On December 7, 2021 Daiichi Sankyo reported that New data from the TROPION-PanTumor01 phase 1 trial of datopotamab deruxtecan (Dato-DXd), a TROP2 directed DXd antibody drug conjugate (ADC) being developed by Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca (LSE/STO/Nasdaq: AZN), continue to show encouraging durable tumor response and disease control in patients with metastatic triple negative breast cancer (TNBC) with disease progression following standard treatment (Press release, Daiichi Sankyo, DEC 7, 2021, View Source [SID1234596575]). These data were featured during an oral presentation (GS1-05) at the 2021 San Antonio Breast Cancer Symposium (#SABCS21).

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TNBC accounts for approximately 10 to 15% of breast cancer cases and is associated with higher disease recurrence and worse prognosis compared to other breast cancer subtypes.1,2,3 It is estimated that only 12.2% of patients with metastatic TNBC survive five years and median overall survival is generally less than two years.2,3

An objective response rate (ORR) of 34% was observed in 15 of 44 patients treated with datopotamab deruxtecan (6 mg/kg [n=42] and 8 mg/kg [n=2]) as assessed by blinded independent central review. Fourteen confirmed complete/partial responses (CR/PRs) with one additional CR/PR awaiting confirmation and stable disease in 17 additional patients were reported after a median follow-up of 7.6 months (range, 4 – 13 months). Median duration of response (DOR) was not reached (range, 2.7 – 7.4+ months) with the majority ongoing at the data cut-off of July 30, 2021. A disease control rate (DCR) of 77% was observed.

In a subgroup of 27 patients with measurable disease and previously untreated with a topoisomerase I inhibitor-based ADC, an ORR of 52% was reported with datopotamab deruxtecan. Thirteen confirmed CR/PRs with one additional CR/PR awaiting confirmation and stable disease were reported in nine additional patients after a median follow-up of 8.8 months (range, 4 – 13 months). A DCR of 81% was observed in this subgroup of patients.

"Despite recent advances in the treatment of triple negative breast cancer, a significant need remains to improve patient outcomes, underscoring the importance of developing new and effective therapies," said Ian E. Krop, MD, PhD, Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana Farber Cancer Institute. "These preliminary results with datopotamab deruxtecan in pre-treated patients with metastatic triple negative breast cancer are very encouraging and further evaluation of this TROP2 directed ADC is warranted."

The overall safety profile of datopotamab deruxtecan in TNBC in TROPION-PanTumor01 was consistent with what has been previously reported with no new safety signals. Treatment emergent adverse events (TEAEs) occurring in ≥15% of patients included nausea, stomatitis, vomiting, fatigue, alopecia, mucosal inflammation, constipation, headache, decreased lymphocyte count, decreased neutrophil count, pyrexia, anemia, pruritis, hypokalemia, diarrhea and cough. Grade 3 or greater treatment-related TEAEs occurred in 23% of patients. No cases of interstitial lung disease (ILD) were observed.

"These updated results continue to show the promise of datopotamab deruxtecan as a durable treatment strategy for patients with previously treated triple negative breast cancer, a historically difficult-to-treat form of breast cancer," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "We are committed to further developing datopotamab deruxtecan and establishing where this specifically engineered TROP2 may be most effective in treating triple negative breast cancer."

"Patients with metastatic triple negative breast cancer face rapid disease progression with currently available treatment options and unmet need remains high for these patients," said Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. "Based on these encouraging results of datopotamab deruxtecan in the triple negative breast cancer cohort of TROPION-PanTumor01, plans are underway to initiate a registrational phase 3 study."

Patients were treated with a median of three prior therapies in the metastatic setting (range, 1-10), including taxanes (91%), platinum-based chemotherapy (52%), immunotherapy (43%), topoisomerase I inhibitor-based ADCs (30%; sacituzumab govitecan, n=10; trastuzumab deruxtecan, n=2; patritumab deruxtecan, n=1) and PARP inhibitors (16%). As of data cut-off on July 30, 2021, 30% of patients remained on treatment with datopotamab deruxtecan.

