On September 10, 2022, SpringWorks Therapeutics, Inc. ("SpringWorks" or the "Company") reported that data from the Phase 3 DeFi trial of nirogacestat, an investigational oral gamma secretase inhibitor, in adult patients with progressing desmoid tumors, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 (Presentation, SpringWorks Therapeutics, SEP 10, 2022, View Source [SID1234619433]).

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On September 10, 2022 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported the publication of data showing the best-in-class potential of ADG126, a masked, anti-CTLA-4 SAFEbody (Press release, Adagene, SEP 10, 2022, View Source [SID1234619402]). Interim results from the Phase 1 portion of an ongoing Phase 1b/2 trial of ADG126 are being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris, September 9 – 13, 2022.

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The poster, titled "Phase 1 Results Demonstrate Highly Differentiated Safety and PK Profile of ADG126, a Masked anti-CTLA-4 SAFEbody in Patients with Advanced Solid Tumors," reviewed data from the first-in-human, open label, phase 1 dose-escalation and dose expansion. The poster reports data on 26 patients with advanced metastatic solid tumors, the majority (58%) of whom received three or more lines of prior therapies and nearly half (42%) of whom progressed from prior immuno-oncology (IO) therapy.

Key findings include:

Safety: ADG126 monotherapy showed an unprecedented clinical safety profile at dosing levels up to 20 mg/kg when administered to this heavily pretreated patient population once every three weeks. ADG126 was well tolerated, with no dose-limiting toxicities or treatment-related Grade 3 or higher adverse events observed. The most frequent treatment related adverse events (TRAEs) (≥10%) were fatigue (12%), pruritis (12%), rash (12%) and diarrhea (12%). Dose escalation is completed at 20 mg/kg and dose expansion is ongoing at 10 mg/kg.

Antitumor Activity in Cold Tumors: With 18 cycles of treatment at 1 mg/kg, an ovarian cancer patient experienced significant, continued reduction of an established ovarian cancer biomarker, CA125, dropping 90% to within the normal range for full clinical benefit. As of cycle 16, the patient experienced a 22% decrease in target lesions. Previously, this patient had surgery and five prior lines of systemic therapies. At the data cut-off of August 17, 2022, the disease control rate was 39% (9/23 evaluable patients).

Pharmacokinetics: ADG126 plasma pharmacokinetics (PK) were approximately linear and activated ADG126 accumulated steadily during repeat dosing across different dose levels. This suggests prolonged exposures of activated ADG126 in the tumor microenvironment (TME), with cleaved ADG126 on average accumulating ≥3-fold during repeat dosing, resulting from an approximately 1.5-fold longer half-life of total ADG126 compared with its parental antibody.
"ADG126 continues to demonstrate a remarkable safety profile, highly differentiated from both the currently approved anti-CTLA-4 therapy and others in development, as well as antitumor activity in heavily pre-treated patients with cold tumors," said Dr. Gary Richardson, OAM, MBBS, FRACP, Group Director at Cabrini Health Research, Neil Beauglehall Endowed Chair, Medical Oncology Research, and Professor of Medicine at Monash University, Australia, said, "An intriguing case study of our poster is the experience of a patient with ovarian cancer, whose tumor reduced by 22 percent accompanied by normalization of an established clinical biomarker, CA125, dropping by tenfold after more than one year of treatment with ADG126 administered every three weeks at only 1 mg/kg. These data clearly demonstrate the monotherapy activity of this novel antibody, ADG126, supporting its ongoing evaluation as both monotherapy and in combination with anti-PD-1 agents."

Trials evaluating the combination of ADG126 and anti-PD-1 therapies are ongoing in patients with advanced, metastatic tumors in the US, China and Asia Pacific (APAC), evaluating optimized doses of ADG126 in targeted tumors.

ADG126 SAFEbody applies precision-masking technology to the parental anti-CTLA-4 antibody, ADG116, for conditional activation in the TME to expand the therapeutic index and further address safety concerns with existing CTLA-4 therapies. Binding to the same unique epitope as ADG116, the masked ADG126 is designed to provide enhanced safety and efficacy profiles due to the combination of the potent Treg depletion in the TME and partial ligand blocking by the activated ADG126, which is accumulated steadily for the prolonged tumor killing effect in TME.

