Talk with your doctor and family members or friends about deciding to join a study. ENHERTU (5.4mg/kg) is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial. deruxtecan Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or durvalumab, and carboplatin for participants to be enrolled in relevant cohorts. Representative images for pretreatment tumor, tumors treated with Dato-DXd on days 1, 3, and 7, and tumors treated with control ADC or datopotamab on day 1 were also shown. Okajima, D. et al. The human lung cancer cell line COR-L23 was purchased from the European Collection of Authenticated Cell Cultures. Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication. Triple negative breast cancer: Pitfalls and progress S2A). Objective Response Rate (ORR) is defined as the proportion of participants who achieved a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), assessed by the Investigator per RECIST Version 1.1. The most common Grade 3 or higher TEAEs occurring in greater than 10% of patients were neutropenia (11.9% (5.4mg/kg), 34.0% (6.4mg/kg)), anemia (8.9% (5.4mg/kg), 14.0% (6.4mg/kg)) and leukopenia (2.0% (5.4mg/kg), 14.0% (6.4mg/kg)). Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. Devel Dynamics. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or pembrolizumab. For more information about the trial, visit ClinicalTrials.gov. 2021 Sept 16 20; Abstract LBA51. Oncotarget. Pipeline Warnings and Precautions Stock Market | FinancialContent Business Page To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Datopotamab Deruxtecan Each value represents the mean and SE (N = 6), and statistically significant difference compared with the vehicle control analyzed by Dunnett multiple comparison test (*, P < 0.01). Is not a candidate for surgical resection or chemoradiation with curative intent. AstraZeneca provides this link as a service to website visitors. mainly due to increased R&D investment in 3ADCs (trastuzumab deruxtecan, datopotamab deruxtecan: Dato-DXd/DS-1062 and patritumab deruxtecan: HER3- DXd/U3-1402). Camizestrant significantly improved progression-free survival vs Datopotamab is a human IgG1 mAb (Supplementary Fig. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Has left ventricular ejection fraction (LVEF) 50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before randomization. Has received prior systemic treatment for advanced or metastatic NSCLC. Has an adequate treatment washout period before Cycle 1 Day 1. Substudy 1 (Endometrial Cancer); MONO: Dato-DXd monotherapy COMBO; Dato-DXd + durvalumab, Dato-DXd + AZD5305, Dato-DXd + durvalumab +AZD5305, Substudy 2 (Gastric Cancer); Dato-DXd + capecitabine, Dato-DXd + 5-fluorouracil (5-FU), Dato-DXd + chemotherapy (capecitabine or 5-FU) + nivolumab, Substudy 3 (mCRPC); MONO and Dato-DXd + AZD5305, Substudy 4 (Ovarian Cancer); MONO and Dato-DXd + carboplatin, Dato-DXd + AZD5305, Substudy 5 (CRC); MONO and Dato-DXd + 5-FU + leucovorin (LV) + bevacizumab or Dato-DXd + capecitabine + bevacizumab. A Phase II, Multicentre, Open-label, Master Protocol to Evaluate the Efficacy and Safety of Datopotamab Deruxtecan (Dato-DXd) as Monotherapy and in Combination With Anticancer Agents in Patients With Advanced/Metastatic Solid Tumours (TROPION-PanTumor03) Actual Study Start Date : September 6, 2022: Estimated Primary Completion Date : May 2, 2025 IASLC 2021 WCLC World Conference on Lung Cancer | Denver These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. Among these patients 65% were exposed for >6 months and 39% were exposed for >1 year. These variation in the internalization and release of DXd might be due to the difference in the factors related to intracellular trafficking pathways such as clathlin- or caveolin-mediated endocytosis, or lysosomal enzyme activities (40). Objective Response Rate (ORR) is defined as the proportion of participants who achieved a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), assessed by BICR per RECIST Version 1.1. D. Okajima: Conceptualization, data curation, formal analysis, validation, investigation, visualization, methodology, writingoriginal draft, project administration, writingreview and editing. Has provided a formalin-fixed tumor tissue sample for the measurement of trophoblast cell surface protein 2 (TROP2) protein