Summary of TROPION-PanTumor01 TNBC Results

Efficacy Measure

All TNBC Patients
(n=44)i,

Patients without Prior Topoisomerase I-Based ADC and with Measurable Disease
(n=27)ii

ORR, %

34% (n=15)

52% (n=14)

(CR/PR) (confirmed)

n=14

n=13

(CR/PR) (pending confirmation)

n=1iii

n=1iii

SD, %

39% (n=17)

33% (n=9)

PD, %

18% (n=8)

15% (n=4)

DCR, %

77% (n=34)

81% (n=22)

CR; complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease

i Includes response evaluable patients who had ≥1 postbaseline tumor assessment or discontinued treatment. Postbaseline tumor assessments were not yet available for 2 patients at the data cut-off. Three patients were not confirmed to have a target lesion per BICR and therefore had a best overall response of non-CR/non-PD.

ii Includes response evaluable patients who had ≥1 postbaseline tumor assessment or discontinued treatment. Postbaseline tumor assessments were not

yet available for 1 patient at the data cut-off.

iii Includes patients with an unconfirmed response but are ongoing treatment.

About TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicenter phase 1 trial evaluating the safety, tolerability and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumors refractory to or relapsed from standard treatment or for whom no standard treatment is available, including non-small cell lung cancer (NSCLC), TNBC, hormone receptor (HR) positive/HER2 negative breast cancer, small cell lung cancer, urothelial, gastric and esophageal cancer.

The dose escalation part of the study, which was limited to patients with NSCLC, assessed the safety and tolerability of increasing doses of datopotamab deruxtecan to determine the maximum tolerated dose and/or recommended dose for expansion. The dose expansion part of the study further assessed the safety and tolerability of datopotamab deruxtecan in patients with additional solid tumors. Based on the preliminary efficacy and safety profile, the 6 mg/kg dose has been chosen for further development.4,5

Safety endpoints include dose limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DCR, DOR, time to response, progression-free survival and overall survival. Pharmacokinetic, biomarker and immunogenicity endpoints also are being evaluated.

About Triple Negative Breast Cancer
Approximately 10 to 15% of breast cancers are considered triple negative, a breast cancer subtype that is defined by tumors that test negative for estrogen and progesterone hormone receptors (HRs) as well as human epidermal growth factor 2 receptor (HER2).1,2,6 An estimated 260,000 new cases of TNBC were reported globally in 2018 with it being more common in younger women and those who are Black.1,2,7 Compared to patients with other breast cancer subtypes, prognosis for patients with metastatic TNBC is generally worse and the disease is more likely to recur following treatment with initial chemotherapy.1,3 Five-year survival of metastatic TNBC is estimated at 12.2% and median overall survival is generally less than two years.2,3

About TROP2
TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein overexpressed in several types of solid tumors, including breast cancer.8 TROP2 overexpression has been detected in multiple breast cancer subtypes, including approximately 80% of patients with TNBC.9,10,11 High TROP2 expression is an unfavorable prognostic factor for overall survival in all types of breast cancer.12

About Datopotamab Deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of three lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG13 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker.13

A comprehensive development program called TROPION is underway globally with trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple solid tumors, including NSCLC, TNBC, HR positive/HER2 negative breast cancer, small cell lung cancer, urothelial, gastric and esophageal cancer. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of datopotamab deruxtecan.

About Daiichi Sankyo in Oncology
The oncology portfolio of Daiichi Sankyo is powered by our team of world-class scientists that push beyond traditional thinking to create transformative medicines for people with cancer. Anchored by our DXd antibody drug conjugate (ADC) technology, our research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in the U.S. We also work alongside leading academic and business collaborators to further advance the understanding of cancer as Daiichi Sankyo builds towards our ambitious goal of becoming a global leader in oncology by 2025.

