patritumab deruxtecan moa

1 The regulatory decision, which is designed to accelerate the . In the 23 of 57 patients with known EGFR-related resistance mechanisms (excluding T790M), the confirmed ORR was 35% (CR/PR, 8; SD, 7; PD, 5; NE, 3). Events included neutrophil count decrease, platelet count decrease, white blood cell count decrease, anemia, alanine aminotransferase increase, aspartate aminotransferase increase, decreased appetite, nausea, fatigue, diarrhea, malaise, stomatitis, and vomiting. Although the confirmed ORR was 43% (17/40) in these patients, the confirmed ORR was 68% (13/19) in patients with early clearance of ctDNA compared with 19% (4/21) in patients without early clearance. On the basis of these nonclinical data, a phase I, dose escalation/expansion study was initiated, and patients with locally advanced or metastatic NSCLC were enrolled (study U31402-A-U102; clinicaltrials.gov NCT03260491; EudraCT 2017-000543-41; JapicCTI 194868). Among the 36 patients in the dose escalation part, 5 patients experienced dose-limiting toxicities: 1 patient in the 5.6 mg/kg dose group experienced grade 3 febrile neutropenia and grade 4 platelet count decrease; 1 patient in the 4.8 mg/kg dose group experienced grade 3 neutrophil count decreased, grade 4 platelet count decrease, and white blood cell count decrease; and 3 patients in the 6.4 mg/kg dose group experienced grade 4 platelet count decrease. It was designed to bind to the receptor tyrosine-protein kinase ERBB3, which is a membrane-bound receptor protein. 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 Primary endpoints included AEs, serious AEs (SAE), and other safety assessments. tokyo & munich & basking ridge, n.j., june 03, 2022 -- ( business wire )--new data from daiichi sankyo's (tse: 4568) patritumab deruxtecan (her3-dxd) showed clinically meaningful and durable. Daiichi Sankyo. Blood samples were analyzed for ctDNA to validate findings from tumor tissue samples as part of these exploratory analyses. SAEs starting or worsening after 47 days, if reported as related to the study treatment, were also defined as TEAEs. aFatigue (two patients); decreased appetite, interstitial lung disease (ILD), neutrophil count decrease, pneumonitis, and upper respiratory tract infection (one patient each). 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 advanced or metastaticEGFR-mutated non-small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. U31402-A-U102 is a phase I, global, multicenter, dose escalation and dose expansion study evaluating HER3-DXd in patients with locally advanced or metastatic NSCLC, including patients with NSCLC harboring an EGFR-activating mutation and prior EGFR TKI therapy. Patients with HER2-positive MBC received a median of 5.5 (range, 2-11) prior therapies. This is a global, open-label, multiple-dose, two-part, phase I study conducted at 22 sites in the United States, Japan, Asia, and Europe (Supplementary Fig. S1). 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. An ADC using the same linker-payload technology but directed against HER2 [trastuzumab deruxtecan (T-DXd)] was recently approved for the treatment of HER2+ metastatic breast and gastric cancers (29, 30). End-of-treatment biopsies were optional; on-study biopsies were optional for all cohorts except for cohort 3. Analyses of HER3 membrane H-score and clearance of ctDNA were performed for the patients in dose escalation and dose expansion cohort 1 who received the HER3-DXd RDE (5.6 mg/kg, i.v. patritumab deruxtecan is an adc consisting of a fully human anti-her3 immunoglobulin g1 monoclonal antibody (patritumab) covalently linked to a topoisomerase i inhibitor payload (maaa-1181a, a derivative of exatecan; henceforth referred to as dxd) via a tetrapeptide-based cleavable linker, with a drug-to-antibody ratio of approximately 8. The safety profile was consistent with previous reports. Efficacy was shown across EGFR TKI resistance mechanisms. HER3 membrane expression was quantified using an IHC-based H-score (0300 scale). At ASCO 2021 Annual Meeting they presented extended follow-up of patients receiving the recommended dose for expansion of 5.6 mg/kg i.v. TEAEs were associated with death in 6% of patients (5/81), but none were judged by the investigator to be related to study treatment [disease progression, 2; respiratory failure, 2; and shock (infection induced), 1; Table 2]. Tumor response as assessed by BICR in patients treated with HER3-DXd at 5.6 mg/kg (n = 57). ), once every 3 weeks]: 3.2 mg/kg (n = 4), 4.8 mg/kg (n = 15), 5.6 mg/kg (n = 12), and 6.4 mg/kg (n = 5; Supplementary Fig. dTEAEs associated with death were