On December 8, 2023 MEDSIR, a global leader in oncology research, reported significant breakthroughs in the fight against aggressive breast cancer at the 46th San Antonio Breast Cancer Symposium (SABCS) that have the potential to transform the lives of breast cancer patients (Press release, MedSIR, DEC 8, 2023, View Source [SID1234638347]). The results from the ATRACTIB trial, focusing on advanced triple-negative breast cancer (TNBC), and DEBBRAH Cohort 5, centered on HER2[+] or HER2-Low advanced breast cancer with leptomeningeal carcinomatosis, offer new hope for patients with limited treatment alternatives.

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ATRACTIB: Transforming the Landscape for TNBC Patients

This phase II clinical trial highlights the success of a combined therapy approach as a first-line treatment for advanced TNBC patients. Specifically, the combination of anti-PD-L1 atezolizumab and antiangiogenic bevacizumab with chemotherapy agent paclitaxel, demonstrated significant antitumor activity. This breakthrough holds particular significance since most of the patients included in this trial had PD-L1 negative tumors.

Dr. María Gion, Medical Oncologist at Ramón y Cajal University Hospital and first author of the study, presented the study’s outcomes, revealing a median progression-free survival of 11 months—a substantial delay in cancer progression compared to previous data on similar patient populations—. Impressively, 63% of patients responded positively to the treatment, achieving 13 complete responses and 50 partial responses, with a median duration of response reaching 10 months. Notably, the clinical benefit was observed in 79% of patients.

In the trial, 100 adult patients with untreated advanced TNBC received intravenous atezolizumab, bevacizumab, and paclitaxel until disease progression, intolerable toxicity, death, or patient withdrawal. The safety considerations revealed that peripheral neuropathy (68%) and fatigue (62%) were the most common side effects. Grade 3/4 adverse events, occurred in 47% of patients, primarily peripheral neuropathy (13%) and neutropenia (12%). Importantly, there were no drug-related deaths.

The combination of immunotherapy, antiangiogenic therapy, and chemotherapy demonstrated a manageable safety profile and merits further research for PD-L1-negative advanced TNBC patients.

DEBBRAH Cohort 5: Shaping the future for HER2[+] and HER2-Low Advanced Breast Cancer with Leptomeningeal Carcinomatosis

The DEBBRAH trial, focusing on HER2[+] or HER2-Low advanced breast cancer patients with brain metastases and/or leptomeningeal carcinomatosis, showcased promising results from Cohort 5, which specifically included patients with pathologically confirmed leptomeningeal carcinomatosis. This rare but serious complication occurs in approximately 10% of advanced breast cancer patients and is associated with poor outcomes and limited therapeutic options. Currently, there are no specific drugs approved for metastatic breast cancer patients with brain metastases and/or leptomeningeal carcinomatosis, and there is no consensus on how to manage these cases.

This trial was designed to address this gap in knowledge, aiming to investigate whether an antibody-drug conjugate called trastuzumab deruxtecan, which has shown promise in treating breast cancer that has spread to the brain and elsewhere in the body, can help improve the treatment for this specific group of patients. The antibody-drug conjugate, under evaluation demonstrated notable activity with no new safety concerns. The results of the Cohort 5, which included 7 patients, were presented by Dr. Marta Vaz, Medical Oncologist at Hospital Professor Doutor Fernando Fonseca, showing a remarkable median overall survival of 13.3 months, meeting the primary endpoint. Five patients (71.4%) experienced prolonged disease stabilization for at least 24 weeks, and the median progression-free survival was 8.9 months. The safety profile was consistent with previous studies.

The results of the DEBBRAH trial are extremely interesting and suggest that leptomeningeal carcinomatosis may become a more treatable condition with the introduction of new antibody-drug conjugates targeting HER2. These encouraging data warrant further investigation to address the unmet need in this difficult-to-treat disease.

ABOUT ATRACTIB

The ATRACTIB phase II study explored a combined treatment approach for advanced triple-negative breast cancer (a type of breast cancer characterized by the fact that the cancer cells don’t have estrogen or progesterone receptors, and do not have any or much of a protein called Human Epidermal Growth Factor Receptor-2). The trial evaluated the first-line therapy atezolizumab (an immunotherapy drug), bevacizumab (an antiangiogenic drug), and paclitaxel (a chemotherapy agent) in a cohort of 100 patients, regardless of their PD-L1 tumor expression. Primarily, the study looked at progression-free survival, or how long the disease remained stable. Secondly, it also assessed overall survival, response to treatment, and safety. The results were encouraging, showing that this combination treatment had a positive impact on advanced TNBC patients, even when tumors didn’t express PD-L1. Additionally, the safety profile of the treatment was consistent with what was known from previous studies.

