On October 16, 2023 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported the presentation of promising new data showcasing BeiGene’s robust, science-driven solid tumor portfolio of commercialized and pipeline medicines at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (Press release, BeiGene, OCT 16, 2023, View Source [SID1234635991]).

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Highlights include the presentations of two late-breaking abstracts for tislelizumab, an anti-PD-1 antibody and the first medicine to emerge from BeiGene’s immuno-oncology biologics program:

Final analysis from the global, Phase 3 RATIONALE-305 study (NCT03777657) evaluating tislelizumab plus chemotherapy as a first-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC)
Final analysis of pathological response to neoadjuvant tislelizumab plus chemotherapy in patients with resectable Stage II-IIIA non-small cell lung cancer (NSCLC) in results from the Phase 3 RATIONALE-315 study (NCT04379635)
"At ESMO (Free ESMO Whitepaper) 2023, we look forward to presenting results from several clinical trials of tislelizumab in combination with other therapies across multiple disease areas and lines of treatment," said Mark Lanasa, M.D., Ph.D., Chief Medical Officer, Solid Tumors at BeiGene. "Tislelizumab is the cornerstone of BeiGene’s diverse pipeline of pan-solid tumor programs for the next wave of immuno-oncology targets. We are delighted to have recently regained the global rights to this important medicine and remain dedicated to following the science and data to advance new combination strategies for the treatment of solid tumors."

TEVIMBRA (tislelizumab) was recently approved in the European Union (EU) as monotherapy for the treatment of adult patients with unresectable, locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) after prior platinum-based chemotherapy. Additionally, the U.S. Food and Drug Administration (FDA) recently accepted for review a Biologics License Application for tislelizumab as a first-line treatment for patients with unresectable, recurrent, locally advanced, or metastatic ESCC.

More details on BeiGene’s abstracts are available in the ESMO (Free ESMO Whitepaper) Programme.

Presentations of Company-Sponsored Trials

Tislelizumab

Tislelizumab (TIS) Plus Chemotherapy (Chemo) vs Placebo (PBO) Plus Chemo as First-Line (1L) Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (GC/GEJC): Final Analysis Results of the RATIONALE-305 Study (Abstract #LBA80)
Mini oral presentation, Saturday, October 21, 5:25-5:30 PM CEST
Pathological Response to Neoadjuvant Tislelizumab (TIS) Plus Platinum-Doublet (PtDb) Chemotherapy (CT) in Resectable Stage II-IIIA NSCLC Patients (pts) in the Phase 3 (Ph3) RATIONALE-315 Trial (Abstract #LBA58)
Mini oral presentation, Monday, October 23, 2:55-3:00 PM CEST
Randomized, Global, Phase 3 Study of Tislelizumab (tis) + Chemotherapy (chemo) vs Placebo (PBO) + Chemo as First-line (1L) Treatment for Advanced/Metastatic Esophageal Squamous Cell Carcinoma (ESCC): RATIONALE-306 Study Update (Abstract #1514P)
Poster presentation, Monday, October 23
Long-term Follow-up of a Phase 2 Study of Tislelizumab (TIS) Monotherapy in Patients (pts) With Previously Treated, Locally Advanced, Unresectable or Metastatic Microsatellite Instability-high (MSI-H) or Mismatch Repair-deficient (dMMR) Solid Tumors. BGB-A317-209 Study (Abstract #1057P)
Poster presentation, Monday, October 23
Ociperlimab Development Program

