On June 15, 2023 REVEAL GENOMICS, S.L., a Barcelona-based biotech start-up seeking to revolutionize precision oncology through diagnostic innovation, reported another validation of HER2DX, the world’s first specialized genomic test for HER2+ breast cancer (Press release, REVEAL GENOMICS, JUN 15, 2023, View Source [SID1234632762]). The results were obtained from analysis of HER2DX in tumor samples from the PHERGAIN phase II clinical trial, led by MEDSIR (Spain). Last year, REVEAL GENOMICS and MEDSIR announced a strategic partnership.

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MEDSIR´s PHERGAIN trial, the first results of which were published in the Lancet Oncology in 2021 and recently announced at ASCO (Free ASCO Whitepaper) Congress, randomized 356 patients with newly diagnosed HER2+ breast cancer to neoadjuvant systemic therapy with 6 cycles of multi-agent chemotherapy, trastuzumab, and pertuzumab (i.e., arm A) or 2 cycles of chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab (i.e., arm B). After 2 cycles of treatment in arm B, patients underwent a 18F-FDG-PET. If a metabolic response was observed, patients continued treatment with 6 additional cycles of chemotherapy-free dual HER2 blockade (i.e., a total of 8 cycles). If no metabolic response was observed by 18F-FDG-PET, patients received 6 cycles of multi-agent chemotherapy, trastuzumab, and pertuzumab. The co-primary endpoints were pathological complete response (pCR) rate after surgery following 8 cycles of chemotherapy-free dual HER2 blockade, and 3-year invasive disease-free survival (iDFS) of patients in arm B.

HER2DX genomic test was applied in 292 (82.0%) baseline pre-treatment tumor biopsies. The HER2DX pCR-score was found to be significantly associated with pCR, regardless of the treatment regime, 18F-FDG-PET metabolic response, and hormone receptor status. Despite a short median follow-up of 3.6 years, 85.0% and 100.0% of events were identified as high-risk according to the 2 pre-specified cutoffs of the HER2DX risk-score. In contrast, 98% and 100% of patients with HER2DX low-risk were disease-free at last follow-up, according to the 2 pre-specified cutoffs of the HER2DX risk-score.

"The results of HER2DX in PHERGAIN are remarkable and support the strong predictive and prognostic value of the test in patients with early-stage HER2+ breast cancer. The test will help to select which patients might be treated with trastuzumab and pertuzumab without chemotherapy, a treatment strategy with better quality of life than multi-agent chemotherapy," commented Dr. Antonio Llombart, Principal Investigator of the PHERGAIN trial, Co-founder of MEDSIR, and Head of the Medical Oncology Department at Hospital Arnau de Vilanova (Valencia, Spain).

Dr. Javier Cortés, Chief of the International Breast Cancer Center (IBCC, Spain) and Co-founder of MEDSIR, added, "Today’s positive results confirm the ability of the HER2DX scores to predict pCR and survival outcome following different anti-HER2-based treatments, including chemotherapy-free regimes. The test has extensive clinical validation across many studies and patients, and, in my opinion, should be recommended and included in clinical guidelines".

Dr. Patricia Villagrasa, CEO and Co-founder of REVEAL GENOMICS concluded, "Today’s positive results for HER2DX are a significant step forward for our company. We look forward to continuing to work with healthcare payers and providers to make this test reimbursed and available worldwide."

Detailed results of this study will be presented at a future medical congress and submitted for publication.

About the HER2DX test
HER2DX is the world’s first diagnostic test formulated specifically for HER2+ breast cancer. Marketed by REVEAL GENOMICS since January 2022, the HER2DX is a standardized 27-gene expression test for patients with early-stage HER2+ breast cancer.

HER2DX️ is a prognostic, predictive assay based on clinical and genomic data. The test integrates clinical information (i.e., tumor size and nodal status) with biological information tracking immune response, luminal differentiation, tumor cell proliferation, and expression of the HER2 17q12-21 chromosomal amplicon, including the ERBB2 gene.

