On January 8, 2025 Ambry Genetics, a leader in clinical genomic testing, reported its contribution to a study published in Nature that significantly advances our understanding of BRCA2 gene variants (Press release, Ambry Genetics, JAN 8, 2025, View Source [SID1234649524]). As the uptake of genetic testing continues to grow, the need for scalable interpretation of the vast number of variants detected has become critical. This study was designed to leverage CRISPR/cas-9 gene editing to aid in the functional characterization of nearly 7,000 BRCA2 variants, helping to resolve variants of uncertain significance (VUS) and guide better clinical management.

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BRCA2 is a well-established and clinically actionable gene associated with cancer predisposition.1 Testing BRCA2 has long been a staple of hereditary cancer testing, as pathogenic variants in the gene are associated with cancers of the breast, ovary, prostate, and pancreas.2-5 Despite the well-understood importance of BRCA2, at the time of this research, more than 5,000 BRCA2 variants are categorized as VUS in the National Institute of Health’s (NIH) ClinVar database (a catalogue of genomic variants and their classifications). Many of these are classified as VUS because there has been insufficient evidence to their classification.6

The study, led by Fergus J. Couch, PhD, of Mayo Clinic, brought together an interdisciplinary team of researchers from Mayo Clinic, H. Lee Moffitt Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Hospital Clinico San Carlos, Memorial Sloan Kettering Cancer Center, and Duke University, as well as Ambry Genetics, to understand and evaluate BRCA2 variants for their functional contributions to cancer pathogenesis.

The results of this study were integrated into a ClinGen/ACMG/AMP model for clinical interpretation, resulting in a 91% rate of classification showing the promise for improving the future of hereditary cancer testing results across all test providers.

"These findings illustrate the power of integrating functional genetic data with clinical analysis to improve understanding of hereditary cancer risk and optimize clinical management approaches," said Marcy Richardson, PhD, Associate Director of Clinical Research at Ambry Genetics. "Functional testing of cancer-associated genes enables the clinical community to offer patients better data-informed recommendations on how best to mitigate cancer risk."

"These findings demonstrate the value of collaborative research in advancing our understanding of BRCA2 variants, improving classification methods that support more accurate risk assessments and informed clinical care," said Fergus Couch, Ph.D., Professor at Mayo Clinic and lead author of the study. "By integrating functional studies with clinical data, we can provide clinicians with valuable tools to guide patients in managing their hereditary cancer risks."

"Genetic testing and variant analysis are paving the way towards truly personalized clinical care for patients before they have cancer, moving us well beyond the time when clinical decision-making based on family history left many clinicians and patients feeling powerless to intervene prior to cancer onset," said Elizabeth Chao, MD, FACMG, Chief Medical Officer at Ambry Genetics. "Improving the quality of data available in our genetic databases allows us to better classify variants across diverse populations, offering a more inclusive approach to genetic testing, giving clinicians new tools for recommending measures to prevent cancer."

This paper is co-published alongside another related study with the NIH, which examines the same issues using a different model. Together, these studies represent a major step forward in variant classification, providing essential data that helps clinicians better assess cancer risks tied to genetic mutations.

On January 8, 2025 Adicet Bio, Inc. (Nasdaq: ACET), a clinical stage biotechnology company discovering and developing allogeneic gamma delta T cell therapies for autoimmune diseases and cancer, reported corporate updates and highlighted upcoming milestones for 2025 (Press release, Adicet Bio, JAN 8, 2025, View Source [SID1234649523]).

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"2024 was a momentous year for Adicet as we amplified our efforts in autoimmune diseases and solid tumors. We dosed our first patients in our clinical trials evaluating our gamma delta 1 chimeric antigen receptor (CAR) T cell candidates, ADI-001 in LN and ADI-270 in ccRCC. Notably, ADI-270 is the first gamma delta CAR T cell therapy to enter clinical development for solid tumors, underscoring our commitment to pioneering innovative treatments. In the first half of 2025, we look forward to reporting preliminary data for both programs," said Chen Schor, President and Chief Executive Officer at Adicet Bio. "Within our autoimmune portfolio, the successful expansion of our Phase 1 trial of ADI-001 into six autoimmune indications, building upon clinical biomarker data demonstrating ADI-001’s robust tissue trafficking and complete CD19+ B cell depletion in secondary lymphoid tissue, further reinforces ADI-001’s potential as an off-the-shelf treatment option.

Mr. Schor continued: "In our oncology pipeline, the initiation of our Phase 1 trial of ADI-270 in ccRCC patients marked a crucial achievement as the first gamma delta 1 CAR T cell product candidate for the treatment of solid tumors. As we look ahead to 2025, we believe we are well positioned to build on this momentum to advance our product candidates to patients living with autoimmune diseases and cancer."

