Spearman rank correlation coefficients were calculated by comparing the amount of the released DXd and the cell-surface expression level of TROP2 in each cancer cell line. Liu L, et al. Promptly investigate evidence of ILD. The most common (20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%). The immunogenicity of Dato-DXd in combination with pembrolizumab will be assessed. Chen R, et al. U.S. Department of Health and Human Services. See Supplementary Materials and Methods for further information. Datopotamab deruxtecan is an antibody drug conjugate currently in development for multiple tumours that commonly express the cell-surface glycoprotein TROP2. Two dose levels of Dato-DXd (4.0 mg/kg and 6.0 mg/kg) will be studied in combination with fixed-dose durvalumab (1120mg), with or without 4 cycles of carboplatin in 4 study cohorts. 37). Dato-DXd induced the phosphorylation of H2AX, KAP1 and Chk1 and the cleavage of caspase 3 and PARP, respectively and time-dependently as well as DXd, but neither datopotamab nor control ADC induced these changes (Fig. We encourage you to read the privacy policy of every website you visit. 622TROPION-Lung01NSCLCDato-DXddatopotamab deruxtecanTROP2 In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF. 3C). Overall Survival (OS) is defined as the time from randomization to death due to any cause. By continuing to use our website, you are agreeing to, Cancer Epidemiology, Biomarkers & Prevention, Collection: Patient-Focused Therapies in Breast Cancer, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, https://doi.org/10.1158/1535-7163.MCT-21-0206, Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death, The bispecific tumor antigen-conditional 4-1BB x 5T4 agonist, ALG.APV-527, mediates strong T cell activation and potent anti-tumor activity in preclinical studies, Sustained Supratherapeutic Paclitaxel Delivery Enhances Irreversible Sarcoma Cell Death, Establishment and Evaluation of Dual HDAC/BET Inhibitors as Therapeutic Options for Germ Cell Tumors and Other Urological Malignancies, Cancer Epidemiology, Biomarkers, & Prevention, Intravenous, every 3 weeks for 3 months (five times in total), 5/sex/group (2-month recovery): 0 and 200 mg/kg, 2/sex/group (2-month recovery): 30 and 80 mg/kg, 200 mg/kg: decreased WBC, RET, NEU, and LYM, 200 mg/kg: decreased ALB and increased UN, 30 mg/kg: lung, cornea, skin, thymus, liver, 200 mg/kg: lung, skin, bone marrow, spleen, testis, epididymis, mammary gland, ovary, vagina. ENHERTU (5.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. 1B). (Clinical Trial), A Phase 1b, Multicenter, 2-Part, Open-Label Study of Datopotamab Deruxtecan (Data-DXd) in Combination With Durvalumab With or Without Carboplatin in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer (TROPION-Lung04), Experimental: Datopotamab deruxtecan (Dato-DXd), 18 Years and older (Adult, Older Adult), Contact: AstraZeneca Clinical Study Information Center, Santa Ana, California, United States, 92705, Saint Louis, Missouri, United States, 63110, Hackensack, New Jersey, United States, 07601, Philadelphia, Pennsylvania, United States, 19111. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. 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. Spira, A., Lisberg, A., Sands, J., Greenberg, J., Phillips, P., Guevara, F., Shimizu, T. (2021). 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. B, DAR distribution of Dato-DXd. Myocardial infarction within 6 months prior to randomization. 3F). Contacts Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. Malignancy treated with curative intent and with no known active disease 3 years before the first dose of study treatment and of low potential risk for recurrence. Condition or disease Intervention/treatment of Korea, Seoul St. Mary'S Hospital, Szczecin, Zachodniopomorskie, Poland, 70-784, Hospital Universitario Fundacion Jimenez Diaz, National Cheng Kung University Hospital Nckuh. Evaluate patients with suspected ILD by radiographic imaging. 2020;12:1758835920937902. patritumab deruxtecan; Treatment of lung cancer; MHRA-100385-PIP01-21: datopotamab deruxtecan; Treatment of breast cancer; Oncology; W: decision granting a waiver in all age groups for the listed condition(s). LVEF <50% by ECHO or MUGA scan within 28 days before randomization. Progression-free Survival 2 (PFS2) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed by local standard clinical practice. LVEF <50% by ECHO or MUGA scan within 28 days before randomization. 1C). Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. Studies a U.S. FDA-regulated Drug Product: Studies a U.S. FDA-regulated Device Product: Progression-free Survival Based on Blinded Independent Central Review in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization until disease progression or death (whichever occurs first), up to approximately 32 months], Overall Survival in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization until date of death due to any cause, up to approximately 53 months], Objective Response Rate by Blinded Independent Central Review in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization until disease progression or death (whichever occurs first), up to approximately 32 months], Progression-free Survival by Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization until disease progression or death (whichever occurs first), up to approximately 32 months], Progression-free Survival 2 in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization until disease progression or death (whichever occurs first), up to approximately 53 months], Objective Response Rate by Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization until disease progression or death (whichever occurs first), up to approximately 32 months], Duration of Response by BICR and Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From date of first objective response (CR or PR) to date of first radiographic disease progression or death due to any cause (whichever occurs first), up to approximately 32 months], Time to Response by BICR and Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization to date of first objective response (CR or PR), up to approximately 32 months], Disease Control Rate by BICR and Investigator in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization until disease progression or death (whichever occurs first), up to approximately 32 months], Time to Deterioration in Participants Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:From randomization until disease progression or death (whichever occurs first), up to approximately 53 months], Number of Participants With Treatment-emergent Adverse Events (TEAE) Who Were Administered Dato-DXd in Combination With Pembrolizumab Compared With Pembrolizumab [TimeFrame:Up to 53 months], Proportion of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) and Proportion of Participants Who Have Treatment-emergent ADA [TimeFrame:Baseline and up to 53 months]. NSCLC is diagnosed at an advanced stage in nearly 50% of patients and often has a poor prognosis with worsening outcomes after each line of subsequent therapy. Mok TSK, et al. To confirm the binding specificity of Dato-DXd, we assessed its binding activity to human TROP family proteins, EpCAM (TROP1) and TROP2, by ELISA. Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Area under the plasma concentration-time curve up to last quantifiable time (AUClast) and area under the plasma concentration-time curve during dosing interval (AUCtau) will be assessed. The AUC reflects the actual body exposure to drug after administration. Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Median time to first onset was 5 months (range: 0.9 to 23). Participants will be randomized to receive 200 mg pembrolizumab plus 500 mg/m^2 pemetrexed plus platinum chemotherapy (cisplatin 75 mg/m^2 or carboplatin area under the curve [AUC) 5]). One complete response (CR) was observed in each arm (5.4mg/kg: 1.9%, 6.4mg/kg: 3.6%), with 27 (51.9%) partial responses (PR) observed in the 5.4mg/kg arm and 11 (39.3%) PRs observed in the 6.4mg/kg arm. The Company's focus is on some of the most challenging cancers. Regulatory applications for ENHERTU in breast and gastric cancer are currently under review in several countries based on the DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Gastric01 and DESTINY-Gastric02 trials, respectively. - The negative effect on core operating profit from Datopotamab deruxtecan is a specifically designed TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo. CHO-K1 cells expressing human, cynomolgus monkey, rat and mouse TROP2 were incubated with Dato-DXd and binding activities were measured by cell-based ELISA. Febrile neutropenia was reported in 1.1% of patients. Please remove one or more studies before adding more. Datopotamab Deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Datopotamab deruxtecan is a specifically designed TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo. Eligible participants will be randomized in a 1:1 ratio to the control arm (pembrolizumab alone) or the experimental arm (Dato-DXd and pembrolizumab). ENHERTU is a HER2-directed ADC. Mol. 20. Results will be presented today as a late-breaking presentation at the European Society for Medical Oncology (ESMO) Congress 2022. J. Yamaguchi: Data curation, formal analysis, validation, investigation, methodology. 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). Histologically documented NSCLC that meets all of the following criteria: Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant setting: Uncontrolled or significant cardiovascular disease, including: 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. A TEAE is defined as an AE with a start or worsening date on or after the start date of study treatment until 37 days after the end date of study treatment. Is willing and able to participate in the collection of patient-reported outcomes (PRO) data. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. - The negative effect on core operating profit from foreign exchange was JPY1.4 billion in total. Overall Survival (OS) is defined as the time from randomization to death due to any cause. For general information, Learn About Clinical Studies. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Our exploratory evaluation revealed that TROP2-directed DXd-ADC with higher DAR (DAR 7) showed a narrower therapeutic window due to less tolerable safety profiles in cynomolgus monkeys compared with that with DAR of 4. So the study is not a true 2-arm study, it is a 2-part study. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. All the readings were normalized to the percentage of the value derived from control untreated wells and the GI50 values were calculated by a Sigmoid Emax model. Lung Cancer Survival Rates. Among these patients 65% were exposed for >6 months and 39% were exposed for >1 year. Each value represents the mean (red bar) and individual data (light blue; N = 3). Area under the curve is the integral of the concentration-time curve. Within each substudy, Dato-DXd will be evaluated as monotherapy (for all substudies except Substudy 2, (Gastric Cancer) and in combination with approved or novel anticancer agents that may be active in the tumour type being evaluated. AbstractTrophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. Neutropenia Centers for Disease Control and Prevention and National Cancer Institute. This study will be conducted sequentially and dose escalation will occur according to lower dose to higher dose in the same combination regimen (4.0 mg/kg to 6.0 mg/kg) and from 2-drug combination (Dato-DXd and durvalumab) to 3-drug combination regimen (Dato-DXd, durvalumab, and carboplatin). HER2m and HER2-overexpressing NSCLC In previously untreated patients, ORRs of 62% (eight of the 13 patients receiving doublet therapy) and 50% (10 of 20 patients receiving triplet therapy) were observed. AstraZeneca is also collaborating with Daiichi Sankyo to explore the potential of TROP2-directed ADC, datopotamab deruxtecan, in this setting. 3A). 3. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. The pharmacokinetic parameters were estimated by noncompartmental analysis with Phoenix WinNonlin (Ver. Sacituzumab govitecan has shown promising efficacy in patients with several types of TROP2-expressing cancers (2124) and in preclinical models (25). datopotamab deruxtecan TROPION-Breast01 - Phase III Close. 18. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3 C or a sustained temperature of 38 C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level. No disclosures were reported by the other authors. AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. The response seen in this trial, along with the disease control observed support ENHERTU as a potential treatment option in this type of non-small cell lung cancer., Cristian Massacesi, Chief Medical Officer & Oncology Chief Development Officer, AstraZeneca, said: The clinically meaningful activity, together with the favorable safety profile seen in the DESTINY-Lung02 trial helps establish the optimal dose of ENHERTU at 5.4 milligrams per kilogram in previously-treated HER2-mutant non-small cell lung cancer. Trastuzumab deruxtecan (ENHERTU, T-DXd, DS-8201), a novel HER2-directed ADC with this DXd-ADC technology, demonstrated potent antitumor activity with acceptable safety profiles in preclinical models and patients with HER2-positive cancers (2, 48). Each value represents the mean and SD (N = 3). C, Intracellular trafficking of Dato-DXd to lysosome. 1. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Choosing to participate in a study is an important personal decision. The percent drug release (%) was calculated as the ratio of the released DXd determined by LC/MS-MS to the hypothetical total DXd conjugated to Dato-DXd. 2020; 70(5): 287-294. Adib E, et al. On the other hand, DXd was accumulated in tumor after the administration of Dato-DXd (Fig. For Media contacts, clickhere. Thrombocytopenia Cancer Today. After overnight incubation, Dato-DXd, datopotamab, control ADC or DXd in the dilution range of 0.321,000 nmol/L was added to the designated well. Designed using Daiichi Sankyos proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZenecas ADC scientific platform. C, Binding specificity of Dato-DXd against human TROP family proteins. For any participant receiving an approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine, please follow the vaccine label and/or local guidance. Datopotamab deruxtecan (Dato-DXd) 2021 Jul;32(7):881-895. These results support the therapeutic potential of Dato-DXd against TROP2-expressing tumors including NSCLC. Each value represents the mean and SD of triplicates. WILMINGTON, Del.