On December 7, 2021 Legend Biotech Corporation (NASDAQ: LEGN), a global, clinical-stage biotechnology company developing and manufacturing novel therapies, reported the submission of a New Drug Application (NDA) to the Japanese Ministry of Health, Labour and Welfare (MHLW) for ciltacabtagene autoleucel (cilta-cel) by its collaboration partner, Janssen Pharmaceutical K.K. (Janssen) (Press release, Legend Biotech, DEC 7, 2021, View Source [SID1234596574]). Cilta-cel is an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy for the treatment of adults with relapsed or refractory multiple myeloma who have received at least three prior therapies, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 antibody.

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The submission is based on results from the Phase 1b/2 CARTITUDE-1 study conducted in the US and Japan, which evaluated the efficacy and safety of cilta-cel for patients with relapsed or refractory multiple myeloma.1 Cilta-cel is currently under regulatory review by several health authorities around the world, including the United States and Europe.

"Today’s submission is an encouraging step in our mission to provide a potentially transformative cell therapy option to patients with multiple myeloma," said Ying Huang, PhD, CEO and CFO of Legend Biotech. "We look forward to closely collaborating with our partner Janssen and the MHLW in order to make cilta-cel available to patients living with relapsed or refractory multiple myeloma, who have exhausted several standard-of-care treatments and are facing poor prognoses."

About Ciltacabtagene Autoleucel

Cilta-cel is an investigational chimeric antigen receptor T cell (CAR-T) therapy, formerly identified as JNJ-4528 in the U.S. and Europe and LCAR-B38M CAR-T cells in China, that is being studied in a comprehensive clinical development program for the treatment of patients with relapsed or refractory multiple myeloma and in earlier lines of treatment. The design consists of a structurally differentiated CAR-T with two BCMA-targeting single domain antibodies. In December 2017, Legend Biotech, Inc. entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel. In addition to a Breakthrough Therapy Designation (BTD) granted in the U.S. in December 2019, cilta-cel received a Priority Medicines (PRiME) designation from the European Commission in April 2019, and a BTD in China in August 2020. In addition, Orphan Drug Designation was granted for cilta-cel by the U.S. FDA in February 2019, and by the European Commission in February 2020. A Biologics License Application seeking approval of cilta-cel was submitted to the U.S. FDA and a Marketing Authorization Application was submitted to the European Medicines Agency.

About the CARTITUDE-1 Study

CARTITUDE-1 (NCT03548207) is a Phase 1b/2, open-label, multicenter study evaluating the safety and efficacy of cilta-cel in adults with relapsed or refractory with multiple myeloma who have received at least 3 prior lines of therapy or are double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), received a PI, an IMiD, and anti-CD38 antibody and documented disease progression within 12 months of starting the most recent therapy.1

About Multiple Myeloma

Multiple myeloma, an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.2 In Japan, there were more than 7,000 new cases of multiple myeloma and nearly 5,000 deaths.3 Although treatment may result in remission, most patients experience relapse.4 Relapsed myeloma is when the disease has returned after a period of initial, partial or complete remission and does not meet the definition of being refractory.5 Refractory multiple myeloma is when a patient’s disease is non-responsive or progresses within 60 days of their last therapy.6,7 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed by symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.8 Patients who relapse after treatment with standard therapies, including protease inhibitors and immunomodulatory agents, have poor prognoses and few treatment options available.9

On December 7, 2021 Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global, clinical-stage biotechnology company developing and manufacturing novel therapies, reported that it will host a hybrid event featuring key opinion leaders (KOLs) in multiple myeloma on Monday, December 13 at 8pm ET (Press release, Legend Biotech, DEC 7, 2021, View Source [SID1234596573]).

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The meeting will detail new and updated data from the CARTITUDE Clinical Development Program for ciltacabtagene autoleucel (cilta-cel). Cilta-cel is an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (CAR-T) therapy being studied for the treatment of patients with relapsed and/or refractory multiple myeloma. The meeting will follow the oral and poster presentations of the studies at the 63rd ASH (Free ASH Whitepaper) Annual Meeting & Exposition.