Clinical Program Progress and Upcoming Milestones:

Autoimmune Diseases Clinical Programs

In June 2024, the Company announced that the Food and Drug Administration (FDA) had granted Fast Track Designation to ADI-001 for the potential treatment of relapsed/refractory class III or class IV LN.
In September 2024, Adicet presented clinical biomarker data from the Phase 1 GLEAN trial of ADI-001 at the 9th Annual CAR-TCR Summit demonstrating robust tissue trafficking resulting in high levels of ADI-001, significant CAR T cell activation, and complete CD19+ B cell depletion in secondary lymphoid tissue.
In October 2024, the Company received FDA clearance for an amendment to its Investigational New Drug (IND) application to evaluate ADI-001 in IIM and SPS as part of the Phase 1 trial of ADI-001 in autoimmune diseases. This followed the clearance of an IND amendment in August 2024 to expand clinical development of ADI-001 in the Phase 1 trial beyond LN to include SLE, SSc and AAV.
In November 2024, Adicet announced the dosing of the first LN patient in the Phase 1 trial of ADI-001 in autoimmune diseases. The Company expects to initiate enrollment for patients with SLE, SSc, IIM, and SPS in the first quarter of 2025, and for patients with AAV in the second half of 2025.
Preliminary clinical data from the Phase 1 trial of ADI-001’s LN patient cohort are anticipated in the first half of 2025. Preliminary data from the Phase 1 trial’s other patient cohorts are expected in the second half of 2025.
Hematologic Malignancies and Solid Tumor Clinical Programs

In April 2024, Adicet presented preclinical data for ADI-270 at the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) showing robust anti-tumor activity in an in vivo model of ccRCC, including tumor infiltration, resistance to the immunosuppressive tumor microenvironment, and potent activity via CAR and innate-mediated targeting.
In July 2024, the Company announced that FDA Fast Track Designation had been granted to ADI-270 for the potential treatment of patients with metastatic/advanced ccRCC who have been treated with an immune checkpoint inhibitor and a vascular endothelial growth factor inhibitor.
In December 2024, Adicet announced the dosing of the first patient in the Phase 1 clinical trial evaluating ADI-270 in patients with metastatic/advanced ccRCC.
Preliminary clinical data from the ADI-270 Phase 1 trial in ccRCC are expected in the first half of 2025.

On January 8, 2025 Annals of Oncology (IF: 56.7), a top oncology journal globally, reported remarkable long-term follow-up results of a phase 1b/2 clinical trial on Disitamab Vedotin (DV) (developed by Remegen Co., Ltd) combined with Toripalimab in treating locally advanced or metastatic urothelial carcinoma (la/mUC) (NCT04264936, study ID: RC48-C014) (Press release, RemeGen, JAN 8, 2025, View Source [SID1234649522]). This trial was supervised by Professor Jun Guo and Professor Xi’nan Sheng’s teams from Peking University Cancer Hospital.

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It is the first time that long-term follow-up data has been released for a HER2-targeted antibody-drug conjugate (ADC) and PD-1 inhibitor combination therapy in treating la/mUC, marking it a significant milestone. The nearly-three-year follow-up data revealed an objective response rate (ORR) of 73.2% and median overall survival (OS) of 33.1 months, superior to data published from any other prospective clinical studies on ADC plus PD-1 combination therapies for la/mUC.

New Treatment Options for Patients with La/mUC

UC is the sixth most common cancer worldwide. GLOBOCAN 2022 estimated the year 2021 saw 614,298 new cases and 220,596 deaths of UC. In recent years, the prognosis for patients with la/mUC has significantly improved with new drugs and combination therapies approved, among which ADCs demonstrated outstanding potential.

As a HER2-targeted ADC, DV has been approved in China for patients with HER2-overexpressing (defined as immunohistochemistry [IHC] test results of 2+ or 3+) la/mUC previously treated with platinum-containing chemotherapy. The approval is based on the pooled results of two studies (NCT03507166 and NCT03809013, study IDs: RC48-C005 and RC48-C009) where the ORR registered 50.5% and the median duration of response (DOR) registered 7.3 months.

Multiple clinical studies on la/mUCin recent years have confirmed the synergistic antitumor effects of ADC combined with immunotherapy. NCT04264936 offered stronger evidence as its long-term follow-up results published in the Annals of Oncology demonstrated the high response rate, significant survival benefits, and manageable safety profile of the DV and Toripalimab combination therapy.