AdvanTIG-203: Phase 2 Randomized, Multicenter Study of Ociperlimab (OCI) + Tislelizumab (TIS) in Patients (pts) With Unresectable, Locally Advanced, Recurrent/Metastatic Esophageal Squamous Cell Carcinoma (ESCC) and Programmed Cell Death-Ligand 1 (PDL1) Positivity (Abstract #1020MO)
Mini oral presentation, Saturday, October 21, 4:30-4:35 PM CEST
AdvanTIG-206: Phase 2 randomized open-label study of ociperlimab (oci) + tislelizumab (tis) + BAT1706 (bevacizumab biosimilar) versus tis + BAT1706 in patients (pts) with advanced hepatocellular carcinoma (HCC) (Abstract #945MO)
Mini oral presentation, Saturday, October 21, 4:30-4:35 PM CEST
AdvanTIG-202: Phase 2 Randomized, Multicenter, Open-Label Study of Tislelizumab (tis) With or Without Ociperlimab (oci) in Patients (pts) With Previously Treated Recurrent/Metastatic (R/M) Cervical Cancer (CC) (Abstract #744MO)
Mini oral presentation, Sunday, October 22, 10:55-11:00 AM CEST
AdvanTIG-105: Phase 1b Dose-expansion Study of Ociperlimab (OCI) + Tislelizumab (TIS) with Chemotherapy (CT) in Patients (pts) with Metastatic Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC) (Abstract #1533P)
Poster presentation, Monday, October 23
Additional Pipeline Assets

Zanidatamab (zani) Plus Chemotherapy (chemo) and Tislelizumab (tis) as First-line (1L) Therapy for Patients (pts) With Advanced HER2-positive (+) Gastric/Gastroesophageal Junction Adenocarcinoma (GC/GEJC): Updated Results From a Phase 1b/2 Study (Abstract #1518P)
Poster presentation, Monday, October 23
Phase (Ph) 1/2 Study of Sitravatinib (sitra) Alone or With Tislelizumab (tis) in Advanced Hepatocellular Carcinoma (HCC) and Gastric/Gastroesophageal Junction Cancer (GC/GEJC) (Abstract #948P)
Poster presentation, Monday, October 23
About Tislelizumab

Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody, with high affinity and binding specificity against PD-1, specifically designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors. In pre-clinical studies, binding to Fcγ receptors on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.i,ii,iii,iv

The tislelizumab development program encompasses 21 registration-enabling clinical trials in more than 30 countries and regions. To date, BeiGene has announced positive readouts from 10 Phase 3 pivotal studies across multiple tumor types and disease settings, such as NSCLC, small cell lung cancer, gastric cancer, ESCC, hepatocellular cancer, and nasopharyngeal cancer. More information on the clinical trial program for tislelizumab can be found at: View Source

Tislelizumab is currently under review by the FDA and received approval by the European Commission for advanced or metastatic ESCC after prior chemotherapy. Additionally, the FDA recently accepted for review a Biologics License Application for tislelizumab as a first-line treatment for patients with unresectable, recurrent, locally advanced, or metastatic ESCC. The EMA is reviewing a marketing authorization application for tislelizumab as a treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy, and in combination with chemotherapy for previously untreated locally advanced or metastatic NSCLC.

Regulatory submissions for tislelizumab are also under review by authorities in Australia, Brazil, China, Korea, Israel, New Zealand, Singapore, Switzerland, and the U.K. Tislelizumab is approved as a treatment in 11 indications in China and is the leading PD-1 inhibitor in the country.

On October 16, 2023 AskGene Pharma Inc. reported that the Center for Drug Evaluation (CDE) of the Chinese National Medicinal Product Administration (NMPA) has granted clearance for the initiation of a Phase III clinical trial to evaluate the efficacy and safety of ASKB589 (anti-CLDN18.2 monoclonal antibody) in combination with CAPOX (capecitabine and oxaliplatin) and a PD-1 inhibitor for the first-line treatment of CLDN18.2 positive, inoperable, locally advanced, recurrent or metastatic gastric and esophagogastric junction (G&GEJ) cancer in China (Press release, AskGene Pharmaceuticals, OCT 16, 2023, View Source [SID1234635990]). The Phase III initiation marks AskGene’s entry into the first tier of pivotal clinical studies for anti-claudin 18.2 antibody targeted therapy for gastric cancer.

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ASKG589 Clinical Progress

ASKB589 is a second generation anti-CLDN18.2 humanized monoclonal antibody with ADCC enhancement. To support the Phase III study, more than 200 patients have been enrolled into a number of Phase I/II studies, including ASKB589 monotherapy, combination with chemotherapy, and combination with PD-1 inhibitor and chemotherapy. No dose limiting toxicity (DLT) has been observed so far, with monotherapy up to 20 mg/kg, and combination therapy up to 15 mg/kg. Thus, a maximum tolerated dose (MTD) has not yet been reached, indicating that ASKB589 is well-tolerated.