On September 10, 2022 Eisai reported that results from a post-hoc analysis of three randomized, pivotal, Phase 3 studies (EMBRACE trial/Study 305, Study 301, and Study 304) evaluating the efficacy of eribulin mesylate (marketed as HALAVEN) versus other chemotherapies (Treatment of Physician’s Choice [TPC], capecitabine, and vinorelbine, respectively) in patients living with metastatic breast cancer (mBC) whose tumors have low or no HER2 expression. These data were presented as a poster (Presentation: #259P) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting (#ESMO22), held virtually and in-person in Paris, France from September 9-13, 2022 (Press release, Eisai, SEP 10, 2022, View Source [SID1234619385]).

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The HER2-low breast cancer subtype is a newly defined subset consisting of tumors that would have previously been considered HER2-negative based on an immunohistochemistry (IHC) assay and an in situ hybridization (ISH) assay. HER2-low tumors express low amounts of the HER2 protein, but not enough to be considered HER2-positive. HER2-low is defined as an IHC of 1+ or 2 with a negative ISH. Of the approximate 288,000 new cases of female breast cancer expected to be diagnosed in the U.S. in 2022, it is estimated that approximately 80-85% of patients would previously have been considered to have the HER2-negative subtype. Of those patients, about 60% would now be considered to have the HER2-low subtype.

"In this post-hoc analysis, the outcomes seen in mBC patients whose tumors are considered HER2-low are consistent with the results of the three pivotal Phase 3 clinical trials," said Dr. Takashi Owa, Chief Scientific Officer, Senior Vice President, Eisai Co., Ltd. "As the oncology community’s understanding of mBC continues to evolve, it’s important that we continue to evaluate the role of existing therapies in new contexts to contribute to the body of knowledge that is available to health care professionals."

Data from the Post-Hoc Analysis
The post-hoc analysis included data from three trials— eribulin vs. TPC (NCT00388726, EMBRACE trial/Study 305), eribulin vs. capecitabine (NCT00337103, Study 301), and eribulin vs. vinorelbine (NCT02225470, Study 304) in patients with locally recurrent or mBC who had prior lines of chemotherapy treatments (≤2 for Study 301; 2-5 for Study 304 and EMBRACE Trial/Study 305) including an anthracycline and a taxane. A total of 1,589 eligible patients were enrolled in the EMBRACE trial/Study 305, Study 301, and Study 304, and baseline characteristics were generally balanced between treatment arms in all studies.

Median overall survival (OS), median progression free survival (PFS) and objective response rate (ORR) were analyzed. PFS and ORR were measured per Response Evaluation Criteria in Solid Tumors Version (RECIST) (v1.0 for EMBRACE trial/Study 305 and Study 301; v1.1 for Study 304) by independent imaging review. ORR was measured in evaluable patients (EMBRACE trial/Study 305) and in the intent-to-treat population (Study 301 and Study 304).

In the post-hoc analysis, OS, PFS, and ORR among patients with HER2-low or HER2-negative status were generally similar to those of the eribulin treatment arms overall in each of the EMBRACE trial/Study 305, Study 301 and Study 304. Efficacy results for patients with HER2-low and HER2-negative status across all three studies are summarized in the table below:

*CI: Confidence Interval, HR: Hazard Ratio, NE: Not Evaluable

About Metastatic Breast Cancer
Metastatic breast cancer (mBC) is an advanced stage of the disease that occurs when cancer spreads beyond the breast to other parts of the body. It is estimated there were more than 2,261,000 new cases of breast cancer and more than 684,000 deaths from the disease globally in 2020. In 2022, it is estimated that approximately 288,000 women will be diagnosed with breast cancer in the United States and over 43,000 women will die from the disease. It is estimated that 30% of people with early-stage breast cancers will go on to develop metastatic disease, and approximately 6% of women with breast cancer will have metastatic disease at the time of diagnosis. Metastatic breast cancer has a poor prognosis compared to non-metastatic breast cancer. The estimated 5-year relative survival rate for women with mBC is 28%.

About HALAVEN (eribulin mesylate) Injection
HALAVEN (eribulin mesylate) Injection is indicated for the treatment of patients with metastatic breast cancer (mBC) who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Eribulin is a microtubule dynamics inhibitor in the halichondrin class with a novel mechanism of action, developed in-house by Eisai. Structurally, eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, non-clinical studies showed eribulin’s unique actions in the tumor microenvironment such as an increase in vascular perfusion and permeability in tumor cores, promotion of the epithelial state, decrease in capacity of breast cancer cells to migrate, etc.

Important Safety Information
Warnings and Precautions
Neutropenia: Severe neutropenia (ANC <500/mm3) lasting >1 week occurred in 12% of patients with mBC. Febrile neutropenia occurred in 5% of patients with mBC and 2 patients (0.4%) died from complications. Patients with mBC with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels. Monitor complete blood cell counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting >7 days.