The event participants will include Ying Huang, PhD, CEO and CFO of Legend Biotech, and the following professionals in hematology and oncology:

Sundar Jagannath, MD, Professor of Medicine, Hematology and Medical Oncology, Mount Sinai School of Medicine; Director, Multiple Myeloma Program at Mount Sinai Hospital
Saad Usmani, MD, Professor of Medicine, Weill Cornell Medical College; Chief of Myeloma Service, Memorial Sloan Kettering Cancer Center of New York
This meeting will be available to investors and other interested parties by accessing the Legend Biotech website at Events and Presentations.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.1 Although treatment may result in remission, unfortunately, patients will most likely relapse.2 Relapsed myeloma is when the disease has returned after a period of initial, partial or complete remission and does not meet the definition of being refractory.3 Refractory multiple myeloma is when a patient’s disease is non-responsive or progresses within 60 days of their last therapy.4,5 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.6 Patients who relapse after treatment with standard therapies, including protease inhibitors and immunomodulatory agents, have poor prognoses and few treatment options available.7

About Cilta-cel
Cilta-cel is an investigational chimeric antigen receptor T cell (CAR-T) therapy, formerly identified as JNJ-4528 in the U.S. and Europe and LCAR-B38M CAR-T cells in China, that is being studied in a comprehensive clinical development program for the treatment of patients with relapsed or refractory multiple myeloma and in earlier lines of treatment. The design consists of a structurally differentiated CAR-T with two BCMA-targeting single domain antibodies. In December 2017, Legend Biotech, Inc. entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel. In addition to a Breakthrough Therapy Designation (BTD) granted in the U.S. in December 2019, cilta-cel received a Priority Medicines (PRiME) designation from the European Commission in April 2019, and a BTD in China in August 2020. In addition, Orphan Drug Designation was granted for cilta-cel by the U.S. FDA in February 2019, and by the European Commission in February 2020. A Biologics License Application seeking approval of cilta-cel was submitted to the U.S. FDA and a Marketing Authorization Application was submitted to the European Medicines Agency.

On December 7, 2021 Twist Bioscience Corporation (NASDAQ: TWST), a company enabling customers to succeed through its offering of synthetic DNA using its silicon platform, reported the launch of the Twist cfDNA Pan-cancer Reference Standards, a high-quality standardized control for use in the development and continuous monitoring of liquid biopsy tests to detect cancer from blood samples (Press release, Twist Bioscience, DEC 7, 2021, View Source [SID1234596571]).

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Liquid biopsy tests, which rely on NGS-based circulating tumor DNA (ctDNA) analysis, are a promising and growing area in clinical oncology. Liquid biopsy assays can accurately identify a single tumor variant in the presence of thousands of healthy cells. The most sought-after applications in the ctDNA field include early detection of disease, personalization of therapy, monitoring response to therapy, and monitoring for relapse of disease. Developing and standardizing these ultra-sensitive yet accurate ctDNA-based assays is paramount to ensure the resulting analysis from the test informs clinical decisions reliably.

"As the number of clinical validations of liquid biopsies increase, a true ctDNA pan-cancer reference standard, beyond the few variants that are widely available today, will increase liquid biopsies’ accuracy in detecting specific oncogenes and variants," said Florian Battke, director of development at CeGaT GmbH. "There is an obvious benefit of using a synthetic approach like the Twist ctDNA standards, as they are very high quality and closely mimic the properties of real samples without the instability."

The Twist cfDNA Pan-cancer Reference Standards material consists of synthetically designed variant sequences that mimic ctDNA combined with background DNA that is derived from, and closely mimics, human-derived cell-free DNA (cfDNA).

