If available, results from local testing were included in the list of detected genomic alterations. Antibodydrug conjugates (ADC) are a class of cancer therapy in which antibodies specific for tumor-associated antigens are used to selectively target the delivery of cytotoxic drugs (22). Here, we report the safety, clinical activity, biomarker analyses, and pharmacokinetics of HER3-DXd in patients with advanced or metastatic EGFR-mutated NSCLC treated in this study. once every 3 weeks (n = 57), the median treatment duration was 5.5 months (range, 0.718.6 months)]. Methods Patients with HR-positive/HER2-negative disease received a median of 6 (range, 2-13) prior lines of therapy in the advanced setting. C. Yu: Conceptualization, resources, data curation, formal analysis, supervision, methodology, writingoriginal draft, writingreview and editing, approval. 2022 May 3;17 (5):e0267027. The risk or severity of adverse effects can be increased when Patritumab is combined with Aducanumab. In December 2021, the FDA granted patritumab deruxtecan a breakthrough therapy designation for the treatment of patients with metastatic or locally advanced NSCLC harboring an EGFR mutation,. S1). According to Ian E. Krop, MD, PhD, patritumab deruxtecan is responsible for producing clinically meaningful and durable antitumor activity in patients with HER3-expressing metastatic breast cancer, warranting further research. Jnne has a patent for EGFR mutations issued and licensed to LabCorp. The most commonly occurring genomic alterations were additional mutations in EGFR [61 instances, including T790M (28 instances) and C797X (12 instances)], mutations in PIK3CA (17 instances), and mutations in KRAS (7 instances). Those with metastatic TNBC received a median of 2 (range, 1-13) prior therapies. After disease progression on EGFR TKI therapy (which may include sequential EGFR TKIs), patients are commonly treated with chemotherapy or investigational genotype-directed therapies targeting an identified resistance mechanism (e.g., MET amplification), if known. There were 24 instances of amplification (including 10 instances of EGFR amplification) and 5 instances of fusion. Furthermore, the response was independent of baseline HER3 gene expression and HER3 protein levels, reported Aleix Prat, from the Hospital Clinic of Barcelona in . M. Koczywas: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, methodology, writingoriginal draft, writingreview and editing, approval. A pivotal, phase II study of HER3-DXd in patients withEGFR-mutated NSCLC after failure of EGFR TKI and platinum-based chemotherapy has been initiated. Patritumab Deruxtecan in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer. Patritumab deruxtecan (U3-1402, HER3-DXd) is a novel, investigational, HER3-directed ADC composed of a human immunoglobulin G1 mAb to HER3 (patritumab) covalently linked to a topoisomerase I inhibitor payload (MAAA-1181a, an exatecan derivative) via a tetrapeptide-based cleavable linker with a drug-to-antibody ratio of approximately 8 (2326). 22, 26). 15]. Section 1734 solely to indicate this fact. Pharmacokinetic (PK) parameters for released MAAA-1181a (the HER3-DXd payload) and MAAA-1181aconjugated antibody for the patients in dose escalation and dose expansion cohort 1 are summarized in Supplementary Table S6. Please enable JavaScript on your browser, so that you can use all features of this website. Two formulations were dosed in this study: frozen liquid drug product and lyophilized drug product. As other deruxtecan-based ADCs, high DAR (8) and membrane permeability, thus able to elicit a potent bystander effect, characterize it. H. Hayashi reports personal fees from Daiichi Sankyo Co., Ltd, AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Kyorin Pharmaceutical Co. Ltd, Merck Biopharma Co., Ltd., MSD K.K., Novartis Pharmaceuticals K.K., Ono Pharmaceutical Co. Ltd., Shanghai Haihe Biopharm, Taiho Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Company Limited; personal fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Pfizer Japan Inc., Shanghai Haihe Biopharm, Takeda Pharmaceutical Company Limited and Merck Biopharma Co., Ltd.; and grants from AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Ono Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., grants, Pfizer Japan Inc., Bristol Myers Squibb Company, Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Serono Co., Ltd./Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Limited, AbbVie Inc, inVentiv Health Japan, ICON Japan K.K., GRITSONE ONCOLOGY, INC, PAREXEL International Corp., Kissei Pharmaceutical Co., Ltd., EPS Corp., Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc./IQVIA Services JAPAN K.K., EP-CRSU CO., LTD., Linical Co., Ltd., Eisai Co., Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co., Ltd, Bayer Yakuhin, Ltd., EPS International Co., Ltd.; grants from Daiichi Sankyo Co., Ltd during the conduct of the study; and grants from Otsuka Pharmaceutical Co., Ltd., outside the submitted work. Improve clinical decision support with information on. Among patients with prior platinum-based chemotherapy, ORR was 37% (19 of 52 patients; 95% CI 23.6%-51.0%). 