Peripheral Neuropathy: Grade 3 peripheral neuropathy occurred in 8% of patients with mBC (Grade 4=0.4%) and 22% developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Neuropathy lasting >1 year occurred in 5% of patients with mBC. Patients should be monitored for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

Embryo-Fetal Toxicity: HALAVEN can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with HALAVEN and for 3.5 months following the final dose.

QT Prolongation: Monitor for prolonged QT intervals in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome.

Adverse Reactions
In patients with mBC receiving HALAVEN, the most common adverse reactions (≥25%) were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%). Febrile neutropenia (4%) and neutropenia (2%) were the most common serious adverse reactions. The most common adverse reaction resulting in discontinuation was peripheral neuropathy (5%).

Use in Specific Populations
Lactation: Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final dose.

Hepatic and Renal Impairment: A reduction in starting dose is recommended for patients with mild or moderate hepatic impairment and/or moderate or severe renal impairment.

For more information about HALAVEN, click here for the full Prescribing Information.
HALAVEN is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.

On September 10, 2022 CatalYm, reported that data from its first-in-human GDFather-1 trial (GDF-15-neutralizing antibody-mediated human effector cell relocation) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 held in Paris, France (Press release, Catalym, SEP 10, 2022, View Source [SID1234619379]). The clinical trial evaluated the GDF-15 neutralizing antibody visugromab (previously known as CTL-002), in combination with anti-PD-1 therapy nivolumab in advanced-stage solid tumor patients who had exhausted all previous lines of treatment and had relapsed on or were refractory to prior anti-PD-1/PD-L1 treatment. The data presented during today’s oral "Investigational Immunotherapy" session showed an excellent safety and tolerability profile as well as significant tumor regression at therapeutic doses and lasting response levels in a patient population with an otherwise poor prognosis.

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The presentation at ESMO (Free ESMO Whitepaper) by International Coordinating Investigator Prof. Dr. Ignacio Melero Bermejo, MD, Co-Director of Immunology and Immunotherapy (CIMA) at the Universidad de Navarra, Pamplona/Spain builds on the interim analyses announced in October and November of 2021. The current analysis reconfirms the excellent safety and tolerability profile with no dose-limiting toxicity observed and no grade 4 or 5 treatment emergent adverse events (TEAE). Pharmacokinetics and pharmacodynamic data indicated complete neutralization of GDF-15 with no signs for formation of anti-drug antibodies that could affect efficacy or safety. Furthermore, triple tumor biopsy analyses revealed a tumor-selective increase in CD8+ and CD4+ T cell infiltration following visugromab monotherapy treatment in the majority of patients investigated which continued under the addition of nivolumab. In addition, the majority of patients analyzed showed an increase in T cell proliferation and Granzyme B expression in the tumor microenvironment with both monotherapy and combination, reflective of the induction of an adaptive immune response.

"These mature Phase 1 trial data clearly demonstrate the significant clinical potential of visugromab in a highly refractory solid tumor patient population. Neutralizing GDF-15 in last-line tumor patients that also have failed prior anti-PD-1/PD-L1 therapy may offer a new and promising treatment regimen for patients that have exhausted all other options," said Prof. Dr. Eugen Leo, Chief Medical Officer at CatalYm. "The outcome of the pharmacodynamic and biomarker analyses is very promising as it not only provides a robust proof-of-mechanism for visugromab at this early stage of development, but also identified valuable biomarkers of interest that can support future responder-patient selection strategies."

Dr. Phil L’Huillier, Chief Executive Officer at CatalYm added: "Today’s results demonstrate the progress we have made in executing on our goal of providing novel treatment options by targeting GDF-15 to overcome the immunosuppression challenges seen in GDF-15 expressing tumors. I am grateful to the patients and clinicians participating in the trial and my colleagues at CatalYm, who enabled the delivery of our clinical phase 1 development program in solid tumor indications ahead of time. Following these excellent results that demonstrated active drug properties, we launched a broad multi-arm Phase 2 development program (GDFATHER-2) in early 2022 and anticipate sharing additional updates in the near future."

At data cut-off, 6 out of 18 patients on dose levels three to five (DL3-5) in combination with nivolumab experienced significant clinical benefit with overall tumor regression rates of 22% (for DL3-5) and 25% (for DL4-5) and several partial remission and long-term stable disease. Three out of the six patients (one with cancer of unknown primary origin, one with mesothelioma, one with hepatocellular cancer) achieved a confirmed partial response (PR): one continuing currently up to and beyond 12 months of treatment, together with a long-term stable disease patient. These data demonstrate an encouraging clinical benefit at higher dose levels in this highly refractory, last-line patient population. The PRs occurred in patients that were in fourth, fifth and seventh line of treatment.