The Phase I/II clinical results were first presented at ASCO (Free ASCO Whitepaper) GI (the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancer Symposium) in January 2023, and later at IGCC (the International Gastric Cancer Congress) in June 2023. For those patients in the Phase II dose expansion study with measurable lesions, at least one post-treatment tumor assessment, medium to high CLDN18.2 expression, and treatment with 6 or 10 mg/kg ASKB589 in combination with CAPOX (capecitabine and oxaliplatin), the investigator-confirmed objective response rate (cORR) was 79.2%, and the disease control rate (DCR) was 95.8%.

In order to better identify patients who can benefit from the treatment, AskGene has also developed a CLDN18.2 immunohistochemistry-based companion diagnostic kit. With its high sensitivity and selectivity, the diagnostic kit will become an essential component of the ASKB589 Phase III program.

The approval of Phase III clinical trial is a major milestone for ASKB589 as an innovative patient-centered first-line treatment of G&GEJ cancer. The combination therapy targets both CLDN18.2 and PD-1, and could provide a more effective treatment by boosting both innate and adaptive immune responses.

Barbara Hickingbottom, J.D., M.D., Chief Medical Officer of AskGene, commented: "Claudin 18.2 has recently been validated as a new molecular target that demonstrates the potential for clinical benefit for patients with gastric and gastroesophageal cancer. Our Phase I/II clinical trial shows that ASKB589, particularly in combination with chemotherapy or PD-1 plus chemotherapy, can be administered safely in patients with these types of cancer and results in a high rate of deep and durable responses, as well as a remarkable disease control rate. The clearance for starting the registrational trial marks a major milestone for the clinical development ASKB589. We look forward to conducting an efficient and successful Phase III trial and advancing ASKB589 to meet the significant unmet medical needs of gastric and gastroesophageal cancer patients in China and beyond."

About Gastric Cancer

Gastric cancer, also known as stomach cancer, is one of the most common cancers in the world, with more than 1 million new cases and 769,000 deaths each year worldwide. It ranks fifth in incidence rate among malignant tumors and fourth in mortality. According to data from the World Health Organization, there were approximately 480,000 new gastric cancer cases and 370,000 deaths in China in 2020, accounting for 44% and 48.6% of the global gastric cancer new cases and deaths, respectively.

About ASKB589

ASKB589 is an innovative biological drug discovered and developed by AskGene. It is a recombinant humanized monoclonal antibody targeting CLDN18.2. ASKB589 is among the top 3 most advanced therapies against this target with no marketed drugs yet. ASKB589 mediates antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through high-affinity binding to cancer cells. Enrollment in dose escalation for ASKB589 as monotherapy and in combination with CAPOX chemotherapy was completed in 2022. Enrollment continues in expansion cohorts of first-line advanced or metastatic patients with CLDN18.2-positive G&GEJ cancers that are being treated with ASKB589 in combination with chemotherapy. In addition to G&GEJ cancers, ASKB589 is being tested in clinical trials for other CLDN18.2-positive solid tumors such as pancreatic cancer. A pivotal study of ASKB589 in the treatment of gastric cancer has received CDE approval and is under way.

On October 16, 2023 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage precision oncology company developing highly differentiated oral kinase inhibitors to treat hematologic malignancies, reported that two abstracts on tuspetinib, Aptose’s Phase 1/2 myeloid kinase inhibitor in development for acute myeloid leukemia (AML), have been accepted for poster presentations at the European School of Haematology (ESH) 6th International Conference: Acute Myeloid Leukemia "Molecular and Translational": Advances in Biology and Treatment, being held October 29-31, 2023, in Estoril, Portugal (Press release, Aptose Biosciences, OCT 16, 2023, View Source [SID1234635989]).

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Aptose is planning to hold a clinical update webcast on October 30, 2023, to provide additional up-to-date data on tuspetinib. Details will be forthcoming.

The posters accepted for presentation are listed below and can be viewed beginning October 29, 2023, on site at the ESH poster exhibit hall and online on the Aptose website here.