8 - 11 P.A. Colorectal Cancer Pipeline constitutes 125+ key companies continuously working towards developing 150+ Colorectal Cancer treatment therapies, analyzes DelveInsight DelveInsight's 'Colorectal . The risk or severity of adverse effects can be increased when Adalimumab is combined with Patritumab. Jnne: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, methodology, writingoriginal draft, writingreview and editing, approval. Beyond radiographic and clinical measures of antitumor activity, this study also demonstrated an increased response rate and prolonged PFS in the subset of patients who achieved early clearance of ctDNA; this has been observed previously for a broad range of therapies, including EGFR TKIs and immune checkpoint inhibitors (3436). H. Murakami reports grants and personal fees from Daiichi Sankyo during the conduct of the study; AstraZeneca, Chugai Pharma, Takeda; grants from AbbVie and IQVIA; personal fees from Ono Pharmaceutical, Bristol-Myers Squibb Japan, MSD, Pfizer, Novartis, Eli Lilly Japan, and personal fees from Taiho Pharmaceutical outside the submitted work. HER3-DXd is in clinical evaluation for NSCLC, metastatic breast cancer, and colorectal cancer. Patritumab deruxtecan (HER3-DXd) is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. ESMO Call to Action on COVID-19 Vaccinations and Patients with Cancer: Vaccinate. Median follow-up was 10.2 month (range, 5.2-19.9 month). Y. Qiu: Conceptualization, resources, data curation, formal analysis, supervision, methodology, writingoriginal draft, writingreview and editing, approval. All funding for this site is provided directly by ESMO. Patritumab deruxtecan is comprised of a fully human anti-ERBB3 (HER3) immunoglobulin G1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Although the analysis of ctDNA is an investigational approach to monitor tumor dynamics and response to therapy, the clinical utility of these data at the current time has not yet been determined. HER3 is ubiquitously expressed in EGFR-mutant non-small cell lung cancer (NSCLC) irrespective of resistant mechanisms to EGFR tyrosine kinase inhibitors, thus garnering attention as a valuable therapeutic target. 37). TOKYO & MUNICH & BASKING RIDGE, N.J., June 03, 2022--Patritumab Deruxtecan Continues to Show Promising Clinical Activity in Patients Across Subtypes of Metastatic Breast or Lung Cancer No patient discontinued study treatment due to thrombocytopenia; when it occurred, the onset of grade 3 thrombocytopenia was typically early during study treatment (median time to first onset, 8 days) and was transient (median duration, 8 days). This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated nonsmall cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. For the dose expansion part, the primary objective was to assess the antitumor activity of HER3-DXd. There were 3 (1.6%) incidents of grade 3 ILD and 1 (0.5%) grade 5 event, but most ILDs were mild. News release. 17). In patients with prior osimertinib and platinum-based chemotherapy, ORR was 39% (17 of 44 patients; 95% CI 24.4%-54.5%). Patritumab Patritumab ( INN) is a human monoclonal antibody designed for the treatment of cancer. Furthermore, the response was independent of baseline HER3 gene expression and HER3 protein levels, reported Aleix Prat, from the Hospital Clinic of Barcelona in Spain, at the ESMO Breast Cancer Congress 2022 in Berlin, Germany. Investigators obtained written informed consent from all patients prior to study participation. The TOT-HER3 trial is now enrolling patients with early-stage triple-negative breast cancer and also exploring a lower dose of HER3-DXd, and another trial SOLTI-VALENTINE will test HER3-DXd alone or in combination with endocrine therapy as neoadjuvant treatment in HR+/HER2 early disease, Prat concluded. Treatment was discontinued due to TEAEs in 9% of patients (7/81), and no patient discontinued study treatment due to thrombocytopenia. In these patients, EGFR-targeted tyrosine kinase inhibitors (TKI) result in high response rates [objective response