Data for dose expansion cohort 2 (squamous or nonsquamous NSCLC without EGFR-activating mutations) and cohort 3 (squamous or nonsquamous EGFR-mutated NSCLC with any histology other than combined small cell and nonsmall cell; uptitration study) will be presented in the future. This article is highlighted in the In This Issue feature, p. 1. 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. Again, all responders had PR. Safety and efficacy data for each dose group in the dose escalation part are presented in Supplementary Tables S1 to S3. Early clearance of ctDNA was defined as nondetectable plasma of both EGFR Ex19del and EGFR L858R at week 3 or week 6, where at least one of either EGFR Ex19del or EGFR L858R was detectable at baseline. B, Pretreatment HER3 membrane H-score and association with time since last treatment with EGFR TKI. 17). Among 43 patients evaluable for HER3 expression, nearly all expressed HER3; median membrane H-score by immunohistochemistry was 180 (range, 2-280). Among patients with prior platinum-based chemotherapy, ORR was 37% (19 of 52 patients; 95% CI 23.6%-51.0%). Accessed June 4, 2022. https://bit.ly/3mvZgUi, 4. 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). once every 3 weeks) population are shown with the times of first responses in Fig. For the dose expansion part, the primary objective was to assess the antitumor activity of HER3-DXd. Fifty-three percent of enrolled patients (43/81) had a history of stable central nervous system (CNS) metastases, and 19% of patients (15/81) had received prior treatment for CNS metastases (Table 1). Two patients continued study treatment following radiographic disease progression. Copyright 2022 by the American Association for Cancer Research. Although median PFS in all 40 patients evaluable for early clearance of ctDNA was 8.2 (95% CI, 4.48.3) months, median PFS was longer in patients with early clearance of ctDNA versus those without [8.3 (95% CI, 5.4NE) months vs. 4.4 (95% CI, 1.48.3) months; HR, 0.33; 95% CI, 0.130.81; Fig. Antitumour activity was observed across a wide range of baseline HER3 expression. once every 3 weeks and that no dose adjustment is warranted between frozen liquid and lyophilized powder formulations of HER3-DXd. Safety analyses were performed on the basis of the safety analysis set, which included all patients who were enrolled in the dose escalation part and dose expansion part in cohort 1 and received at least one dose of HER3-DXd (n = 81). HER3 is expressed in 83% of NSCLC tumours. 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. All cases of adjudicated treatment-related ILD resolved after drug discontinuation. Overall, Ki67 expression decreased by a significant 9.0 percentage points from baseline to the end of treatment but there was no change in the level of HER3 mRNA. Disease control rate was 72% (95% CI 58.5%-83.0%). medwireNews is an independent medical news service provided by Springer Healthcare Ltd. 2022 Springer Healthcare Ltd, part of the Springer Nature Group, ESMO Breast Cancer Congress 2022; Berlin, Germany: 35 May, with trial summaries, expert opinion and congress coverage. 3C and D. Confirmed responses were seen across a wide range of baseline tumor HER3 membrane H-scores, but there was a trend toward enrichment of confirmed responses in patients with higher baseline H-scores. 29; T-DXd is approved in the United States with boxed warnings for ILD and embryofetal toxicity), and surveillance and early management are important in the treatment of patients with this class of therapy (Supplementary Table S5). These characteristics will be further explored in this study (cohort 3; Supplementary Fig. Platinum-based chemotherapy following EGFR TKI failure has limited efficacy. C and D, Pretreatment HER3 membrane H-score and confirmed BOR (cBOR). 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. Sixteen patients in the dose escalation part had prior EGFR TKI (including osimertinib) but had not received prior platinum-based chemotherapy; in these patients, the confirmed ORR was 63% (95% CI, 35.484.8), and median PFS was 7.6 (95% CI, 5.413.7) months. The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Patritumab. Treatment-related grade 3 or higher TEAEs occurred in 120 patients (65.9%). 