Poster Presentations

Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy as Monotherapy and Combined with Venetoclax in Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

Abstract Summary: Tuspetinib (TUS) is a potent once daily oral myeloid kinase inhibitor of SYK, mutated and unmutated forms of FLT3, JAK1/2, RSK, mutant forms of KIT, and TAK1-TAB1 kinases that mediate dysregulated cellular proliferation in acute myeloid leukemia (AML). As a single agent, TUS was well-tolerated and highly active across four dose levels among diverse AML genotypes and delivered a 42% CR/CRh across evaluable venetoclax (VEN) naïve patients at the 80mg daily RP2D. In the ongoing APTIVATE clinical study, tuspetinib is being evaluated clinically as monotherapy (TUS) and in combination with venetoclax (TUS/VEN) in a global Phase 1/2 trial of patients with R/R AML. The TUS/VEN doublet also has been well tolerated and has achieved multiple responses to date in patients who previously failed VEN (Prior-VEN failure AML), including Prior-VEN failure patients who also previously failed FLT3 inhibitors, all of whom represent emerging populations of high unmet medical need. Notably, TUS targets VEN resistance mechanisms and appears to re-sensitize Prior-VEN failure patients to VEN.
Tuspetinib Oral Myeloid Kinase Inhibitor Creates Synthetic Lethal Vulnerability to Venetoclax

Abstract Summary: Tuspetinib (TUS), a once daily oral agent, simultaneously suppresses a limited set of key oncogenic signaling pathways that mediate resistance to acute myeloid leukemia (AML) drugs by potently inhibiting SYK, mutated and unmutated forms of FLT3, JAK1/2, RSK, mutant forms of KIT, and TAK1-TAB1 kinases. TUS as a single agent produces complete remissions in relapsed/refractory (R/R) AML patients, and the tuspetinib/venetoclax (TUS/VEN) combination doublet achieves multiple responses among very difficult to treat AML subpopulations in the ongoing Phase 1/2 APTIVATE trial. We investigated the effects of TUS on key elements of the phosphokinome and apoptotic proteome in both parental and TUS-resistant AML cells. In parental cells, TUS acutely inhibits key oncogenic signaling pathways and shifts the balance of pro- and anti-apoptotic proteins in favor of apoptosis, suggesting that it may generate vulnerability to VEN. Indeed, acquired TUS resistance generated a synthetic lethal vulnerability to VEN of unusually high magnitude. Concurrent administration of TUS and VEN may eliminate cells that carry this form of TUS resistance at the start of therapy and discourage the emergence of TUS resistance during treatment.

On October 16, 2023 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported highlights of two posters presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), October 14, 2023 in Boston, MA (Press release, Aprea, OCT 16, 2023, View Source [SID1234635988]). The data in the posters include first-in-human clinical data from the ongoing Phase 1 dose escalation trial of ATR inhibitor, ATRN-119 LINK to Poster, and pre-clinical data from the WEE1 inhibitor, ATRN-1051 LINK with planned IND submission Q4 2023.

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ATRN-119 is in an ongoing Phase 1/2a dose escalation trial in solid tumors to determine the recommended Phase 2 dose, with a daily dosing administration over a 56-day cycle. To date, no hematologic or liver function toxicities in these heavily pretreated solid tumor patients have been observed across the first three cohorts at dose levels of 50mg, 100mg, and 200mg (3 + 3 trial design) NCT04905914. The efficacy findings are still early in the dose escalation portion of the trial and there was one Stable Disease (SD) patient at the 50mg low dose cohort determined at end of cycle 1 (56-day cycle) (September 20, 2023 data cutoff). The company is actively enrolling cohort 4 at 350mg (subsequent 550mg cohort 5 and 800mg cohort 6 are planned) and anticipates dose expansion of the trial in Q2 2024.

The second poster presented focused on ATRN-1051, the WEE1 inhibitor, and highlights the selectivity of ATRN-1051 with low off-target activity against PLK1, PLK2 and PLK3, a family of kinases that promote M phase entry, a critical phase in the cell cycle. The selectivity of ATRN-1051 relative to the WEE1 class is also highlighted by its limited effects on red blood cell counts, hERG inhibition, and body weight loss in the pre-clinical data. PLK off-target activity has been a challenge for other WEE1 inhibitors in this class, as this off-target activity substantially counters the effects of WEE1 inhibition.