DV Combined with Toripalimab: High Response Rate and Prolonged Survival

NCT04264936 is an open-label, multicenter, investigator-initiated phase 1b/2 clinical trial investigating the safety and efficacy of DV in combination with Toripalimab for the treatment of patients with HER2-expressing la/mUC. The dose-escalation study (phase 1b) assessed two dose levels of DV (1.5 and 2.0 mg/kg) combined with Toripalimab (3.0 mg/kg) to determine the recommended phase 2 dose which was then evaluated in the dose-expansion stage (phase 2).

From August 2020 to December 2021, 41 patients were enrolled with a median age of 66 years. 53.7% of the participants were male, 70.7% had an ECOG performance status score of 1, 17 (41.5%) had lung metastasis, and 10 (24.4%) had liver metastasis.

As of March 1, 2024, among all participants, the ORR was 73.2% with 4 (9.8%) achieving complete response and 26 (63.4%) achieving partial response, the DCR was 90.2%, the median progression-free survival (PFS) was 9.3 months, the median DOR was 8.6 months, the median OS was 33.1 months and the 36-month OS rate was 49.2%.

Subgroup analysis revealed ORR benefits across all subgroups regardless of the number of prior lines of systemic treatments, HER2 expression (IHC 1+/2+/3+), and PD-L1 expression status. The ORRs for chemotherapy-naïve patients and those who progressed on platinum-based chemotherapy were 76.0% (19/25) and 68.8% (11/16), respectively. The ORRs for patients with HER2 IHC 3+, 2+, 1+, or 0 were 80.0%, 84.2%, 64.3%, and 33.3%, respectively. Compared with the three HER2 IHC 0 participants (one of whom achieved partial response), those with HER2 expression (IHC 1+/2+/3+) had a higher ORR (76.3% vs 33.3%) and longer PFS (median PFS: 9.3 vs 1.7 months).

In summary, the DV and Toripalimab combination therapy has preliminarily demonstrated promising efficacy and manageable safety profile among patients with la/mUC, wherein those with HER2 expression (IHC 1+/2+/3+) achieved high response rates and long-term survival benefits. These findings support the further exploration and validation of the benefits of DV combined with PD-1 inhibitors in treating la/mUC.

On January 8, 2025 Myeloid Therapeutics, Inc. ("Myeloid"), a clinical-stage immunology company advancing RNA therapeutics to conquer cancer, reported its participation at the 43rd Annual JP Morgan Healthcare Conference, taking place January 13-16, 2025 (Press release, Myeloid Therapeutics, JAN 8, 2025, View Source [SID1234649521]).

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Daniel Getts, Ph.D., CEO of Myeloid, will present on Wednesday, January 15, 2025, at 8:30 am PT. Company management will also participate in one-on-one meetings with investors during the conference.

On January 8, 2025 Marengo Therapeutics, Inc., a clinical-stage biotechnology company pioneering novel approaches for precision T cell activation, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation (FTD) to invikafusp alfa (STAR0602), Marengo’s first-in-class selective dual T cell agonist being studied as a potential new treatment for advanced colorectal cancer with TMB-H (Press release, Marengo Therapeutics, JAN 8, 2025, View Source [SID1234649520]). Fast Track designation is designed to facilitate the development and expedite the review of therapies intended to treat serious or life-threatening conditions with unmet medical needs.

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"The FDA’s Fast Track designation is an important milestone for the STAR0602 program and further positions our unique selective dual T cell agonist platform as a promising solution to address key challenges that perpetuate significant unmet needs in oncology," said Zhen Su, M.D., MBA, Chief Executive Officer of Marengo Therapeutics. "This recognition specifically validates the promise of STAR0602 as a novel treatment option for patients with TMB-H metastatic colorectal cancer, which is insensitive to PD-1 treatment."

The FDA’s decision is informed by the encouraging results from Marengo’s first-in-human Phase 1 clinical study of invikafusp alfa in heavily pretreated cancer patients, which were recently presented during a plenary oral session at the 2024 SITC (Free SITC Whitepaper) Annual Meeting and an oral presentation at the 2024 ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress. The data reinforce invikafusp alfa’s anti-tumor activity and favorable safety profile.

"Marengo’s selective Vβ T cell activation approach targeting specific T cell subsets enriched in Tumor-infiltrating lymphocytes to enhance anti-tumor activity is unique and highly promising," said Bruce Chabner, M.D., Clinical Director Emeritus for the Massachusetts General Hospital Cancer Center and Professor of Medicine at Harvard Medical School. "The Phase 2 clinical investigation of invikafusp alfa is ongoing and this novel treatment could lead to a new class of therapeutics for tumor types that are PD-1 insensitive or resistant, especially in colorectal cancer where current treatment options remain limited."

Marengo is committed to advancing STAR0602 – the asset entered Phase 2 clinical trials at the end of 2024, and the company expects to report additional efficacy results later this year.