rate (ORR), 76%80%; ref. K.A. In the dose escalation part, HER3-DXd was assessed in patients with metastatic or unresectable EGFR-mutated NSCLC who had acquired resistance to EGFR TKI (per Jackman criteria; ref. C, KaplanMeier plot of overall survival probability. HER3-DXd is an antibodydrug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. Several studies have reported successful treatment (response rates, 30%47%) of patients with MET amplification as an EGFR TKI resistance mechanism with a combination of an EGFR TKI and MET TKI (12, 13). Accessed June 4, 2022. https://bit.ly/3mvZgUi, 4. To sign up for ESMO newsletters,create a myESMO account hereand select the newsletters youd like to receive. Exploratory objectives included identification of biomarkers that correlate with HER3-DXd activity. August 8, 2022 - 8:00 am. The median progression-free survival (PFS) was 7.4 months (95% CI, 4.7-8.4) and the median overall survival (OS) was 14.6 months (95% CI, 11.3-19.5). The median treatment duration was 5.9 months (range, 0.7-30.6). Investigators conducted a pooled analysis of patients with HER3-high or HER3-low, HR-positive/HER2-negative MBC (n = 113); HER3-high TNBC (n = 53); or HER3-high, HER2-positive MBC (n = 14). In the dose escalation part, the recommended dose for expansion (RDE) of HER3-DXd was determined to be 5.6 mg/kg, i.v. trastuzumab deruxtecan is indicated for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (when cancer cells spread to other parts of the body) her2-positive breast cancer who have received two or more prior anti-her2-based regimens in the metastatic setting and for adults with locally advanced or patritumab deruxtecan is also under investigation in the pivotal phase 2 herthena-lung01 trial (nct04619004) in patients with locally advanced or metastatic egfr -mutated nsclc previously. once every 3 weeks (Table 3). It is comprised of 3 components: an anti-HER3 monoclonal antibody, patritumab, that is linked (connected) to a chemotherapy (topoisomerase I inhibitor0 payload, and an exatecan derivative, through a tetrapeptide-based cleavable linker. Patients with stable brain metastases were allowed. Generic Name Patritumab DrugBank Accession Number DB12090 Background Patritumab has been used in trials studying the treatment of LUNG CANCER, Solid Tumors, Neoplasms by Site, Head and Neck Neoplasms, and Non-small Cell Lung Cancer, among others. Treatment was ongoing in 18 patients (32%). Stable brain metastases were allowed. At data cut-off of 24 September 2020, 57 patients were treated with HER3-DXd at recommended dose of 5.6 mg/kg i.v. Exploratory objectives included the identification of biomarkers that correlate with HER3-DXd activity. Blood samples were analyzed for ctDNA to validate findings from tumor tissue samples as part of these exploratory analyses. Grade 3 TEAEs occurred in 64% of patients (52/81), with the most common (10%) being thrombocytopenia (26%, 21/81; grade 4, 13.6%, 11/81; grade 5, 0), neutropenia (15%, 12/81; grade 4, 9.9%, 8/81; grade 5, 0), and fatigue (10%, 8/81; Table 2). In total, 47% had a history of brain metastases. Via Ginevra 4, 6900 Lugano - CH Copyright 2022 European Society for Medical Oncology All rights reserved worldwide. Patritumab, also known as AMG 888 and U3-1287 Linker Peptide cleavable linker. In the other case, treatment continued because PD was determined by BICR but not by the local investigator (the study treatment discontinuation criteria were based on local tumor assessment). medwireNews: One dose of patritumab deruxtecan (HER3-DXd) induces a clinically meaningful response in women with hormone receptor-positive, HER2-negative (HR+, HER2) early breast cancer, show data from the SOLTI TOT-HER3 trial. In addition, analysis is ongoing into identifying markers beyond HER3 expression, including internalization, drug processing, and DNA damage repair, using patient samples from this study. Investigators defined HER3 high as 75% or greater membrane positivity and HER3 low as 25% to 74% membrane positivity. EGFR-mutated NSCLC is associated with higher expression of HER3 compared with EGFR wild-type NSCLC (20). Among the 7 of 57 patients with atypical EGFR-activating mutations (G719X, L861Q, and Ex19ins), the BORs were one CR and three PRs (confirmed); one patient had SD, and two were not evaluable for response. In terms of safety, the presenter said that the adverse event (AE) profile was consistent with that previously reported for the drug. The majority (95%) of patients experienced an AE of any grade and 14% experienced a grade 3 or worse AE, most commonly neutropenia (8%). aDCR = rate of confirmed BOR of CR, PR, or SD. Genomic alterations known to be associated with EGFR TKI resistance were identified in 78% of patients [62/80; identified in assays of tumor tissue or circulating tumor DNA (ctDNA) in blood collected prior to treatment with HER3-DXd for 80 of 81 patients or identified by local testing as captured by electronic case report forms]. ORR was 22.6% (95% CI, 12.3%-36.2%) in patients with HER3-high metastatic TNBC. The study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation consolidated Guideline E6 for Good Clinical Practice, and applicable local regulatory requirements. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. 1 The regulatory decision, which is designed to accelerate the . The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences. once every 3 weeks. Patients in the dose escalation part received 3.2 to 6.4 mg/kg HER3-DXd, i.v. Among 44 patients in the study who received prior osimertinib (Tagrisso) and platinum-based chemotherapy, the confirmed ORR was 39% (95% CI, 24%-55%), with a DCR of 68% (95% CI, 52%-81%) and a median PFS of 8.2 months (95% CI, 4.0NE). Antitumour activity was observed across a wide range of baseline HER3 expression. HER3-DXd is an antibody drug conjugate consisting of a fully human monoclonal antibody to HER3 attached to a topoisomerase I inhibitor payload via a . The risk or severity of adverse effects can be increased when Alirocumab is combined with Patritumab. In addition, most first-line osimertinib-resistant lung cancers do not harbor an obvious, currently targetable genomic mechanism of resistance (11). 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 PLoS One. The method for measuring the released payload MAAA-1181a was a liquid chromatographymass spectrometry assay in human serum with a quantitation range of 10 to 2,000 pg/mL. 4B]. This site uses cookies. H.A. The absence of an interaction does not necessarily mean no interactions exist. 4); however, relapse is typical with the development of resistance to EGFR TKI treatment (57). aMarkers show the time of the initial response for confirmed responses. Both the MTD and the RDE were determined to be 5.6 mg/kg. C. Baik: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, methodology, writingoriginal draft, writingreview and editing, approval. Treatment-related ILDs occurred in 5% of patients (4/81; Table 2). Confirmed responses occurred at a similar frequency among the subgroups of patients who had received EGFR TKI and platinum-based chemotherapy prior to study entry (n = 52; Supplementary Table S3; Supplementary Fig. The study was approved by the institutional review board or ethics committee for each site. SoD, sum of diameters. cTEAEs associated with death were respiratory failure (two patients) and disease progression and shock (one patient each). Patritumab deruxtecan (HER3-DXd, U3-1402) is a novel, investigational HER3 directed ADC that includes 3 key components: a fully human anti-HER3 immunoglobulin G1 (IgG1) mAb (patritumab), covalently linked to a topoisomerase I inhibitor payload (an exatecan derivative) via a tetrapeptide-based cleavable linker ( S2 Fig ). 3B). cBOR, Confirmed BOR. Distribution of the time-to-event endpoints was estimated using the KaplanMeier method. Jnne reports grants and personal fees from Daiichi Sankyo during the conduct of the study; grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Takeda; personal fees from Pfizer, Roche/Genentech, Chugai, LOXO Oncology, SFJ Pharmaceuticals, Voronoi, Biocartis, Novartis, Sanofi, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Allorion Therapeutics, Accutar Biotech, AbbVie; grants from Astellas, PUMA, and grants from Revolution Medicines outside the submitted work; in addition, P.A. Interstitial lung disease (ILD) has been identified as an important risk in previous studies of T-DXd, which is also an ADC with a DXd-based topoisomerase I payload (29). patritumab deruxtecan (her3-dxd), an antibody drug conjugate consisting of a fully human monoclonal antibody to her3 attached to a topoisomerase i inhibitor payload via a tetrapeptide-based cleavable linker, achieved clinically meaningful, durable efficacy in a phase i dose escalation and dose expansion study conducted in patients with locally Safety outcomes for each dose group are shown in Supplementary Table S2. Drug created at October 20, 2016 21:19 / Updated at February 21, 2021 18:53. The protocol specified analysis included all part I and part II patients ( n = 184) treated with trastuzumab deruxtecan at dose of 5.4 mg/kg.
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