ABOUT DEBBRAH

The DEBBRAH phase II trial was designed to evaluate the efficacy and safety of trastuzumab deruxtecan in patients with HER2[+] and HER2-low advanced breast cancer (meaning that tumors were characterized by the presence of either high or low levels of HER2 protein) with a history of brain metastases and/or leptomeningeal carcinomatosis. Patients were enrolled into one of five cohorts based on the HER2 protein level and type of central nervous system involvement. At SABCS 2023, results of Cohort 5 were presented, which specifically included 7 patients with leptomeningeal carcinomatosis. The main objective for this cohort was to measure the overall survival, or amount of time from the start of the treatment until death from any cause. With a median follow-up of 12 months (range, 2.5-18.6), results showed that treatment with trastuzumab deruxtecan led to a remarkable median overall survival of 13.3 months, meeting the primary endpoint. Five (71.4%) patients experienced a prolonged stabilization of their disease for at least 24 weeks, and the median time before their disease worsened again (known as progression free survival), was 8.9 months.

On December 8, 2023 STORM Therapeutics Ltd. (STORM), the clinical stage biotechnology company discovering and developing novel small molecule therapies targeting RNA modifying enzymes (RMEs) for oncology and other diseases, reported that data on its METTL1 tRNA methyltransferase inhibitor will be presented by collaborator Dr Konstantinos Tzelepis at the 65th Annual ASH (Free ASH Whitepaper) Meeting in San Diego, USA on Friday 8 December, 2023 (Press release, STORM Therapeutics, DEC 8, 2023, View Source [SID1234638345]).

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The presentation entitled "Overcoming Therapy Resistance in AML Using Novel Epitranscriptomic Modalities" details results showing that pharmacological inhibition of a tRNA methyltransferase affects tumour cell growth in in vitro and in vivo models.

Preclinical data demonstrated that:

STORM METTL1 inhibitors exhibit METTL1 inhibition in vitro at low nanomolar concentrations while displaying high selectivity over other RNA and protein methyltransferases.
Mechanistically, METTL1 inhibition leads to reduced tRNA methylation and reduced stability of a subgroup of tRNAs.
In several cancer models, METTL1 inhibition impairs cell proliferation and cell cycle progression accompanied by elevation of differentiation markers.
In vivo, METTL1i treatment induced strong tumour growth inhibition in cell-line derived xenografts and syngeneic in vivo cancer models (haematological and solid malignancies).
Jerry McMahon, Chief Executive Officer & President of STORM Therapeutics, said: "It is very exciting to be able share for the first time that inhibition of the tRNA methyltransferase METTL1 with a small molecule shows anti-cancer properties. We continue to expand our pipeline of novel and proprietary chemistries to modulate enzymes which modify RNA. We look forward to advancing our first-in-class METTL1 program towards the clinic."

Dr Konstantinos Tzelepis, Principal Investigator at University of Cambridge and Cambridge Stem Cell Institute, commented: "We are very excited to present novel data on the development and characterisation of the first-in-class bioavailable tRNA methyltransferase inhibitor against METTL1. This is a fantastic collaborative effort which expands significantly the therapeutic landscape of the epitranscriptomics field and capitalises on our previous published work which shown that METTL1 is a key player in oncogenesis."

Details of the conference and presentation are as follow:

Presented Talk Title: Overcoming Therapy Resistance in AML Using Novel Epitranscriptomic Modalities
Presenter: Dr Konstantinos Tzelepis, Principal Investigator, University of Cambridge and Wellcome-MRC Cambridge Stem Cell Institute
Date and Time: 8 December, 2023 at 2:45pm PST

On December 8, 2023 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of targeted radiotherapies, reported that clinical data from its Iomab-B and Actimab-A programs will be featured in four presentations at the 65th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper) being held in San Diego on December 9-12, 2023 (Press release, Actinium Pharmaceuticals, DEC 8, 2023, View Source [SID1234638338]). These include an oral presentation and two poster presentations detailing results from the completed and positive Phase 3 SIERRA trial of Iomab-B in patients age 55 and above with active relapsed or refractory acute myeloid leukemia (r/r AML) as well as one poster presentation of Phase 1b results from the novel Actimab-A + Venetoclax combination trial for r/r AML.