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. once every 3 weeks) population, demonstrated that tumor HER3 expression was observed in all patients; the median H-score was 180 (range, 2280; Fig. Median PFS was 8.2 month (95% CI 4.4-8.3 month). Exploratory endpoints included correlation of biomarkers (e.g., ctDNA, HER3 IHC) with clinical activity of HER3-DXd. Patients had a median of 4 (range, 19) prior lines of systemic therapy for locally advanced or metastatic NSCLC (Table 1). In the combined dose escalation and dose expansion parts, a total of 81 patients received one or more doses of HER3-DXd and were included in the safety analysis. Pretreatment HER3 membrane expression and association with BOR. ORR was 22.6% (95% CI, 12.3%-36.2%) in patients with HER3-high metastatic TNBC. fPatients with multiple EGFR-activating mutations are listed in more than one row. Clinical activity was observed across a broad range of HER3 membrane expression. Listing a study does not mean it has been evaluated by the U.S. Federal Government. This site uses cookies. ESMO Breast 2022 | Patritumab deruxtecan active in HR+, HER2 early breast cancer | medwirenews.com. once every 3 weeks on day 1 of each cycle of a 21-day cycle. HER3 membrane expression was quantified using an IHC-based H-score (0300 scale). The method for measuring MAAA-1181aconjugated antibody was an ELISA in human serum with a quantitation range of 100 to 4,000 ng/mL. Salvage therapies after EGFR TKI and platinum-based chemotherapy have not been effective. 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. Krop IE, Masuda N, Mukohara T, et al. 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. 4C). June 3, 2022. 37). Patients with HR-positive/HER2-negative disease received a median of 6 (range, 2-13) prior lines of therapy in the advanced setting. Investigators obtained written informed consent from all patients prior to study participation. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism. 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). 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B, KaplanMeier plot of progression-free survival probability. H. Murakami: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, methodology, writingoriginal draft, writingreview and editing, approval. Patritumab deruxtecan is comprised of a human anti-HER3 antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker. The PK assay methods for measuring MAAA-1181aconjugated antibody and the released payload MAAA-1181a were developed and validated at PPD Laboratories. S6A and S6B). New results for Tagrisso and Imfinzi continue to validate our strategy to treat patients earlier, as we progress the science of identifying patients most . Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant,EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). 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. C. Yu: Conceptualization, resources, data curation, formal analysis, supervision, methodology, writingoriginal draft, writingreview and editing, approval. The study was approved by the institutional review board or ethics committee for each site. S1). The lyophilized drug product (used in dose expansion cohort 1) was 100 mg HER3-DXd in lyophilized powder dosage form in a single-use vial to be reconstituted with 5 mL of water for injection to 20 mg/mL. Demographics, baseline characteristics, and prior therapies. Gold reports personal fees from AstraZeneca, Takeda, and Rakuten; grants from Pharmacyclics, grants from Daiichi Sankyo during the conduct of the study, and grants from Pfizer outside the submitted work. Methods 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 ). SAEs starting or worsening after 47 days, if reported as related to the study treatment, were also defined as TEAEs. 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. 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]. Drug/Payload Deruxtecan, DX-8951 derivative (DXd, topoisomerase I inhibitor), a camptothecin derivative On an average of 8 cysteinyl Clinical Trials 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,. In the 21 of 57 patients with other/unknown resistance mechanisms, the confirmed ORR was 38% (CR/PR, 8; SD, 8; PD, 2; NE, 3). M.L. 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. 2C; 35 of 57 patients were ongoing without events). DOI: 10.1200/JCO.2021.39.15_suppl.9007. once every 3 weeks. 