Importantly, the pharmacokinetic analysis in this study showed there was no significant difference between the serum concentration of T-DXd and that of the antibody itself; thus, low systemic exposure of DXd was observed. Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. 1Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 Japan, 2Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan, 3Department of Surgery, Osaka Prefectural General Medical Centre, 3-1-56 Bandaihigashi, Sumiyoshi-ku, Osaka, 558-8558 Japan, 4Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan, 5Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004 Japan, 6Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, Japan. Patritumab deruxtecan is comprised of a human anti-HER3 antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation. Currently, there are no dose adjustment recommendations for patients with mild or moderate hepatic impairment; however, the prescribing information for patients states that patients with moderate hepatic impairment should be closely monitored for increased toxicities related to DXd [29, 30]. Oncol Rev. The cells were washed twice with stain buffer and resuspended in secondary antibody, 10 g/mL Alexa Fluor 647 goat antihuman IgG in stain buffer, and incubated on ice for 1 hour under dark conditions. In addition, 2% to 13% of patients showed HER2 amplification at the time of acquired resistance to EGFR-TKIs, revealing HER-2directed ADCs as an appealing treatment option. J Natl Cancer Inst. Cell-growth inhibition activity of HER3-DXd, patritumab, and payload against MDA-MB-231 cells transduced with HER3WT, HER3 mutations, and HER3EV in the absence (A) or presence (B) of HER2 overexpression.a Mean SD. Telisotuzumab vedotin (ABBV-399) is an ADC composed of the antic-MET mAb (ABT-700) coupled with microtubule inhibitor (monomethyl auristatin E). This statement is stricter than those used in the DESTINY-Gastric01 trial [25]. Janjigian YY, Viglianti N, Liu F, Mendoza-Naranjo A, Croydon L. A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03). Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L, Helfrich B, et al. Finally, the effects of T-DXd treatment in patients without targeted lesions, patients with a poor Eastern Cooperative Oncology Group performance status (ECOG PS), and patients with peritoneal dissemination and severe ascites who were not included in previous clinical trials will become clear as real-world clinical data become available. Copyright 2022 by the American Association for Cancer Research. 1). Together, these findings in this monkey toxicology model may suggest a possible involvement of target independent T-DXd uptake by alveolar macrophages potentially followed by linker cleavage and release of free DXd. As previously mentioned, nausea and vomiting are commonly reported with T-DXd treatment (nausea any grade, 6378%; nausea grade3, 58%; vomiting any grade, 2646%; vomiting grade3, 04%) [25, 40], which highlights a need for effective management. In the SUMMIT study of the pan-HER TKI neratinib for patients with various types of solid tumors, neratinib had no antitumor activity in any of the 16 patients expressing mutated HER3 [21]. One cohort will include patients with HER3 high expression (IHC 3+ or 2+), and the second cohort will include patients with HER3 low/HER3 negative expression (IHC 1+ or 0). The tumor expression level of HER2 has been shown to have an impact on the efficacy of T-DXd. E Baba reports grants and personal fees from Taiho, Chugai, Astellas, Merck Biopharma, Daiichi Sankyo, Ono, Kyowa-Kirin, Eisai, Eli Lilly, MSD, Sanofi, Yakult, and Takeda. Kubo K, Azuma A, Kanazawa M, Kameda H, Kusumoto M, Genma A, et al. In: ASCO 2020 Gastrointestinal Cancers Symposium; 2223 January 2020; San Francisco, CA. Treatment-related Grade 3 TEAEs occurred in 24 patients (51.1%) and included neutropenia, fatigue, thrombocytopenia, hypokalemia, anemia, leukopenia and pneumonia. NDA/BLA multi-disciplinary review and evaluation (BLA 761139). [8] In 2020, there will be an estimated 147,950 new cases of colorectal cancer diagnosed in the U.S. and an estimated 53,200 deaths. ERBB2 is also overexpressed in subsets of patients with a variety of other cancers, including gastric, non-small cell lung, colon, bladder, and biliary cancers [1, 36]. Overall, these data suggest a key role for HER3 mutations in the development, progression, and immune escape of tumors, making them an important consideration for HER3 directed treatment strategies [3]. https://www.daiichisankyo.com, Phase 2 study to evaluate patritumab deruxtecan, a potential first-in-class HER3 directed antibody drug conjugate, in previously treated patients with HER3 expressing advanced/metastatic colorectal cancer, Initiation of third clinical study of patritumab deruxtecan demonstrates the commitment of Daiichi Sankyo to evaluate targeting of HER3 across a range of cancers including breast, non-small cell lung cancer and colorectal cancer, There currently are no approved HER3 directed therapies for any type of cancer. The level of lysosomal trafficking was also expressed as a trafficking index, calculated by multiplying the number of dots per cell by the delta dot signal intensity. A FLAG-negative cell line was used as a negative control. on. (2022) Patritumab deruxtecan (HER3-DXd), a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against breast cancer cells expressing HER3 mutations with and without HER2 overexpression. BNP brain natriuretic peptide; CMV cytomegalovirus; CRP c-reactive protein; CT computed tomography; DLCO diffusing capacity of the lung carbon monoxide; HRCT high resolution computed tomography; ILD interstitial lung disease, KL-6 Krebs von den Lungen-6; LDH lactate dehydrogenase; SP-D pulmonary surfactant protein-D; T-DXd trastuzumab deruxtecan. Kim, and J.B. Lee contributed equally to this article. The current Japanese treatment guidelines recommend T-DXd as third- or later-line treatment for previously treated HER2-positive [16]. Cell-surface binding of HER3-DXd in MDA-MB-231 cells transduced with HER3WT, HER3 mutations, or HER3EV in the absence (A) or presence (B) of HER2 overexpression. Median DOR was 5.9 months (95% CI: 3.0-8.4). Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that was in development for the treatment of cancer starting in 1994. Advanced breast and lung cancer are two of the leading causes of cancer-related death in the U.S. with five-year survival rates of 30% and 7%, respectively.1,2 New therapeutic approaches are needed to improve outcomes for these cancers and HER3 is a promising target for therapeutic development. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Bethesda, MD 20894, Web Policies The effects of 10 nM of HER3-DXd, patritumab, IgG-ADC (Daiichi Sankyo Co., Ltd.) [16], or DXd (MAAA-1181d) payload (Daiichi Sankyo Co., Ltd.) on the growth of the HER3 transfectants after 6 days of incubation were assessed in triplicate or more by measuring the amount of ATP using CellTiter-Glo (Promega Corporation, Madison, WI) luminescent cell viability assay, using EnVision multimode plate reader (PerkinElmer Inc.). This feature is particularly desirable when targeting tumors with heterogenous expression of the targeted antigen, as is the case for HER2-positive GC. At least one treatment-emergent adverse event (TEAE) was reported for all patients in both trials. Grade3 was 3.7% [38, 39]. Intriguingly, EGFR-directed ADCs have also been developed and tested in EGFR-mutated NSCLC progressed on standard treatment. The MFI of an unstained sample was used as background and subtracted from the result for each stained sample. Patritumab deruxtecan (U3-1402) is one of three lead DXd antibody drug conjugates (ADC) in the oncology pipeline of Daiichi Sankyo. Furthermore, the response was independent of baseline HER3 gene expression and HER3 protein levels, reported Aleix Prat, from the Hospital Clinic of Barcelona in . One confirmed complete response and 21 partial responses were observed. The overexpression of HER2 had little or no impact on the cell-surface binding of HER3-DXd to the various transduced cells (Fig 1), under the levels of HER2 overexpression as shown in S3 Fig. One potential strategy is prophylactic administration of antiemetic medications; however, the frequency at which this management strategy is used is unknown, and there are no data available outlining whether this strategy is preventative in patients treated with T-DXd. HHS Vulnerability Disclosure, Help Designed using Daiichi Sankyo's proprietary DXd ADC technology, patritumab deruxtecan is comprised of a human anti-HER3 antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based . Safety and efficacy have not been established. Trastuzumab deruxtecan (genetic recombination). The mechanism of action of ADCs is complex and may be payload-dependent or -independent; some ADCs can interfere with target function, dampen downstream signaling, and/or elicit antitumor immunity [15]. To address this, DXd was conjugated to cysteine residues on trastuzumab using an enzymatically cleavable peptide-based linker [24]. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. View source version on businesswire.com: https://www.businesswire.com/news/home/20220602005951/en/, Global/US: Sarah McGovernDaiichi Sankyo, Inc.smcgovern@dsi.com +1 908 992 6614 (office)+1 908 821 7376 (mobile)EU: Simone Jendsch-DoweDaiichi Sankyo Europe GmbHsimone.dowe@daiichi-sankyo.eu +49 (176) 11780822 (mobile)Japan: Masashi KawaseDaiichi Sankyo Co., Ltd.kawase.masashi.a2@daiichisankyo.co.jp +81 3 6225 1126 (office)Investor Relations Contact: DaiichiSankyoIR@daiichisankyo.co.jp, Cancer Stat Facts: Female Breast Cancer Subtypes, https://www.businesswire.com/news/home/20220602005951/en/, Covid Curbs Increased in China Factory Hub Guangzhou as Outbreak Balloons, Asian shares fall ahead of U.S. CPI, crypto worries mount, Oil falls for a fourth day as China COVID concerns grow, GLOBAL MARKETS-Asian shares fall ahead of U.S. CPI, crypto worries mount, JPMorgan Team Says Crypto Markets Face Cascade of Margin Calls. How to say Deruxtecan in English? Before Results from patients in exploratory cohorts in the DESTINY-Gastric01 trial who were confirmed to have HER2-low tumors (IHC 2+/ISH- [cohort 1] or IHC 1+[cohort 2]) demonstrated that T-DXd had some anti-tumor activity [53]. http://creativecommons.org/licenses/by/4.0/, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer, https://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4291452, https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric-adenocarcinomas, https://www.daiichisankyo.com/media/press_release/detail/index_4116.html, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/761139Orig1s000TOC.cfm, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf, https://www.pmda.go.jp/RMP/www/430574/d0b29598-fe09-4105-a18e-b5ae425a092e/430574_42914D0D1026_002RMP.pdf, https://www.pmda.go.jp/RMP/www/430574/d0b29598-fe09-4105-a18e-b5ae425a092e/430574_42914D0D1026_10_002RMPm.pdf, https://www.info.pmda.go.jp/go/pack/4291452D1029_1_02/, https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf, https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf, https://s3.amazonaws.com/files.oncologymeetings.org/prod/s3fs-public/2020-01/GI20-ESOPHAGEAL-AND-GASTRIC-CANCER.pdf?null, https://s3.amazonaws.com/files.oncologymeetings.org/prod/s3fs-public/2021-01/GI21-REV-ESOPHAGEAL-AND-GASTRIC-CANCER-1UP.pdf?null. 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