respiratory failure and disease progression (two patients each) and shock (one patient). In the dose expansion part, HER3-DXd is being assessed in three cohorts: cohort 1, EGFR-mutated (G719X, Ex19del, L858R, or L861Q; other EGFR-activating mutations may be eligible following discussion with the sponsor) adenocarcinoma NSCLC treated with one or more prior EGFR TKIs and one or more prior platinum-based chemotherapy regimens; cohort 2, squamous or nonsquamous NSCLC without EGFR-activating mutations and with prior antiPD-1/PD-L1 therapy (unless unable or unwilling); and cohort 3: EGFR-mutated (G719X, Ex19del, L858R, or L861Q; other EGFR-activating mutations may be eligible following discussion with the sponsor) NSCLC, including any histology other than combined small cell and nonsmall cell with one or more prior EGFR TKIs and one or more prior platinum-based chemotherapy regimens. 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. HER3 is expressed in 83% of NSCLC tumours [1]. doi: 10.1371/journal.pone.0267027. H.A. The study team previously presented efficacy and safety data with a median follow-up of 5.4 month from this ongoing study. All responses were partial responses (PR). Because of the antigen specificity of HER3-DXd, we explored the association of HER3 expression in pretreatment tumor tissues with clinical response. 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 ). Secondary endpoints included ORR by investigator per RECIST 1.1, DCR, DOR, TTR, PFS by BICR and by investigator per RECIST 1.1, and OS. 2C; 35 of 57 patients were ongoing without events). 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). 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. The median DOR was 8.3 months (95% CI, 2.8-26.4), with a median PFS of 11.0 months (95% CI, 4.4-16.4) and median OS of 19.5 months (95% CI, 12.2-NE). An important area of future investigation is to understand the utility of alternative measures of HER3 expression, other biomarkers related to the expression of HER3 dimerization partners, and the dynamics of HER3 expression to predict clinical benefit in patients treated with HER3-DXd. 2022 May 3;17 (5):e0267027. 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). Third-generation EGFR TKIs, such as osimertinib, overcome some resistance mechanisms and have been shown to confer improved overall survival (OS) compared with first-generation EGFR TKIs (median OS, 38.6 vs. 31.8 months; ref. 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. In the 17 patients not evaluable for early clearance of ctDNA, responses were CR/PR, 29%; SD, 24%; PD, 17%; and NE, 35%. D.-W. Kim: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, methodology, writingoriginal draft, writingreview and editing, approval. There were 24 instances of amplification (including 10 instances of EGFR amplification) and 5 instances of fusion. aEarly clearance of ctDNA was defined as nondetectable plasma of both EGFR Ex19del and EGFR L858R at week 3 or week 6, where one or more allele comprising EGFR Ex19del or EGFR L858R was detectable at baseline. Early clearance of ctDNA was defined as non-detectable plasma of either EGFR Ex19del or EGFR L858R at week 3 or 6, where either mutation was detectable at baseline (evaluable in 40 of 57 patients). 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 The median time to the first documentation of objective response (CR or PR) was 2.6 (range, 1.25.4) months. Section 1734 solely to indicate this fact. At a median follow-up of 31.9 months (range, 15-56), the objective response rate (ORR) was 30.1% (95% CI, 21.8%-39.4%) in patients with HER3-high or HER3-low, HR-positive/HER2-negative MBC. Patients in the dose escalation part received 3.2 to 6.4 mg/kg HER3-DXd, i.v. In the dose escalation part, the recommended dose for expansion (RDE) of HER3-DXd was determined to be 5.6 mg/kg, i.v. Approximately 10% to 15% of patients with NSCLC in the United States and Europe and 30% to 40% of those in Asia have an EGFR-activating mutation (termed EGFR-mutated; ref. 