This reference standard can be used by researchers to assist in the development of liquid biopsy assays to establish the analytical limit of detection (LoD) for specific cancer variants and as a control to track the quality of an NGS assay workflow to ensure the fidelity of the assay process.

The Twist cfDNA Pan-cancer Reference Standards can be used within the liquid biopsy workflow, which includes Twist Library Preparation Kit and the Twist Mechanical Fragmentation Kit, for maximum efficacy and provides a large and diverse number of clinically relevant variants, combining best in class methods for variant synthesis with unrivaled control over the specific target allele frequencies in a format which closely mimics the size distribution and fragmentation profile of cfDNA. In contrast, traditional reference standards are limited in the number and variation of variants and typically use cell line-derived DNA which can carry unwanted sequence variations and variable fragment length.

Emily Leproust, CEO and co-founder of Twist Bioscience said, "Building on the success of our SARS-CoV-2 positive controls that are now used in COVID-19 tests worldwide, we believe having precise standard cancer reference controls that can be used in a validated workflow will be a gamechanger to confirm clinical insights from genetic information. While it is possible to create cell-based controls specific to each test, using a robust, precise control set that detects variation in test assays will be pivotal in both development and ongoing monitoring of a wide variety of liquid biopsy assays."

Applying the right reference materials is essential to benchmark the complexity and biological content of DNA found in liquid biopsy samples for assay development and validation. The Twist ctDNA reference material contains over 400 variants, including SNVs, indels, fusions and structural variants, as well as more than 140 clinically relevant variants. All variants are offered with a unique tiling design, which accurately mimics the pattern of naturally derived ctDNAs. All of these features make the Twist ctDNA reference a high-quality standard for the ctDNA variants that cancer liquid biopsy assays are designed to detect.

To demonstrate the limit of detection (LoD) of an ultra sensitive NGS-based liquid biopsy assay, using an accurately quantified ctDNA control is key. Twist’s silicon platform provides an advantage by specifically writing individual variants of interests, thus preventing any interference caused by contaminants derived from cell culture-based methods. Twist’s ctDNA reference material is also well-characterized and quantified, using industry-standard and proprietary methods (NGS, ddPCR, and fluorescence-based quantification).

On December 7, 2021 Xcovery Holdings, Inc., an oncology focused bio-pharmaceutical company, reported the acquisition of a majority and controlling stake in Meryx Inc., a clinical stage immuno-oncology company based in Chapel Hill, North Carolina developing TKIs in a range of hematologic and solid malignancies, including lung cancer (Press release, Xcovery, DEC 7, 2021, View Source [SID1234596570]). The partnership and synergies between Xcovery and Meryx will accelerate and enhance both Xcovery’s and Meryx’s missions to develop small molecule oncology drugs for patients all over the world. A new leadership and board of directors reflecting the new ownership will be established in the coming weeks.

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"We are thrilled to partner on a global level with Meryx, a firm with whom we already have an out-licensing collaboration in China," said Lieming Ding, M.D., Chairman of the Xcovery Board and Chairman of Betta Pharmaceuticals, a major Chinese pharma company. "Meryx has done a remarkable job of developing an innovative cutting-edge oncology pipeline. We are looking forward to building on this impressive track record and collaborating closely with its team to advance the clinical trials of these promising drug candidates."

"Xcovery is at a very exciting juncture in its history," stated Dr. Giovanni Selvaggi, Xcovery’s CEO and CMO. "We are well positioned to accelerate and further strengthen all Meryx’s ongoing R&D projects, both at clinical and pre-clinical level. Jointly with Meryx, and with the support of Betta, we are building a global company to benefit cancer patients worldwide through innovation and precision," added Dr Selvaggi.

Dr. Stephen Frye, Meryx’s CEO also stated, "Through the new collaboration with Xcovery and with our longstanding collaboration with Betta, Meryx will have the opportunity to advance our exciting clinical-stage and preclinical pipeline at a faster pace to improve cancer patients’ care."

Details of the transaction have not been disclosed.