expression and for the assessment of other exploratory biomarkers. Cells were seeded in 96-well microplates at 2,000 cells per well. While these therapies may improve survival, at least 40 to 60% of tumours do not respond to initial treatment and disease progression occurs, underscoring the need for new therapeutic approaches and options.11-14, TROP2in NSCLC After mounting, the cells with the mounting media containing DAPI (Thermo Fisher Scientific), fluorescent images were acquired by sequential scanning of excitations at 405/488/555 nm and emissions at 410-485/493-555/560-635 nm using confocal microscope TCS-SP8 STED 3X (Leica Microsystems). In cohort 1, a confirmed ORR of 26.5% (95% CI 15.0-41.1) was seen in patients receiving ENHERTU 6.4mg/kg, with a median progression-free survival (PFS) of 5.7 months (95% CI 2.8-7.2) and a median OS of 12.4 months (95% CI 7.8-17.2). Subgroup analyses of patients with or without a presence of baseline asymptomatic brain metastases showed that treatment with ENHERTU resulted in a median PFS of 7.1 months (95% CI 5.5-9.8) and 9.7 months (95% CI 4.5-16.9) respectively, and a median OS of 14.0 months (95% CI: 9.8-19.5) and 27.0 months (95% CI: 15.3-NE), respectively. Dato-DXd significantly inhibited the growth of TROP2-high tumors in Calu-3 model (TROP2 H-score 145) with TGI of 85% (P < 0.001), NCI-H2170 model (TROP2 H-score 115) with TGI of 95% (P < 0.001), HCC827 model (TROP2 H-score 220) with TGI of 90% (P < 0.001), and EBC-1 model (TROP2 H-score 133) with TGI of 100% (P < 0.001), but did not inhibit the growth of TROP2-low tumors in LK-2 model (TROP2 H-score 20) and Calu-6 model (TROP2 H-score 0; Fig. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting. Enhertu approved in the US as the first HER2-directed therapy for Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target and occur in approximately 2-4% of patients with this type of lung cancer.4,5, While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7, Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2-directed therapies in NSCLC prior to the accelerated US approval of ENHERTU in unresectable or metastatic HER2m NSCLC.7,8 Next-generation sequencing has been utilized in the identification of HER2 (ERBB2) mutations.9, HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poorer prognosis.10 It has been reported in approximately 10-15% of patients with NSCLC, with an incidence as high as 30% in those with adenocarcinoma (a subtype of cancer that grows in the glands that line the insides of organs).11-14. 6.3, Certara). International Agency of Cancer Research. Accordingly, Dato-DXd was well tolerated in rats and monkeys following the repeated administration corresponding to the clinical regimen, and the nonclinical safety profile warranted clinical investigation. Dato-DXd was intravenously administered to cynomolgus monkeys at the dose of 6 mg/kg and the concentrations of Dato-DXd, total antibody and DXd in plasma were determined. Secondary endpoints include confirmed disease control rate (DCR), DoR and PFS assessed by investigator and BICR, investigator-assessed OS and safety. The study will be divided into 4 periods: Tissue Screening Period, Screening Period, Treatment Period, and Follow-up Period. 2A). AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting. Has active, known, or suspected autoimmune disease. Embryo-Fetal Toxicity Has received prior systemic treatment for advanced/metastatic NSCLC. U.S. Department of Health and Human Services. Monotherapy and in Combination With We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in Patients were randomized 2:1 to receive ENHERTU 5.4mg/kg (n=102) or ENHERTU 6.4mg/kg (n=50).The primary endpoint of the trial is confirmed ORR as assessed by BICR. Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg) Spira, A., Lisberg, A., Sands, J., Greenberg, J., Phillips, P., Guevara, F., Shimizu, T. (2021). Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Wu Y-L et al. The Company's focus is on some of the most challenging cancers. Trop2: From Development to Disease. EnhertuHER2 Documentation of radiological disease progression while on or after receiving the most recent treatment regimen, if any, for advanced or metastatic NSCLC. The best percentage change from baseline in tumour size will be derived as the maximum reduction from baseline or (in the absence of reduction) the minimum increase from baseline. You are about to access AstraZeneca historic archive material. - The negative effect on core operating profit from The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Bartley A et al. