect the occurrence of unanticipated events. You
should read this article completely and with the understanding that
our actual future results or performance may be materially
different from what we expect. In this article, statements of, or
references to, our intentions or those of any of our Directors or
our Company are made as of the date of this article. Any of these
intentions may alter in light of future development.
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