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Sandesh Seth, Actinium’s Chairman & CEO, said, "We are particularly excited for this year’s ASH (Free ASH Whitepaper) as our four presentations will highlight the differentiated capabilities of Iomab-B and Actimab-A. Better treatment options and outcomes are needed in AML, particularly for elderly patients and those with relapsed or refractory disease who represent a majority of the population. Our strong presence at ASH (Free ASH Whitepaper) is indicative of the potential that our targeted radiotherapies have in the management of patients with difficult to treat AML. We are progressing toward BLA and MAA filings for Iomab-B as well as initiating a pivotal trial Actimab-A next year, which will be significant steps toward achieving our vision of transforming the treatment of AML with our highly differentiated therapies."

Iomab-B and Actimab-A target CD45 and CD33, respectively, both of which are validated targets with significant expression on AML cells. As targeted radiotherapeutics, Iomab-B and Actimab-A have both demonstrated the ability to overcome genetic mutations, including TP53, producing high response rates and improving survival outcomes in patients with difficult to treat, high-risk r/r AML.

Details of Actinium’s presentations at ASH (Free ASH Whitepaper) are as follows:

Iomab-B Oral Presentation

Title: 131I-Apamistamab-Led Allogeneic Hematopoietic Cell Transplant Significantly Improves Overall Survival in Patients with TP53 Mutated R/R AML

Session Name: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Novel Conditioning Regimens for Myeloid Malignancies
Session Date: Sunday, December 10, 2023
Session Time: 9:30 AM – 11:00 AM Pacific Time
Presentation Time: 9:30 AM
Room: Marriott Marquis San Diego Marina, Pacific Ballroom Salons 18-19

Iomab-B Poster Presentations

Title: 131I-Apamistamab Effectively Achieved Durable Responses in Patients with R/R AML Irrespective of the Presence of Multiple High-Risk Factors

Session Name: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster I
Session Date: Saturday, December 9, 2023
Presentation Time: 5:30 PM – 7:30 PM Pacific Time
Location: San Diego Convention Center, Halls G-H

Title: High-Dose Targeted Radiation with 131I-Apamistamab Prior to HCT Demonstrated a Dose-Response for Durable Complete Remission in Patients with R/R AML

Session Name: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster II
Session Date: Sunday, December 10, 2023
Presentation Time: 6:00 PM – 8:00 PM Pacific Time
Location: San Diego Convention Center, Halls G-H

Actimab-A Poster Presentation

Title: Updated Results from Phase 1 Study of Targeted Radiotherapy with Lintuzumab-Ac225 in Combination with Venetoclax in Relapsed/Refractory AML

Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Session Date: Saturday, December 9, 2023:
Presentation Time: 5:30 PM-7:30 PM
Location: San Diego Convention Center, Halls G-H

On December 8, 2023 Onconova Therapeutics, Inc. (NASDAQ: ONTX), ("Onconova" or "the Company"), a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer, reported preclinical data highlighting narazaciclib’s multi-kinase profile, broad anti-tumor activity and increased anti-tumor immunity, compared to palbociclib and other CDK4/6 inhibitors, in a poster presented at the San Antonio Breast Cancer Symposium (SABCS) on December 8, 2023 (Press release, Onconova, DEC 8, 2023, View Source [SID1234638337]).

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"We are very pleased to share new data characterizing narazaciclib’s differentiated activity, compared to palbociclib and other CDK4/6 inhibitors, especially in breast and ovarian cell lines, in a poster presentation at this year’s San Antonio Breast Cancer Symposium (SABCS 2023)," said Steve Fruchtman, M.D., President and Chief Executive Officer.

Dr. Fruchtman continued, "Narazaciclib impacts a wider array of kinase targets and produced a more substantial reduction in cell viability across several large panels of breast and ovarian cell lines carrying a range of mutations, compared to palbociclib. In addition, narazaciclib treatment induced higher levels of T-cell recruiting chemokines, supporting greater anti-tumor immune activity."

"We believe that the totality of the data presented at SABCS supports narazaciclib’s multi-kinase activity, its ability to target resistance pathways missed by other CDK4/6 inhibitors, and its differentiated anti-tumor and immunomodulatory activity. We hope to further demonstrate the promise of narazaciclib’s differentiated profile in patients as we progress the clinical program in 2024 towards the definition of a recommended Phase 2 dose (RP2D). We are also preparing to initiate pivotal studies in the lead indication of low grade endometrioid endometrial cancer (LGEEC), and to expand into investigator-sponsored studies in breast and ovarian cancers," concluded Dr. Fruchtman.