HER2DX predicts:

Risk of relapse score (high vs. low): the risk of recurrence in patients with newly diagnosed HER2+ breast cancer.
pCR likelihood score (high vs. medium vs. low): the likelihood of a patient to respond to anti-HER2-based treatment before surgery.
ERBB2 score (high vs. medium vs. low): the quantitative expression of ERBB2 mRNA across HER2-negative, HER2-low and HER2+ breast cancer.
About HER2+ breast cancer
HER2+ breast cancer accounts for 20% of all diagnosed breast tumors. This represents more than 390,000 new cases diagnosed worldwide every year, meaning that, on average, 3 women are diagnosed with HER2+ breast cancer every 4 minutes. HER2+ breast cancer is clinically, and biologically heterogeneous, and standard clinical-pathologic assessment is not sufficient to capture this heterogeneity. Understanding this biological heterogeneity is key to identifying the prognosis of each patient and the benefit from systemic therapies that target HER2.

On June 15, 2023 Biostar Pharma, Inc. (hereinafter referred to as "Biostar"), the US subsidiary of Beijing Biostar Pharmaceuticals Co., Ltd. which is a synthetic biology driven biopharma company focusing on the discovery, development and commercialization of innovative oncology drugs, reported that, after having in-depth discussions with the FDA through pre-IND meetings, the FDA has approved the IND of a phase 2/3 clinical trial with seamless protocol design for the company’s core product utidelone injectable (UTD1) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) (Press release, Biostar, JUN 15, 2023, View Source [SID1234632760]).

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Designated as BG01-2202, this trial is a multi-national, phase 2/3, open-label, randomized, controlled clinical study of utidelone injectable (UTD1) versus docetaxel. The study is going to be conducted at about 50 sites in about 10 countries and regions across US, Europe and Asia -Pacific. About 760 patients are planned to be enrolled, 90 for phase 2 with ORR (objective response rate) as the primary endpoint and 670 for phase 3 with OS (overall survival) as the primary endpoint and PFS (progression free survival), ORR, etc. as the secondary endpoints.

Dr. Li Tang, Chairman of Biostar Pharma commented: "This is an important milestone for global development of utidelone injectable — an innovative anti-cancer drug and new generation epothilone analogue. We are fully committed to advancing this pivotal multi-national study and also willing to partner with global pharmaceutical companies to bring this product to market around the world to benefit more patients".

This study was warranted by a previous open-label, multi-center phase 2 trial conducted in China (NCT03693547) of utidelone as single-agent to treat patients with advanced NSCLC who had received at least two prior systemic regimens including platinum-containing chemotherapy or targeted therapy, which demonstrated promising clinical efficacy and manageable safety profile with outcomes of 19.0% ORR, 81.0% DCR (disease control rate), 4.37 months of median PFS and 71% of 12-month OS rate. The median OS was not reached by the cut-off date. The results were selected by 2022 ELCC (European Lung Cancer Congress) as poster presentation. A phase 3 study to evaluate utidelone versus docetaxel in locally advanced or metastatic NSCLC patients that have failed chemotherapy with a platinum-containing regimen has also been initiated and being in progress now in China.

Unmet Medical Need

Lung cancer remains the leading cause of cancer death worldwide [1]. NSCLC accounts for about 85% of lung cancer cases [2,3] and more than 75% of patients with lung cancer are diagnosed with locally advanced or stage IV disease [4]. Although currently targeted therapies and/or immunotherapies are commonly used for advanced NSCLC, limitations are obvious. Many patients either do not have a targetable driver gene alteration or are not suitable for immunotherapy [5,6]. Besides, acquired resistance to targeted- and immune-therapy is a substantial problem. In this case, chemotherapy, such as platinum- and taxane-based regimens, remains the fundamental treatment. However, acquired resistance to standard chemotherapies still presents challenges, which may limit their efficacy [7,8]. There is a huge unmet clinical need for alternative chemotherapeutic agents that can overcome, or are less susceptible to, drug resistance and have clinical efficacy in heavily pretreated patients.

