On December 9, 2022 Ambrx Biopharma Inc., or Ambrx, (NYSE: AMAM), a clinical stage biopharmaceutical company using its proprietary Engineered Precision Biologics (EPBs) platform to create antibody drug conjugates (ADCs), reported preliminary safety and efficacy data from its Phase 2 ACE‑Breast-03 study during a Spotlight Poster Presentation at the 2022 San Antonio Breast Cancer Symposium (SABCS) (Press release, Ambrx, DEC 9, 2022, View Source [SID1234625003]). The data presented by the investigator demonstrated 51.7% overall response rate (ORR) by RECIST v1.1 and 100% disease control rate (DCR) after treatment with ARX788 in HER2 positive mBC patients who are resistant or refractory to T-DM1.

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ACE-Breast-03 is a Phase 2, multicenter study of ARX788, an anti-HER2 ADC being evaluated for patients whose metastatic disease is resistant or refractory to T-DXd, T-DM1, or tucatinib-containing regimens. The study was conducted in the U.S., Korea, and Australia. As of the data cutoff, seven patients enrolled in the study were previously treated with T-DM1 and received a median of five lines of prior anticancer therapies. Four of seven patients were previously treated with HER2 tyrosine kinase inhibitors (TKIs). The median age was 59 years. The confirmed objective response rate (ORR) per RECIST v1.1 based was 57.1% (4/7). The disease control rate (DCR) was 100% (7/7) for patients treated with ARX788. Patients had a median time on therapy of 7.2 months and treatment remains ongoing. None of the patients experienced drug-related serious adverse events (SAEs) and all adverse events (AEs) were well tolerated with no treatment discontinuations from AEs.

Amplification of the human epidermal growth factor receptor 2 (HER2) gene with consequent HER2 protein overexpression occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. The HER2-targeted ADC trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive mBC after prior trastuzumab and taxane therapy. However, disease progression occurs in T-DM1 treated patients and as such, requires additional therapeutic options. The use of second-generation anti-HER2 ADCs using alternative molecules is being investigated to overcome drug resistance.

"This preliminary safety and efficacy data in a heavily pretreated population further reinforces our view of the stability and precision underlying Ambrx’s proprietary drug-linker and site-specific conjugation technology for ADC design," said Daniel O’Connor, Chief Executive Officer of Ambrx. "Our unique approach offers highly differentiated biologic design so that we can work towards providing better outcomes for patients with difficult-to-treat cancers."

Two Phase 3 studies and one registration enabled Phase 2 study with ARX788 (ACE-Breast-02, ACE-Gastric-02, and ACE-Breast-08) conducted by Amrbrx’s partner, NovoCodex Biopharmaceuticals, are ongoing in China with projected readouts in 2023.

Sara Hurvitz, M.D., Professor at David Geffen School of Medicine at UCLA, stated, "We are encouraged by the response rates and safety results, particularly given the significant need for new therapies among patients whose disease continues to progress after receiving multiple lines of therapy. We thank the San Antonio Breast Cancer Symposium for accepting our abstract as a Spotlight Poster Discussion presentation and the opportunity to show early results from the ACE-Breast-03 Phase 2 clinical trial."

Presentation highlights:

Presentation Title: ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1
Presenting Author: Sara Hurvitz, M.D.
Poster Number: PD18-09
Key Highlights:

ARX788 provided clinical benefit to patients previously treated with T-DM1 who had disease progression
Patients treated with ARX788 had a confirmed ORR of 57.1% (4/7 patients) and unconfirmed ORR of 71.4% (5/7 patients)
The disease control rate was 100% (7/7 patients) for patients treated with ARX788
All adverse events were well tolerated with 85.7% of patients experiencing drug-related AEs (any grade) with 0% of AEs leading to discontinuation and 0% of patients experiencing drug-related SAEs
Treatment with ARX788 remains ongoing in this patient population with the median time of ARX788 therapy of 7.2 months
ARX788 is currently being studied in several registrational trials in breast cancer and gastric/GEJ cancer by Ambrx’s partner, NovoCodex Biopharmaceuticals, in China. Ambrx has recently paused the internal development of ARX788 and is seeking to partner ARX788 outside of China.