Poster Overview

Title: Narazaciclib’s differential targets and kinase inhibitory activity compared to the approved CDK4/6 inhibitors (CDK4/6is) contribute to the enhanced inhibition of tumor growth in preclinical models

Objectives: To explore the activity of narazaciclib and its metabolite, ON1232580, in comparison to the FDA-approved CDK4/6 inhibitor (CDK4/6i) palbociclib, and identify additional targets engaged by narazaciclib. Activity was measured by exposing narazaciclib and other CDK4/6 inhibitors (CDK4/6i’s) to panels of resistant, mutated, or modified tumor cell lines to evaluate each agent’s activity and potency to inhibit growth and reduce cell line viability.

Results:

Comprehensive analysis of cellular targets: "Thermal Shift" assays affirmed that while narazaciclib and palbociclib impact a handful of similar, expected cell pathway targets, including Rb, Akt, and mTOR, narazaciclib and its main metabolite impact more kinases than palbociclib. We believe this observation could contribute to improved efficacy for narazaciclib by overcoming cancer resistance pathways not targeted by other CDK4/6i’s.
Deeper analysis in human breast and ovarian cells/cell lines: Using bioinformatics data from human cancer databases showed that high BUB1 kinase expression is associated with low survival in patients with breast and uterine corpus endometrial carcinomas (UCEC) and was degraded by low doses of narazaciclib. Western blot analysis of data from several breast cancer cell line panels (including those with known mutations or the overexpression of the membrane receptor, FGFr, an independent prognostic factor in some solid tumor cancers and a driver of resistance to CDK4/6 inhibitors), showed that narazaciclib and its metabolite resulted in a more substantial reduction in cell viability compared to other CDK4/6i’s dosed as monotherapy or in combination with autophagy inhibitors. These data support the potential use of narazaciclib in breast cancer and UCEC, either as monotherapy or in combination with other agents.
Ability to induce senescence and T-cell recruiting chemokines: Treatment with narazaciclib/metabolite produced more profound reductions in cell viability in PYMT murine breast cancer cells, compared to palbociclib and other CDK4/6i’s (combined with autophagy inhibitors). In addition, narazaciclib treatment produced significantly higher increases in T-cell recruiting chemokines, including CXCL10, than palbociclib. These results suggest that narazaciclib has the differentiated potential to promote greater levels of anti-tumor immunity, which could enhance its efficacy.
Conclusions: Expansive analysis of narazaciclib and its metabolite, compared to palbociclib and other CDK4/6i’s, shows that narazaciclib has the potential to be differentiated by its:

Multi-kinase profile, including its impact on BUB1 which is associated with poor prognosis in breast and uterine cancers;
Potent ability to inhibit cell viability in a wide range of breast and ovarian cancer cell panels, including those with common mutations and over-expression of the FGFr, with or without autophagy inhibitors;
Ability to produce significantly higher increases in T-cell recruiting chemokines and promote greater anti-tumor immunity.
These data support the potential use of narazaciclib in patients with breast and ovarian cancer, as well as its potential in LGEEC, based on broad, differentiated multi-kinase activity, supported by potential anti-tumor activity and anti-tumor immunity, compared to palbociclib and other CDK4/6i’s. Evaluation across a range of cell lines, mutations, and prognostic factors, with or without autophagy inhibitors, underscores the strength and consistency of these data.

On December 8, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported the closing of its previously announced underwritten public offering of 10,905,171 shares of its common stock at a public offering price of $29.00 per share, which includes the exercise in full by the underwriters of their option to purchase up to an additional 1,422,413 shares of common stock in this offering (Press release, SpringWorks Therapeutics, DEC 8, 2023, View Source [SID1234638336]). The gross proceeds from the offering, before deducting underwriting discounts and commissions and estimated offering expenses, were approximately $316.25 million.

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Goldman Sachs & Co. LLC, J.P. Morgan Securities LLC, Cowen and Company, LLC and Guggenheim Securities, LLC acted as joint book-running managers for the offering.

An automatic shelf registration statement on Form S-3ASR (including a prospectus) relating to these securities has been filed with the Securities and Exchange Commission (SEC) and has become effective.

The offering was made only by means of a prospectus and prospectus supplement that form part of the automatic shelf registration statement. A copy of the final prospectus supplement and accompanying prospectus relating to the offering has been filed with the SEC and may be obtained from: Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, or by telephone at (866) 471-2526 or by email at [email protected]; J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1115 Long Island Avenue, Edgewood, NY 11717, or by telephone at (866) 803-9204, or by email at [email protected]; Cowen and Company, LLC, 599 Lexington Avenue, New York, NY 10022, by email at [email protected] or by telephone at (833) 297-2926; or Guggenheim Securities, LLC, Attention: Equity Syndicate Department, 330 Madison Avenue, 8th Floor, New York, NY 10017, or by telephone at (212) 518-9544, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.