About Utidelone

Being derived from Biostar’s synthetic biology technology platform, utidelone is a genetically engineered best-in-class epothilone analog, which is a class of microtubule-targeting agent that has differential mechanisms of action from taxanes and is developed to overcome drug resistance. Utidelone injectable has been launched in China in 2021 for the treatment of metastatic breast cancer (MBC). It is the only approved new molecular of microtubule inhibitor in the past 10 years around the world. Among all single agent or combination regimen of non-taxane chemotherapies, utidelone injectable is the only one to achieve both PFS and OS benefits for heavily pretreated MBC patients. It demonstrated several advantageous features, such as overcoming taxane-resistant, low hematological toxicity suitable for longer term exposure, ability to cross the blood-brain barrier that is able to prevent and treat tumor brain metastasis. Relevant study results were twice selected for oral presentations at ASCO (Free ASCO Whitepaper) annual meetings and invited to publish in Lancet Oncology and Annals of Oncology.

On June 15, 2023 Avenge Bio, Inc. ("Avenge"), a clinical stage, oncology-focused biotechnology company developing the LOCOcyte Immunotherapy platform for the local administration of potent immune effector molecules to treat solid tumors, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to AVB-001 for the treatment of patients with mesothelioma (Press release, Avenge Bio, JUN 15, 2023, View Source [SID1234632759]).

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Mesothelioma is a highly symptomatic cancer that primarily affects adults. It occurs in the cells that make up the mesothelium of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. In 2022, there were approximately 3,000 new cases reported in the U.S. and approximately 2,500 people died from this cancer. Pleural mesothelioma accounts for approximately 85% of new mesothelioma cases, followed by peritoneal mesothelioma (approximately 15%), and pericardium or tunica vaginalis mesothelioma (<1% combined).

Avenge continues to enroll patients in an ongoing Phase 1/2 clinical trial evaluating AVB-001 for the treatment of refractory ovarian cancer. The Phase 1/2 clinical trial is a first-in-human, single-arm, open-label, dose-escalation and expansion study (NCT05538624) designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of AVB-001 delivered intraperitoneally (IP) to patients with high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube.

In March 2023, Avenge received positive feedback from the FDA on its preclinical and clinical development plans for pleural malignant mesothelioma. Avenge previously published preclinical data establishing the efficacy and safety of pleural administered AVB-001 for the treatment of pleural malignant mesothelioma. The manuscript, entitled "Activation of adaptive and innate immune cells via localized Interleukin-2 cytokine factories eradicates mesothelioma tumors," can be viewed on the Clinical Cancer Research website.

About LOCOcyte Platform

Our LOCOcyte allogeneic cell-based immunotherapy platform enables potent localized modulation of the immune system which also precipitates a systemic immune response, allowing us to treat previously intractable cancers. The technology leverages three unique advantages:

Potent immune effector molecules are generated by synthetically engineering allogeneic cells creating a ready-to-use therapy,
Therapy is localized in proximity to the primary tumor site and generates innate and adaptive immune response, and
The immunomodulator trains the patient’s immune system generating a robust immune response that seeks and eradicates distal metastasis without systemic toxicity.

On June 15, 2023 Recently, the preclinical study results of 9MW2821, the first domestically developed Nectin-4-targeting ADC by Mabwell, were reported in the renowned journal "Molecular Cancer Therapeutics" under the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Mabwell Biotech, JUN 15, 2023, View Source [SID1234632758]). The paper comprehensively elaborated on the development and preclinical study results of 9MW2821 as a new generation Nectin-4-targeting ADC, and systematically compared it with the only approved Nectin-4-targeting ADC on the market (PADCEV, EV).

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Nectin-4 is closely related to the progression and poor prognosis of malignant tumors. Enfortumab Vedotin (EV) is the first Nectin-4-targeting ADC approved by the US Food and Drug Administration (FDA) for the treatment of advanced urothelial carcinoma. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Ocular, pulmonary, and hematological toxic side effects are common in nectin-4-targeting therapy, which frequently results in dose reduction and/or treatment termination. These reasons may limit the wider use of Nectin-4-targeting therapy.