In addition, potential predictive biomarkers were identified that may allow selection of optimal target population for visugromab treatment. When applying these biomarkers retrospectively (present in roughly 1/3 of all last-line patients investigated), a PR rate of up to 50% and a Clinical Benefit Rate > 65% would have been achieved. A confirmatory clinical exploration of these findings is in preparation.

Based on the promising results the company has already initiated the Phase 2 GDFATHER-2 study earlier this year. The on-going study includes different cohorts, representing several main tumor types of interest to further evaluate clinical efficacy as well as safety, pharmacokinetics, and pharmacodynamics including broad biomarker evaluations. The phase 2 program will enroll up to 162 patients at clinical trial sites in Spain, Switzerland and Germany. Early data readouts are expected to become available mid next year.

On September 10, 2022 Exai Bio, a next-generation liquid biopsy company, and researchers at UCSF reported that data from a new study in a poster entitled "Serum-based colorectal cancer detection using orphan noncoding RNAs" at the 2022 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) meeting (Press release, Exai Bio, SEP 10, 2022, View Source [SID1234619378]). This case-control study of 191 subjects demonstrated that Exai’s novel, RNA-based platform accurately predicted colorectal cancer (CRC) cases versus non-cancer controls, both overall and across the full ranges of cancer stages and categories of tumor size/extent.

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Exai Bio’s technology is based on using cell-free RNA sequencing to identify a novel class of cancer-associated small non-coding RNAs, termed orphan non-coding RNAs (oncRNAs). Exai has created a proprietary library of >250,000 oncRNAs found in several types of cancer. Because oncRNAs can be actively secreted by cancer cells, they are readily detectable in the blood of cancer patients and are largely absent in healthy individuals, making them potentially robust biomarkers with high sensitivity and specificity. These features give the Exai Bio RNA-based platform — which uses artificial intelligence (AI) to identify cancer-specific patterns among thousands of oncRNAs — several scientific and practical advantages over tests that use circulating tumor-derived DNA in mutational, epigenomic, or fragmentomic analyses.

In the present poster, the Exai oncRNA-based model, which used machine learning, predicted CRC with a high overall sensitivity of 90.6% at 90% specificity. Predictions were also accurate for stage I cancer (92% sensitivity) and for the lowest categories of tumor size/extent, T1/T2 (92.3% sensitivity), indicating that even the earliest stage cancers and smallest tumors were detectable. Exai Bio is thus positioned to improve patient care by developing a variety of liquid biopsy blood tests for CRC, including for early detection and monitoring of residual disease or recurrence.

Patrick Arensdorf, Chief Executive Officer of Exai Bio, commented, "We are truly excited about these findings. Exai Bio is working to fulfill unmet needs that exist despite recent advances in liquid biopsy testing. This work demonstrates that Exai Bio can measure novel biomarkers in blood-derived samples to accurately predict colorectal cancer, including the earliest-stage and smallest tumors. By achieving greater than 90% sensitivity at 90% specificity, we exceeded the sensitivity hurdle in the published CMS National Coverage Determination for blood-based biomarker tests in CRC screening1. Moreover, the oncRNA-based liquid biopsy technology will be compatible with standard sample requirements enabling easy integration into conventional clinical workflows. These results build on our earlier study in breast cancer and validate the applicability of cell-free RNA methods in yet another tumor type."

NCD for Colorectal Cancer Screening Test (210.3). Medicare Coverage Decision database: Screening for Colorectal Cancer biomarker-based test: CAG-00454N decision memo 01/19/2021; cms.gov.
Details of the ESMO (Free ESMO Whitepaper) 2022 eposter presentation:
Title: Serum-based colorectal cancer detection using orphan noncoding RNAs
Abstract category: Biomarkers (agnostic)
Abstract number: 4635
Authors: Hani Goodarzi, Jeffrey Wang, Oluwadamilare I. Afolabi, Lisa Fish, Helen Li, Kimberly H. Chau, Patrick Arensdorf, Fereydoun Hormozdiari, Babak Alipanahi

Posters will be available on-demand on the EMSO website for attendees (www.emso.org) beginning at 12:00 PM CEST on Friday, September 9, 2022 until Tuesday, September 13, 2022 Upon release at ESMO (Free ESMO Whitepaper), the poster will be accessible on the publications page of the Exai Bio website.