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. Noncompartmental analysis was conducted using Phoenix WinNonlin (Version 8.1; Certara). For ctDNA analysis, a minor allelic frequency of 0.1% was used as a threshold for detection of mutations. HER3-DXd is in clinical evaluation for NSCLC, metastatic breast cancer, and colorectal cancer. Patritumab deruxtecan is a potential first-in-class HER3 directed antibody drug conjugate (ADC) discovered and being developed by Daiichi Sankyo. Prat explained that an initial analysis of the first 30patients enrolled in SOLTI TOT-HER3 demonstrated the biologic and clinical activity of HER3-DXd, a novel HER3-directed antibodydrug conjugate that comprises a human anti-HER3 monoclonal antibody linked to a topoisomerase I inhibitor. The most common grade 3 treatment-emergent adverse events were hematologic toxicities. However, in this study of HER3-DXd, the frequency of adjudicated treatment-related ILD was low (5%, 4/81), analogous to the incidences reported in trials of EGFR TKIs for patients with NSCLC (ILD rate, 0%5.7%; ref. The median duration of response (DOR) was 6.9 [95% CI, 3.1not evaluable (NE)] months. S6A and S6B). The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Patritumab. Assessment of EGFR-mutated (Ex19del and L858R) ctDNA by GeneStrat (Biodesix) was conducted from C1D1 to C5D1 for every cycle, at C7D1 and C9D1, and then on day 1 of every third cycle through end of treatment. J Clin Oncol 2021;39(suppl 15; abstr 9007). Median treatment duration was 5.5 month (range, 0.7-18.6 month). The antitumor activity of HER3-DXd was shown in multiple solid tumor murine xenograft models, including EGFR-mutated NSCLC patient-derived xenograft models with known resistance to EGFR TKI therapy (31). Designed using Daiichi Sankyo's proprietary DXd ADC technology, patritumab deruxtecan is comprised of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I. HER3-DXd has a mechanism of action that is distinct from mAb therapies; as an ADC, it is designed to produce antitumor activity through targeted delivery of its cytotoxic payload. 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 cleavable linker. Treatment was tolerable with manageable safety profile. In all patients in whom the allelic frequency of the EGFR-activating mutations Ex19del or L858R could be quantified in pretreatment ctDNA (where the minor variant frequency was >1%; 25 of 57 patients), reductions relative to baseline were observed (Fig. There appeared to be no correlation between HER3 membrane H-score in the tumor and the time between a patient's last EGFR TKI dose and their analyzed tumor biopsy specimen (Fig. 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. M. Nishio reports grants and personal fees from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, personal fees from Boehringer-Ingelheim, MSD, Novartis, Daiichi Sankyo, and Takeda Pharmaceutical Company Limited; personal fees from Merck Biopharma, TEIJIN PHARMA LIMITED., and personal fees from AbbVie, outside the submitted work; D.-W. Kim reports grants, nonfinancial support, and other support from Daiichi-Sankyo during the conduct of the study; grants and other support from Amgen; grants from Alpha Biopharma, AstraZeneca, Boehringer-Ingelheim, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang, Bridge BioTherapeutics, and grants from GSK outside the submitted work. Samples with analyte concentrations above the respective assay's upper limit of quantitation are diluted into each assay's quantitation range and analyzed. aMarkers show the time of the initial response for confirmed responses. J.C.-H. Yang reports grants, personal fees, and other support from AstraZeneca, personal fees and other support from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo; other support from Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis; personal fees from Ono Pharmaceuticals, Pfizer, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals; other support from JNJ, GlaxoSmithKline, and other support from Puma Biotechnology outside the submitted work. At a median follow-up of 10.2 months, median PFS was 8.2 (95% CI, 4.48.3) months (Fig. Salvage therapies after EGFR TKI and platinum-based chemotherapy have limited efficacy (median PFS, 2.83.2 months; median OS, 7.510.6 months; ref. Platinum-based chemotherapy following EGFR TKI failure has limited efficacy. No single TEAE was identified as a major cause of treatment discontinuation. The recent CHRYSALIS study combined the EGFRMET bispecific antibody amivantamab with the third-generation EGFR TKI lazertinib in patients with EGFR-mutated NSCLC: the ORR was 40% in patients with disease progression on platinum-based chemotherapy (14) and 36% in chemotherapy-nave patients with disease progression on osimertinib [median progression-free survival (PFS) was 4.9 months; ref. Most patients with EGFR-mutated NSCLC have tumors that express membrane HER3 and, because of the breadth of its expression, HER3 is an attractive molecular target for therapeutic intervention (19). Has limited efficacy PFS was 8.2 ( 95 % CI, 3.1not evaluable ( NE ]. By BICR in patients withEGFR-mutated NSCLC after failure of EGFR TKI failure limited. 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