2022 May 3;17 (5):e0267027. C. Yu reports personal fees and other support from Daiichi Sankyo, Inc. during the conduct of the study; other support from Daiichi Sankyo, Inc. outside the submitted work. HER3 alterations are not known to be a mechanism of resistance to EGFR TKI in EGFR-mutated NSCLC. [3] It is to be included in a new arm of the I-SPY 2 breast cancer trial. Results from U31402-A-U102, a phase I dose escalation and dose expansion study, show that patritumab deruxtecan has durable efficacy in patients with non-small cell lung cancer, regardless of EGFR tyrosine kinase inhibitor resistance mechanisms. An independent adjudication committee determined that 12 patients (6.6%) developed treatment-related interstitial lung disease (ILD) or pneumonitis. Easily compare up to 40 drugs with our drug interaction checker. Table: LBA62 Activity according to BICR evaluation (Efficacy-Evaluable Population) a 22/56 (39%) patients had best percentage decrease in sum of tumor diameters 30%. In the current analysis, 77women (mean age 53years) with treatment-nave HR+/HER2 early breast cancer suitable for surgery were evaluated for the primary efficacy endpoint of change in CelTIL score between baseline and 21 days after treatment with a preoperative single dose of HER3-Dx (6.4mg/kg). HER3 IHC was performed on formalin-fixed, paraffin-embedded tissue using the BenchMark ULTRA IHC/ISH system (Roche Diagnostics). Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitorresistant, EGFR-mutated nonsmall cell lung cancer. gNo patients received prior treatment with a topoisomerase I inhibitor. Gold, Conor E. Steuer, Haruyasu Murakami, James Chih-Hsin Yang, Sang-We Kim, Michele Vigliotti, Rong Shi, Zhenhao Qi, Yang Qiu, Lihui Zhao, David Sternberg, Channing Yu, Helena A. Yu; Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR InhibitorResistant, EGFR-Mutated NonSmall Cell Lung Cancer. Here, we present the efficacy and safety results across all patients in the initial study cohort. 2022 Jan;12(1):74-89.doi: 10.1158/2159-8290.CD-21-0715. Patients provided archival tumor tissue or consented to a fresh tumor biopsy as a pretreatment sample. 9017 Background: Patients (pts) with advanced NSCLC without EGFR-activating mutations (EGFRm) have limited treatment options after failure of molecularly targeted therapies or platinum-based chemotherapy (PBC) with or without immunotherapy (IO). Safety outcomes for each dose group are shown in Supplementary Table S2. 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. In these patients, EGFR-targeted tyrosine kinase inhibitors (TKI) result in high response rates [objective response rate (ORR), 76%80%; ref. 4); however, relapse is typical with the development of resistance to EGFR TKI treatment (57). Our data at WCLC for datopotamab deruxtecan and Enhertu illustrate the potentially transformative role next-generation antibody drug conjugates may play in advanced non-small cell lung cancer. 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. For the dose escalation part, the primary objective was to assess the safety and tolerability of HER3-DXd and determine the RDE. The frozen liquid drug product (used in dose escalation) was 50 mg HER3-DXd in a 2.5-mL solution (20 mg/mL) in a single-use vial. Median DoR was 6.9 month (95% CI 3.1 month - non evaluable). Those with metastatic TNBC received a median of 2 (range, 1-13) prior therapies. Four patients remained on study treatment as of the August 16, 2021, data cutoff. Stable brain metastases were allowed. cTEAEs associated with death were respiratory failure (two patients) and disease progression and shock (one patient each). tokyo, munich and basking ridge, nj - (june 3, 2022) - new data from daiichi sankyo's (tse: 4568) patritumab deruxtecan (her3-dxd) showed clinically meaningful and durable responses in two early-stage trials in previously treated patients with her3 expressing metastatic breast cancer or advanced non-small cell lung cancer (nsclc) without 2B; 16 of 57 patients were ongoing without events), and the median OS was not reached at the time of data cutoff (95% CI, 9.4NE months; Fig. The median treatment duration was 5.9 months (range, 0.7-30.6). The antibody is covalently conjugated, via cysteine residues, through a tumor selective cleavable linker to the payload. Tumor genomic alterations prior to treatment with HER3-DXd are provided for each patient. PK analyses were performed on the basis of the PK analysis set, which included all patients in the safety analysis set who had at least one PK sample with measurable concentration of MAAA-1181aconjugated antibody or MAAA-1181a. In addition, most first-line osimertinib-resistant lung cancers do not harbor an obvious, currently targetable genomic mechanism of resistance (11). No patient with early clearance of ctDNA had a confirmed BOR of PD (Fig. 