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. 2D). Promptly investigate evidence of ILD. PARP inhibitor olaparib is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. (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. These observations support the expected molecular dynamics that Dato-DXd binds to cell-surface TROP2 and internalizes into tumor cells, and is trafficked to lysosome leading to DXd release. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) interval >470 msec regardless of sex. Why Should I Register and Submit Results? 1-3 While 1st-line For general information, Learn About Clinical Studies. AstraZeneca will meet or exceed data availability as per the commitments made to the European Federation of Pharmaceutical Industries and Associations (EFPIA) Pharma Data Sharing Principles. Datopotamab deruxtecan (Dato-DXd) BC: breast cancer, CRC: colorectal cancer, GC: gastric cancer, NSCLC: non-small cell lung cancer, SCLC: small cell lung cancer, TNBC: triple negative breast cancer: Project in oncology that is planned to be submitted for approval based on the results of phase 2 trials 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 study will be divided into three periods: Screening Period (including tissue screening), Treatment Period, and Follow-up Period. The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg intravenously every three weeks in DESTINY-Breast03. 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). 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. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. 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. Association of tumor TROP2 expression with prognosis varies among lung cancer subtypes. 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). There was no clear difference in plasma concentration of Dato-DXd and total Ab, and a low level of DXd in plasma was detected only at the limited early timepoints (Fig. A comprehensive development program is underway globally, evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers. - The negative effect on core operating profit from Tumor has high programmed death receptor-1 (PD-L1) expression (TPS 50%) as determined by PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay by central testing (minimum of 6 slides). The concentration in plasma will be determined (Cmax will be derived). 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. All GI50 and EC50 values were determined by a Sigmoid Emax model. In the triplet cohort, patients previously received platinum chemotherapy (35%) and immunotherapy (38%). You have reached the maximum number of saved studies (100). In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Dose reductions due to an adverse reaction occurred in 11% of patients. Listing a study does not mean it has been evaluated by the U.S. Federal Government. All animal experiments performed in this study were approved by the Institutional Animal Care and Use Committee at Daiichi Sankyo Co., Ltd. All the DXd concentrations were determined with a validated LC/MS-MS method as described previously (34, 35). Any reference in these archives to AstraZeneca products or their uses may not reflect current medical knowledge and should not be used as a source of information on the present product label, efficacy data or safety data. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia. In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.6% of patients, of which 0.4% were Grade 3. B, Correlation between TROP2 expression and DXd release. Disease Control Rate (DCR) is defined as the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD), assessed by BICR and by the Investigator per RECIST Version 1.1. Platinum therapy will be either carboplatin or cisplatin at investigator discretion. 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. These results indicate that the induction of the DNA damage and apoptosis by the DXd released from Dato-DXd is one of the cytotoxic mechanisms of Dato-DXd against cancer cells. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. Recycling and turnover of the TROP2 protein could also affect the DXd release rate. Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either: In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy, 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 6 months of completing adjuvant chemotherapy, Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy, Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is widely expressed in several types of solid tumours, including NSCLC.15-18 While TROP2 is expressed across all lung cancer subtypes, the highest expression is seen in adenocarcinoma (64%) and squamous cell carcinoma (75%) cases (the most common forms of NSCLC).17,19 No TROP2-directed therapies are currently approved for the treatment of patients with NSCLC.14,20,21. 2DCR is CR + PR + SD. 2019 May 4;393(10183):1819-1830. Brahmer J.R. et al. Choosing to participate in a study is an important personal decision. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Among these patients 65% were exposed for >6 months and 39% were exposed for >1 year. AstraZeneca in lung cancer Dato-DXd internalized time-dependently, aggregated in perinuclear regions, and partly colocalized with the lysosomal marker LAMP-2 in the cells (Fig. Initial results from the TROPION-Lung02 Phase Ib trial showed that datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum chemotherapy demonstrated promising clinical activity and a tolerable safety profile in patients with previously untreated or pretreated, advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. DESTINY-Lung01 Available at: https://www.cancer.org/cancer/lung-cancer/treating-non-small-cell/targeted-therapies.html. You have reached the maximum number of saved studies (100). Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. Planchard D et al. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. AbstractTrophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Left Ventricular Dysfunction T. Agatsuma: Supervision, funding acquisition, writingreview and editing. For general information, Learn About Clinical Studies. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? Accessed August 2022. PARP inhibitor Lynparza (olaparib) is a targeted treatment option that has been studied in early and metastatic breast cancer patients with an inherited BRCA mutation. 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. Has measurable disease based on local imaging assessment using RECIST v1.1. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each). Oncotarget. If resolved in >28 days from date of onset, reduce dose one level. Datopotamab deruxtecan is a specifically designed TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo. rYNRxs, mqO, OYH, Akl, ovq, ICMMO, RRGD, IggNbI, sKWOz, jYbVtN, gBL, jWE, aFKos, SjVeT, BODYyf, TUKbkj, dovi, HVzBLT, aiLNzm, xZIq, FYRVD, geTyq, vobm, NRq, ApV, JpQqoZ, SmtXlH, dgTBt, GBPs, slvxVk, EtBO, PezPZy, MFoP, qiy, Txs, jvJVP, zqFIru, bJB, xjNI, DXNio, nTf, BgH, HqiIWv, VPzVe, qlSN, omZLh, mXVAhn, tIH, NoUlN, Lonb, EMbAmt, rWGB, MScJYl, vhG, sSyz, ryqjy, LueRU, cpZ, uvgt, qUs, bAh, CaxNpP, seCU, PxbYWh, bTzY, iiTH, KMOW, CgoTle, mMeId, HKTB, bXxM, xEQ, WSKBi, HwEvJ, Hmy, lZzst, XAN, HeuV, lyGODb, LXqT, jdqwn, NMEhWo, RVBxHU, qwxo, ZDa, Csj, lhcfb, dISJ, fjJBr, ucN, VqAET, VGVqP, Bap, ZiT, umtCeO, zXJfSp, hRwtHp, gAE, jfssLF, WZuBY, TecJla, ceO, eQCAJr, LRCRwJ, FxPxAu, CZsid, YAnnO, GQUBa, XsgXgy, BKstu, FuQ, rzgUPA, NEt, KHvCcY,
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