--(BUSINESS WIRE)--Detailed positive results from an interim analysis of the DESTINY-Lung02 Phase II trial showed ENHERTU (fam-trastuzumab deruxtecan-nxki) demonstrated clinically meaningful tumor responses in previously-treated patients with HER2-mutant (HER2m) unresectable and/or metastatic non-squamous non-small cell lung cancer (NSCLC). AstraZeneca and Daiichi Sankyos Enhertu (trastuzumab deruxtecan) has been 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 T. Toki: Conceptualization, writingreview and editing. 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. AstraZeneca and Daiichi Sankyos Enhertu (trastuzumab deruxtecan) has been 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 For details on how to contact the Investor Relations Team, please clickhere. Although there is a report that TROP2 expression is invariably upregulated in various tumor types regardless of the baseline expression level of TROP2 in their normal tissues (30) and the toxicologic sensitivity of ADCs depends on what payload is used, careful drug design is essential for TROP2-directed therapy to minimize the risk of possible on-target toxicity in TROP2-expressing normal tissues. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU. Any anti-programmed death receptor-1 (PD-1), anti-PD-L1, or anti-PD-ligand 2 (L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137). These results suggest that the DXd-ADC technology is widely applicable to various target antigens for cancer therapy. A disease control rate (DCR) of 84% was seen with both the doublet and triplet combination therapy in the overall population that comprised both 1st-line and 2nd-line settings. Received a live vaccine within 30 days prior to the first dose of study treatment. Immunotherapy for Advanced NonSmall Cell Lung Cancer: A Decade of Progress. US Media Mailbox: usmediateam@astrazeneca.com, Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg), Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg), Unresectable or Metastatic HER2-Mutant NSCLC (5.4 mg/kg), Internet Explorer presents a security risk. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. Zaman S, et al. Spira, A., Lisberg, A., Sands, J., Greenberg, J., Phillips, P., Guevara, F., Shimizu, T. (2021). Eight partial responses (PRs) were seen in patients receiving doublet therapy and 10 PRs (three pending confirmation) were seen in patients receiving triplet therapy. 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. Information provided by (Responsible Party): This study is designed to assess the efficacy and safety of datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab versus pembrolizumab alone in participants with advanced or metastatic non-small cell lung cancer (NSCLC). 4. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway. 2020 Oct;15(10):1657-1669. The primary objective of this study will assess the safety and tolerability of datopotamab deruxtecan (Dato-DXd) in combination with durvalumab with or without 4 cycles of carboplatin in participants with advanced or metastatic NSCLC who have either been previously treated or are treatment nave in a metastatic setting. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. In cohort 1a, a confirmed ORR of 34.1% (95% CI 20.1-50.6) was seen in patients receiving ENHERTU 5.4mg/kg, with a median PFS of 6.7 months (95% CI 4.2-8.4), and a median OS of 11.2 months (95% CI 8.4-NE). Devel Dynamics. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU. Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle (starting Datopotamab deruxtecan dose of 4.0 mg/kg), Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle (fixed dose 1120 mg Q3W), Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle (AUC 5). Listing a study does not mean it has been evaluated by the U.S. Federal Government. These results indicate that Dato-DXd is stable in plasma. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Structures and characteristics of Dato-DXd. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each). Progression-free Survival (PFS) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed by the Investigator per RECIST Version 1.1. You have reached the maximum number of saved studies (100). The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. T. Nakada: Resources, data curation, validation, investigation, methodology, writingreview and editing. 2020. WHO. Adequate bone marrow function within 7 days before randomization. Therefore, Dato-DXd can potentially have greater antitumor efficacy via TROP2-directed DXd delivery into tumor cells than conventional chemotherapy with irinotecan in a broad range of TROP2-expressing tumors. For users you are about to access AstraZeneca historic archive material CNS ) metastases and/or carcinomatous meningitis measurable disease on! 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