9MW2821 is a novel Nectin-4-targeting ADC based on inter-chain site specific conjugate technology, composed of specially designed linker, novel antibody molecule, and the cytotoxic drug MMAE. It not only has good tumor binding ability and target specificity, but also differs from existing Nectin-4-targeting ADC therapy (PADCEV, EV). It has more homogeneous composition, more stable structure, and superior tumor delivery ability.

In vitro cell experiments and animal studies have found that the unique structure of 9MW2821 brings the following significant characteristics:

9MW2821 enhances the antibody’s internalization activity, exhibiting similar tumor internalization activity as EV in Nectin-4 high-expressing tumors and superior tumor internalization activity compared to EV in low-abundance tumors.
9MW2821 improves the plasma stability of the drug and significantly improves its pharmacokinetic (PK) characteristics. In PK studies, it had a higher intra-tumoral concentration of MMAE (9MW2821, Cmax: 106 pmol/ml; EV, Cmax: 76 pmol/ml; p＜0.01) and intra-tumoral exposure (9MW2821, AUC0-t: 2452 pmol/mL*h; EV, AUC0-t: 2116 pmol/mL*h; p＜0.05).
In the CDX models, 9MW2821 exhibit comparable activity as EV in urothelial carcinoma, and has superior tumor suppression effects in non-small cell lung cancer and breast cancer. In addition, the PDX models show that it has excellent tumor suppression effects in different tumors, including cervical cancer and lung cancer models, and also has certain tumor therapeutic effects in low- to medium-abundance solid tumors and large volume solid tumors.
9MW2821 has good drug safety, and toxicology studies have shown that it has milder skin toxicity, eye toxicity and gastrointestinal toxicity at equivalent doses.
9MW2821 is an ideal ADC with homogeneous drug-to-antibody ratio, tumor-specific properties, bystander killing effect, ideal efficacy in multiple solid tumors, and an acceptable therapeutic window. Based on the above study results, the company is conducting phase I/II clinical studies for 9MW2821 in multiple solid tumors and validating the related study results.

About 9MW2821

The novel Nectin-4-targeting ADC, developed independently based on the Mabwell ADC Platform and High-throughput Screening Platform, has applied for multiple patents for its antibody molecule, linker, drug molecule, and platform-related site-specific conjugation technology.

Currently, multiple clinical studies covering more than 10 types of tumors are being conducted. Preliminary data shows that at the recommended phase 2 dose (RP2D), among 12 evaluable subjects with urothelial carcinoma, the objective response rate (ORR) reached 50%, and the disease control rate (DCR) reached 100%; among 6 evaluable subjects with cervical cancer, the ORR reached 50%, and the DCR reached 100%. The expansion of multiple cohorts, including urothelial carcinoma, cervical cancer, prostate cancer, HER-2 negative breast cancer, and non-small cell lung cancer, is actively being pursued.

On June 15, 2023 Takeda (TSE:4502/NYSE:TAK) and HUTCHMED (China) Limited (Nasdaq/AIM: HCM, HKEX: 13) ("HUTCHMED") reported that the European Medicines Agency ("EMA") has validated and accepted for regulatory review the marketing authorization application ("MAA") for fruquintinib, a highly selective and potent inhibitor of vascular endothelial growth factor receptors ("VEGFR") -1, -2 and -3 for the treatment of adult patients with previously treated metastatic colorectal cancer ("CRC") (Press release, Hutchison China MediTech, JUN 15, 2023, View Source [SID1234632743]). If approved, fruquintinib will be the first and only highly selective inhibitor of all three VEGF receptors approved in the E.U. for previously treated metastatic CRC.1,2

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"European patients with metastatic colorectal cancer have not benefitted from a treatment advancement in over a decade," said Awny Farajallah, M.D., head of Global Medical Affairs Oncology at Takeda. "We are thrilled to have submitted the marketing authorization application to the EMA, bringing us one step closer to potentially offering this innovative therapy to patients with advanced disease. We believe fruquintinib has the potential to address the longstanding unmet need for patients with previously treated metastatic colorectal cancer regardless of their biomarker status, and we look forward to working with the regulators throughout the process."