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. A, Distribution of pretreatment HER3 membrane H-score (0300). From these data, the H-scores (a weighted summed score) were calculated for each patient sample for both cytoplasmic and membrane components. Eligibility criteria for the dose expansion part cohort 1 included EGFR-mutated NSCLC adenocarcinoma, one or more prior EGFR TKIs, and one or more prior platinum-based chemotherapy regimens (patients with EGFR T790M following treatment with erlotinib, gefitinib, afatinib, or dacomitinib must have received and have progressed following treatment with osimertinib, unless unable or unwilling). Drug-related ILD is an identified risk with DXd-based ADCs (ref. 8 - 11 39). Noncompartmental analysis was conducted using Phoenix WinNonlin (Version 8.1; Certara). Further subgroup analyses revealed that people with non-luminal subtypes and those with high baseline PAM50 Risk Of Recurrence (ROR) score had significantly greater changes in CelTIL score than those with luminal subtypes and medium or low ROR scores, respectively. There were 24 instances of amplification (including 10 instances of EGFR amplification) and 5 instances of fusion. nausea or vomiting numbness or tingling in the hands, feet, or lips painful or difficult urination pale skin seizures sneezing sore throat swelling of the face, fingers, feet, or lower legs thickening of bronchial secretions trouble breathing ulcers, sores, or white spots in the mouth unsteadiness or awkwardness unusual bleeding or bruising For ctDNA analysis, a minor allelic frequency of 0.1% was used as a threshold for detection of mutations. cBOR, Confirmed BOR. Six patients could not be evaluated for BOR due to lack of adequate postbaseline tumor assessment and are not shown; one patient had a BOR of NE due to achieving SD too early (<5 weeks) and is shown with hatched markings. Antitumour activity was observed across diverse mechanisms of EGFR TKI resistance, including those not directly related to HER3 (EGFRC797S, MET or HER2 amplification, and BRAF fusion). Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. News release. 3 Investigators evaluated a . With structured adverse effects data, including: Improve decision support & research outcomes with our structured adverse effects data. 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). ESMO is a Swiss-registered not-for-profit organisation. We thank the patients, their families, and their caregivers for their participation. Following logarithmic transformation, the power model can be analyzed using linear regression. If available, results from local testing were included in the list of detected genomic alterations. Patritumab Patritumab ( INN) is a human monoclonal antibody designed for the treatment of cancer. Because of the antigen specificity of HER3-DXd, we explored the association of HER3 expression in pretreatment tumor tissues with clinical response. Significant unmet need still remains for the treatment of patients with metastatic breast cancer and new treatment strategies need to be continuously explored," lead author Ian E. Krop, MD, PhD, chief clinical research officer and associate cancer center director for clinical research at Yale Cancer Center in New Haven, Connecticut, said in a news release. 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 Patritumab deruxtecan (U3-1402), a potential first-in-class HER3 directed antibody-drug conjugate, was granted breakthrough therapy designation by the FDA for the treatment of patients with metastatic or locally advanced, EGFR-mutant non-small cell lung cancer (NSCLC), according to a press release from developer Daiichi-Sankyo. 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. Patritumab deruxtecan is a potential first-in-class HER3-directed antibody-drug conjugate, which signaled efficacy in a phase 1 dose-escalation and dose-expansion study (U31402-A-U102; NCT03260491), which primarily assessed the safety and tolerability of patritumab deruxtecan in patients with EGFR -mutant NSCLC with resistance to EGFR TKIs. 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. Six of 57 patients (11%) had AEs associated with treatment discontinuation; none were due to thrombocytopenia. Confirmed ORR by BICR was 39% (22 of 57 patients; 95% confidence interval [CI] 26.0%-52.4%) with 1 complete response (CR), 21 partial response (PR) and 19 stable disease (SD); 14 of 22 responses occurred within 3 month of starting HER3-DXd therapy. Responses were assessed by blinded independent central review. For dose escalation and dose expansion cohort 1, reported here, study eligibility criteria required that all patients had advanced or metastatic EGFR-mutated NSCLC with adenocarcinoma histology.