On December 9, 2022 Zymeworks Inc. (NYSE: ZYME), a clinical-stage biopharmaceutical company developing multifunctional biotherapeutics, reported new clinical data for zanidatamab, the company’s investigational HER2-targeted bispecific antibody, in combination with palbociclib, a CDK4/6 inhibitor, and fulvestrant, a selective estrogen receptor degrader, in patients with heavily pretreated HER2-positive hormone-receptor positive metastatic breast cancer (Press release, Zymeworks, DEC 9, 2022, View Source [SID1234625002]). The data were presented today in a spotlight poster session entitled Treatment of HER2-positive (HER2+) hormone-receptor positive (HR+) metastatic breast cancer (mBC) with the novel combination of zanidatamab, palbociclib, and fulvestrant during the San Antonio Breast Cancer Symposium (SABCS) taking place in San Antonio, Texas and virtually.

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Clinical Data Highlights

The data presented at SABCS are from a clinical study of 45 patients with heavily pretreated HER2-positive HR-positive metastatic breast cancer who received zanidatamab in combination with palbociclib and fulvestrant. Patients had received prior regimens containing HER2-targeted agents including trastuzumab (100%), pertuzumab (80%), T-DM1 (98%), and other available options.

In 36 efficacy-evaluable patients, treatment with zanidatamab in combination with palbociclib and fulvestrant resulted in a cORR of 33% and DCR of 92%, and the majority of patients experienced a decrease in tumor size. The mPFS was 9.6 months with seven patients still on study at the time of data cutoff (August 31, 2022). The regimen was generally well-tolerated, with the majority of treatment-related adverse events considered mild to moderate in severity (Grade 1 or 2).

"Zanidatamab together with palbociclib and fulvestrant shows encouraging antitumor activity and a manageable tolerability profile in patients with HER2‑positive hormone-receptor positive breast cancer that has progressed after treatment with multiple HER2-targeted agents," said Neil Josephson, M.D., Chief Medical Officer at Zymeworks. "We are encouraged by the durability of disease control and median progression-free survival in this heavily pretreated patient population indicating that this regimen has the potential to be developed as a chemotherapy-free treatment option for these patients."

The presentation is available to conference registrants on the SABCS conference website and is also available on the publications page of the Zymeworks website at View Source

Title: Treatment of HER2-positive (HER2+) hormone-receptor positive (HR+) metastatic breast cancer (mBC) with the novel combination of zanidatamab, palbociclib, and fulvestrant

Lead Author: Santiago Escrivá-de-Romani, MD, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital; Barcelona, Spain

Program Number: PD18-10

About Zanidatamab

Zanidatamab is a bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks is developing zanidatamab in multiple Phase 1, Phase 2 and pivotal clinical trials globally as a targeted treatment option for patients with solid tumors that express HER2. Zymeworks has entered into separate agreements with each of BeiGene, Ltd. (BeiGene) and Jazz Pharmaceuticals Ireland Limited (Jazz), granting each of BeiGene and Jazz with exclusive rights to develop and commercialize zanidatamab throughout various counties around world.

On December 9, 2022 Prelude Corporation (PreludeDx), a leader in molecular diagnostics and precision medicine for early-stage breast cancer, reported study results demonstrating that DCISionRT provides patients with ductal carcinoma in situ (DCIS) superior recurrence risk stratification and radiation therapy (RT) benefit prediction compared to commonly used clinicopathologic (CP) features (Press release, PreludeDx, DEC 9, 2022, View Source [SID1234625000]). The data was presented in a spotlight presentation at the 2022 San Antonio Breast Cancer Symposium (SABCS).

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Until now, clinicians have relied upon clinicopathologic features alone, such as nuclear grade (NG), tumor size and age to determine which patients may not need radiation therapy.

This study, titled ‘7-gene Predictive Biosignature Improves Risk Stratification for Breast Ductal Carcinoma in Situ Patients Compared to Clinicopathologic Criteria, Identifying a Low-Risk Group Not Clinically Benefiting from Adjuvant Radiotherapy’, revealed in 926 women from four cohorts, that DCISionRT was a superior predictor of 10-year IBR rates and RT benefit compared to clinicopathologic criteria. DCISionRT identified that approximately half of CP-Low Risk patients were classified as elevated risk by the test and significantly benefited from RT with an absolute 17.7% reduction in 10-year ipsilateral breast recurrence. Whereas DCISionRT Low Risk patients, which included about one-third of CP High-Risk patients, had no significant RT benefit, representing a true low risk group.