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway. Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I. Dato-DXd bound to human TROP2, but no binding was detected to human EpCAM (Fig. This study has a modular design, as such a master protocol with independent substudies enables simultaneous evaluation of the safety profile, recommended Phase II dose (RP2D), and efficacy of Dato-DXd in multiple disease populations and treatment combinations. The lower limit of quantitation (LLOQ) was 0.100 ng/mL. Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. Eight partial responses (PRs) were seen in patients receiving doublet therapy and 10 PRs (three pending confirmation) were seen in patients receiving triplet therapy. A Study of Dato-DXd Versus Investigator's Choice Chemotherapy Partnering 2017; 26(144): 170007. Has known human immunodeficiency virus (HIV) infection that is not well controlled. Paz-Ares L, et al. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting. Mechanism: TROP2 ADC Area under investigation:2-3L HR+ HER2- breast cancer Date commenced phase: Q4 2021 First Estimated Filing Acceptance: Country Date >2023: Additional information:Partnered product. The Daiichi Sankyo group is actively engaged in various measures and initiatives such as, but not limited to, contributing to vaccination and drug research and development, ensuring a continuous supply of Daiichi Sankyo group company products, and providing disaster relief support. Three deaths occurred (two within the doublet cohort, one in the triplet cohort), none of which were determined as drug-related. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. The antitumor activity was evaluated approximately 3 weeks after the administration, where tumor growth inhibition (TGI, %) was calculated according to the formula of 100 [1 (average tumor volume of the treatment group)/(average tumor volume of the vehicle control group)], and tumor volumes were compared between the vehicle control group and the treatment groups. Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU (a HER2-directed ADC) in March 2019 and datopotamab deruxtecan (a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. AstraZeneca is not responsible for the privacy policy of any third party websites. ABS buffer containing 10 mmol/L acetate buffer (pH 5.5) and 5% sorbitol was used for the vehicle control group and the diluent of the test substances. Choosing to participate in a study is an important personal decision. Please visit astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS. Dato-DXd internalized time-dependently, aggregated in perinuclear regions, and partly colocalized with the lysosomal marker LAMP-2 in the cells (Fig. 1. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. Variation in Targetable Genomic Alterations in Non-Small Cell Lung Cancer by Genetic Ancestry, Sex, Smoking History, And Histology. ENHERTU Granted Priority Review in the U.S. for Patients with Control ADC was synthesized in the same manner as Dato-DXd using a matched isotype control mAb with a comparable DAR. of Korea, Seoul St. Mary'S Hospital, Szczecin, Zachodniopomorskie, Poland, 70-784, Hospital Universitario Fundacion Jimenez Diaz, National Cheng Kung University Hospital Nckuh. Active, known, or suspected autoimmune disease (has an active autoimmune disease that has required systemic treatment in the past 2 years). The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue. Study of Dato-DXd Plus Pembrolizumab vs Pembrolizumab Alone Condition or disease Intervention/treatment To confirm the binding specificity of Dato-DXd, we assessed its binding activity to human TROP family proteins, EpCAM (TROP1) and TROP2, by ELISA. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >470 msec regardless of sex (based on the average of the 12-lead electrocardiogram determination at screening). Recombinant proteins were incubated with Dato-DXd or isotype control ADC (control ADC) and binding activities were measured by ELISA. Safety profiles were also assessed in rats and cynomolgus monkeys. Pipeline Liu L, et al. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Duration of Response (DoR) is defined as the time from the date of the first documentation of objective response (confirmed CR or confirmed PR) to the date of the first radiographic disease progression or death due to any cause, whichever occurs first, assessed by BICR and by the Investigator per RECIST Version 1.1. Median time to first onset was 5 months (range: 0.9 to 23). Daiichi Sankyo Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialisedatopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Datopotamab deruxtecan is a specifically designed TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo. Daisuke Okajima, Satoru Yasuda, Takanori Maejima, Tsuyoshi Karibe, Ken Sakurai, Tetsuo Aida, Tadashi Toki, Junko Yamaguchi, Michiko Kitamura, Reiko Kamei, Tomomichi Fujitani, Tomoyo Honda, Tomoko Shibutani, Sumie Muramatsu, Takashi Nakada, Riki Goto, Shu Takahashi, Miki Yamaguchi, Hirofumi Hamada, Yutaka Noguchi, Masato Murakami, Yuki Abe, Toshinori Agatsuma; Datopotamab Deruxtecan, a Novel TROP2-directed Antibodydrug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells. 1B). After overnight culture, the cells were treated with 100 nmol/L Dato-DXd and the culture media was collected after 24 hours incubation and DXd concentration was determined. 18. History of another primary malignancy, (beyond NSCLC) except for: To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Plasma concentration of Dato-DXd, total Ab, and DXd (B), and tumor concentration of DXd (C) in NCI-N87 xenograft mice treated with Dato-DXd. This study will evaluate various solid tumour types, including endometrial cancer (Substudy 1), gastric cancer (Substudy 2), metastatic castration-resistant prostate cancer (mCRPC) (Substudy 3), ovarian cancer (Substudy 4), and colorectal cancer (CRC) (Substudy 5) in the advanced or metastatic setting. Datopotamab Deruxtecan (Dato-DXd) in Combination With Durvalumab With or Without Carboplatin in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer (TROPION-Lung04) The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Datopotamab deruxtecan The terminal elimination half-life (T1/2) of Dato-DXd at 6 mg/kg in cynomolgus monkeys was 45.12 13.92 hours to be compared with the T1/2 of sacituzumab govitecan in human at 8 and 10 mg/kg that were 14.4 3.3 and 11.7 3.3 hours, respectively. Antibodydrug conjugate (ADC) is an antibody conjugated with cytotoxic drugs via a chemical linker. However, its half-life in patients is approximately 1115 hours in plasma, and accordingly, frequent dosing is required and the most commonly observed side effects are neutropenia and diarrhea which are similar to irinotecan (26). 1A). Similar toxicity signals were reported in preclinical studies of PF-06664178 using cynomolgus monkeys (29). It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. This advantage in potentially less hematotoxicity might allow the opportunity of the possible combination therapy of Dato-DXd. Enhertu approved in the US as the first HER2-directed therapy for In summary, we generated Dato-DXd, a novel TROP2-directed ADC with DXd-ADC technology, and demonstrated its potent antitumor activity and acceptable safety profiles in preclinical models. Area under the curve is the integral of the concentration-time curve. Results will be presented today as a late-breaking presentation at the European Society for Medical Oncology (ESMO) Congress 2022. Mechanism: TROP2 ADC Area under investigation:1L metastatic NSCLC without Actionable Genomic Alterations and PD-L1 TPS 50% Date commenced phase: Q1 2022 Estimated filing: Country Date >2023: Additional information:Partnered product. D, Species cross-reactivity of Dato-DXd. The Past, Present, and Future of HER2 (ERBB2) in Cancer: Approaches to Molecular Testing and an Evolving Role in Targeted Therapy. When the tumor volume reached approximately 150300 mm3, the tumor-bearing mice were assigned to the vehicle control group, the treatment groups and the satellite sampling groups, and Dato-DXd or other test substances were administered intravenously once on day 0. Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition).
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