"We are excited to share the progress of our encouraging clinical and preclinical programs at this year’s AACR (Free AACR Whitepaper)-NCI-EORTC medical meeting," stated Dr. Oren Gilad, President and CEO of Aprea. "Based on the data to date, daily dosing of our ATR inhibitor, ATRN-119, appears to be well tolerated with a manageable toxicity profile, and no dose-limiting toxicities have been reported to date through data cutoff. We are currently enrolling patients in four US sites with the dose expansion cohort being on track to be initiated in 2Q 2024. The emerging tolerability profile presented in the poster may provide opportunities for potential combinations with multiple anti-cancer agents including our WEE1 inhibitor, ATRN-1051. This preclinical compound exhibits high potency for WEE1 inhibition in vitro and shows low off-target inhibition of the PLK family. The preclinical data findings and sensitivity to our WEE1 asset is guiding our clinical strategy and future patient selection. We look forward to advancing the drug to IND in the fourth quarter of this year."

Poster #1
Title: First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors
Abstract #: C034
Session: Session C; Level 2, Exhibit Hall D
Date/Time: Saturday, October 14 | 12:30pm – 4:00 pm ET
Presenter: Nadeem Q Mirza, M.D., M.P.H., Aprea Therapeutics, Inc.

Poster #2
Title: The DNA replication checkpoint inhibitors, ATRN-1051 (WEE1i) and ATRN-119 (ATRi), are potentially well-tolerated and effective cancer treatments
Abstract #: C147
Session: Session C; Level 2, Exhibit Hall D
Date/Time: Saturday, October 14 | 12:30pm – 4:00 pm ET
Presenter: Eric J. Brown, Ph.D., Perelman School of Medicine, University of Pennsylvania
*head-to-head comparisons have not been conducted

On October 16, 2023 Anaveon, a clinical stage, immuno-oncology company, reported that it will present a poster on its lead program ANV419 at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) annual meeting being held from Friday October 20, 2023, to Tuesday, October 24, 2023, in Madrid, Spain (Press release, Anaveon, OCT 16, 2023, View Source [SID1234635987]).

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ANV419 is a potent and selective IL-2Rβ/γ agonist, designed to enable the delivery of high-dose IL-2 to patients in a safe way. ANV419-001 is a first-in-human, Phase 1 dose escalation study of intravenous single agent ANV419 in patients with advanced solid tumors. Overall, ANV419 was well-tolerated, with all events being self-limiting, reversible, or manageable with standard supportive care. ANV419, at a dose of 243 μg/kg every two weeks (Q2W), was determined as the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). At this dose, PK modeling shows that one injection of ANV419 delivers more IL-2 exposure than a full cycle of high dose aldesleukin.

The abstract is available on the ESMO (Free ESMO Whitepaper) wesite, and the accompanying poster will be on display on the ESMO (Free ESMO Whitepaper) 2023 meeting platform as well as on Anaveon’s website from October 23, 2023.

Poster # 1031P – ANV419, a selective IL-2Rβ/γ agonist in patients with relapsed/refractory advanced solid tumors

Authors: E. Calvo, M. Joerger, H. Läubli, J. Lopez, G. Alonso Casal, E. Corral, D. Hess, D. König, V. S. Perez, E. Gasal, S. Jethwa, D. Di Blasi, E. Garralda

The Poster will be presented on Monday, October 23, 2023, between 12:00 pm and 1:00 pm (CEST).

Anaveon is developing selective cytokine receptor agonists with the potential to therapeutically enhance a patient’s immune system to respond to tumors. ANV419, currently in Phase 2 studies in multiple cancer indications, is designed to preferentially signal through the IL-2 beta/gamma receptor resulting in strong proliferation of effector cells in patients. The follow-on compound, ANV600, targets the selective IL-2 receptor moiety to tumor infiltrating lymphocytes cells and may have therapeutic benefit in less immunogenic tumors. These novel types of therapeutics, if approved, could potentially have a wide utility in oncology, including in combination with cell therapies, vaccines, checkpoint inhibitors and radiotherapy.