"In the DCISionRT Low Risk group, I would have to treat approximately 100 patients to benefit just one patient. In contrast, in the DCISionRT High Risk group, I would have to treat approximately 6 patients to benefit one. This study further validates that the biosignature is far more accurate than using grade or other factors for determining DCIS outcomes," said Rachel Rabinovitch, MD, FASTRO, Professor of Radiation Oncology at University of Colorado. "Traditional methods result in the over-and-under treatment of DCIS. It is a very significant advancement to have a patient specific biosignature tool which predicts RT benefit."

"We are grateful for our prestigious physician-researchers around the world who are working tirelessly to further integrate and share the immense data and clinical value of DCISionRT in shared treatment decision making with DCIS patients," said Dan Forche, President and CEO of PreludeDx. "We are inspired by their enthusiasm and dedicated to continued innovation in the fight against early-stage breast cancer."

About DCISionRT for Breast DCIS
DCISionRT is the only risk assessment test for patients with ductal carcinoma in situ (DCIS) that predicts radiation therapy benefit. Patients with DCIS have cancerous cells lining the milk ducts of the breast, but they have not spread into surrounding breast tissue. In the US, over 60,000 women are newly diagnosed with DCIS each year. DCISionRT, developed by PreludeDx on technology licensed from the University of California San Francisco, and built on research that began with funding from the National Cancer Institute, enables physicians to better understand the biology of DCIS. DCISionRT combines the latest innovations in molecular biology with risk-based assessment scores to assess a woman’s individual tumor biology along with other pathologic risk factors and provide a personalized recurrence risk. The test provides a Decision Score that identifies a woman’s risk as low or elevated. Unlike other risk assessment tools, the DCISionRT test combines protein expression from seven biomarkers and four clinicopathologic factors, using a non-linear algorithm to account for multiple interactions between individual factors in order to better interpret complex biological information. DCISionRT’s intelligent reporting provides a woman’s recurrence risk after breast conserving surgery alone and with the addition of radiation therapy. In turn, this new information may help patients and their physicians to make more informed treatment decisions.

On December 9, 2022 Cytovia Inc.(DBA Cytovia Therapeutics, Inc.), a biopharmaceutical company focused on unlocking the power of natural killer (NK) cell therapeutics through bispecific antibodies and TALEN gene-edited, iPSC-derived NK (iNK) cells, reported new preclinical data for its CD38-targeted Flex-NK bispecific antibody at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s 64th Annual Meeting (ASH 2022) taking place in New Orleans, LA, and virtually December 10-13th, 2022 (Press release, Cytovia Therapeutics, DEC 9, 2022, View Source [SID1234624999]).

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"We’re delighted to see further progress on our CD38-targeted Flex-NK bispecific antibody program, with a pre-clinical package that supports clinical evaluation in 2023," commented Cytovia CEO Dr. Daniel Teper. "The data presented at ASH (Free ASH Whitepaper) suggests that CYT-338, our CD38-targeted Flex-NK Bispecific Antibody, has a differentiated profile compared to daratumumab, the leading CD38-targeted monoclonal antibody and that CYT-338 may have the ability to overcome NK cell exhaustion and dysfunction.

We believe that by redirecting and activating NK cells to kill myeloma cells, bispecific antibodies have the potential to offer new options for patients not responding to first lines of treatment."

Details about the ASH (Free ASH Whitepaper) poster presentation are as follows:

Title: Biological Characterization and Differential Gene Expression Analysis of CYT-338 NK Cell Engager (NKE) Against Multiple Myeloma (MM) Tumors
Abstract Number: 3142
Session Name: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster II
Date and Time: Sunday, December 11th, 2022 (6-8PM CST)
Location: Ernest N. Morial Convention Center, Hall D, New Orleans, LA

The poster is available online on both the Cytovia Therapeutics and American Society of Hematology (ASH) (Free ASH Whitepaper) websites.

The presentations show that Cytovia’s bispecific antibody CYT-338 demonstrated it could increase the ability of both its iPSC-derived (iNK) and Peripheral Blood (PBNK) Natural Killer cells to kill Multiple Myeloma (MM) tumor spheroids in a dose dependent manner that peaked 2-3 days following of initiation of killing. Serial killing activity of iNKs and PBNKs against MM tumors declined over additional rounds of killing but the combination with CYT-338 maintained serial killing at high levels suggesting the ability of CYT-338 to overcome NK cell exhaustion.