The MAA for fruquintinib includes results from the Phase III FRESCO-2 trial along with data from the Phase III FRESCO trial conducted in China. FRESCO-2 is a global Phase III multi-regional clinical trial (MRCT) conducted in the U.S., Europe, Japan and Australia investigating fruquintinib plus BSC vs. placebo plus BSC in patients with previously treated metastatic CRC. The FRESCO-2 trial met its primary and key secondary endpoints, showing a significant and clinically meaningful improvement in overall survival ("OS") and progression-free survival ("PFS"), respectively. Fruquintinib has been generally well tolerated in patients to date.

"Based on fruquintinib’s clinical profile to date, we are optimistic about its potential as a choice for patients and physicians in the E.U. who find treatment options to be limited for previously treated metastatic colorectal cancer," said Dr. Michael Shi, Head of R&D and Chief Medical Officer, HUTCHMED. "We believe the EMA validation of the marketing authorization application for fruquintinib represents an exciting initial step toward advancing treatment for patients in Europe and look forward to supporting Takeda as it pursues this goal."

The validation follows the acceptance by the U.S. Food and Drug Administration ("FDA") of a new drug application ("NDA"), announced on May 25, 2023, which was granted Priority Review and assigned Prescription Drug User Fee Act (PDUFA) goal date of November 30, 2023. Submission of an NDA to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) is also planned in 2023. Fruquintinib is currently approved in China under the brand name ELUNATE. Approval in China was based on the results of the FRESCO study, a Phase III pivotal registration trial of fruquintinib in 416 patients with metastatic CRC in China, published in The Journal of the American Medical Association, JAMA, in June 2018 (NCT02314819).3 In March 2023, HUTCHMED and Takeda closed an exclusive licensing agreement to further the global development, commercialization and manufacture of fruquintinib outside of China.

About Fruquintinib

Fruquintinib is a highly selective and potent oral inhibitor of VEGFR -1, -2 and -3. VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. Fruquintinib was designed to improve kinase selectivity with the intention of minimizing off-target toxicities, improving tolerability and providing more consistent target coverage. Fruquintinib has been generally well tolerated in patients to date and is being investigated in combinations with other anti-cancer therapies.

About FRESCO-2

The FRESCO-2 study is a multi-regional clinical trial conducted in the U.S., Europe, Japan and Australia investigating fruquintinib plus BSC vs placebo plus BSC in patients with previously treated metastatic CRC. As previously disclosed, the 691-patient study met its primary endpoint of OS in patients with metastatic CRC who had progressed on standard chemotherapy and relevant biologic agents and who had progressed on, or were intolerant to, TAS-102 and/or regorafenib. In addition to OS, a statistically significant improvement in PFS, a key secondary endpoint, was observed. Fruquintinib has been generally well tolerated in patients to date. Summary results were initially presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in September 2022.4 Additional details of the study may be found at clinicaltrials.gov, using identifier NCT04322539.

About CRC

CRC is a cancer that starts in either the colon or rectum. According to the International Agency for Research on Cancer, CRC is the third most prevalent cancer worldwide, associated with more than 935,000 deaths in 2020.5 In the U.S., it is estimated that 153,000 patients will be diagnosed with CRC and 53,000 deaths from the disease will occur in 2023.6 In Europe, CRC was the second most common cancer in 2020 with approximately 520,000 new cases and 245,000 deaths. In Japan, CRC was the most common cancer with an estimated 148,000 new cases and 60,000 deaths in 2020.5 Although early-stage CRC can be surgically resected, metastatic CRC remains an area of high unmet need with poor outcomes and limited treatment options. Some patients with metastatic CRC may benefit from personalized therapeutic strategies based on molecular characteristics; however, most patients have tumors that do not harbor actionable mutations.