CYT-338 showed potent dose dependent ADCP against MM tumors indicating an additional effector cell pathway targeted by CYT-338 and dose dependent CDC against MM tumors demonstrating an additional cytotoxicity pathway targeted by CYT-338. Gene expression analysis of autologous patient NK cell and MM co-cultures treated with CYT-338 or daratumumab showed similar and distinct gene expression profiles. The distinct lymphocyte activation gene expression pathways activated by CYT-338 may contribute to the increased NK cell redirected cytotoxicity of MM tumors compared to daratumumab. The above results support further development of CYT-338 as a potent NK cell engager that could also activate macrophages and complement to mediate its anti MM tumor effects.

The data has been developed in collaboration with Lynx Bio, a clinical-stage biotechnology company combining physiologically relevant suspension cell co-culture assays, automated microfluidics, and deep learning analytics with the goal of rapidly advancing drug candidates in oncology and bringing personalized cancer treatments to patients.

About Multiple Myeloma
Multiple Myeloma is a currently incurable cancer, affecting a type of white blood cell known as plasma cells. It leads to an accumulation of tumor cells in the bone marrow, rapidly outnumbering healthy blood cells. Instead of producing beneficial antibodies, cancerous cells release abnormal proteins causing several complications. According to the World Cancer Research Fund, Multiple Myeloma is the 3rd most common blood cancer, with 176,404 new cases worldwide in 2020 including more than 50,000 cases in Europe, 35,318 in the US, and 31,890 in Eastern Asia. There have been more than 117,000 deaths worldwide in 2020 with a median overall survival of less than 12 month in patients refractory to standard of care.

Initial treatment comprises of a combination of different biological and targeted chemotherapies, and bone marrow transplants for eligible patients. Immunotherapy with monoclonal antibodies against CD38 such as daratumumab and isatuximab are the most rapidly growing treatment option. Antibody-drug conjugates and Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA and T-Cell Engager Bispecific Antibodies have recently been approved for Multiple Myeloma but high cost, limited product supply and the need for strict safety monitoring may limit their use.

On December 9, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for talquetamab for the treatment of patients with relapsed or refractory multiple myeloma (Press release, Johnson & Johnson, DEC 9, 2022, View Source [SID1234624998]). Talquetamab is an investigational, off-the-shelf (ready to use), bispecific T-cell engager antibody targeting both GPRC5D, a novel drug target that is on some normal cells but overexpressed on myeloma cells, and separately targets CD3 on T cells.1

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"Despite the therapies that have been developed for the treatment of multiple myeloma, there remains persistent unmet needs for patients who relapse or become refractory," said Peter Lebowitz, M.D., Ph.D., Global Therapeutic Area Head, Oncology, Janssen Research & Development, LLC. "Through our discovery and development of talquetamab, a novel GPRC5DxCD3 bispecific antibody, we remain relentlessly committed to the investigation of innovative therapies for patients and oncologists. We look forward to working closely with the FDA in their review of the talquetamab submission."

This BLA is supported by data from the Phase 1/2, first-in-human MonumenTAL-1 study of talquetamab (Phase 1: NCT03399799; Phase 2: NCT04634552) in patients with relapsed or refractory multiple myeloma who have received more than three prior lines of therapy.1 The first presentation of Phase 2 results from the MonumenTAL-1 study will be highlighted at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting on December 10, 2022 in an oral scientific session (Abstract #157)2 and featured as part of the ASH (Free ASH Whitepaper) Press Briefing.

About Talquetamab
Talquetamab is a first-in-class, off-the-shelf (ready to use), investigational bispecific T-cell engager antibody targeting both GPRC5D, a novel multiple myeloma target, and CD3, a primary component of the T-cell receptor.1 CD3 is involved in activating T cells, and GPRC5D is highly expressed on multiple myeloma cells.3,4

Talquetamab, which is given by subcutaneous injection, is currently being evaluated in the Phase 1/2 MonumenTAL-1 clinical study for the treatment of relapsed or refractory multiple myeloma (NCT03399799), and in combination studies RedirecTT-1 (NCT04586426), TRIMM-2 (NCT04108195), TRIMM-3 (NCT05338775), MonumenTAL-2 (NCT05050097) and MonumenTAL-3 (NCT05455320).

Talquetamab received Breakthrough Therapy designation from the U.S. FDA in June 2022 for the treatment of adult patients with relapsed or refractory multiple myeloma, who have previously received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. In May 2021 and August 2021, talquetamab received an Orphan Drug designation for the treatment of multiple myeloma by the U.S. FDA and the European Commission, respectively. In January 2021, talquetamab received a PRIME designation by the European Commission.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.5 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.6 In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.7 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.