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dc.contributor.authorGan, Hui K-
dc.contributor.authorMillward, Michael-
dc.contributor.authorJalving, Mathilde-
dc.contributor.authorGarrido-Laguna, Ignacio-
dc.contributor.authorLickliter, Jason D-
dc.contributor.authorSchellens, Jan H M-
dc.contributor.authorLolkema, Martijn P-
dc.contributor.authorVan Herpen, Carla L M-
dc.contributor.authorHug, Bruce-
dc.contributor.authorTang, Lihua-
dc.contributor.authorO'Connor-Semmes, Robin-
dc.contributor.authorGagnon, Robert-
dc.contributor.authorEllis, Catherine-
dc.contributor.authorGanji, Gopinath-
dc.contributor.authorMatheny, Christopher-
dc.contributor.authorDrilon, Alexander-
dc.identifier.citationThe Oncologist 2021; 26(10): e1844-e1853en
dc.description.abstractGSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors. Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly. Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC). GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers. This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.en
dc.subjectNRG1 fusionen
dc.titleA Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors.en
dc.typeJournal Articleen
dc.identifier.journaltitleThe Oncologisten
dc.identifier.affiliationDepartment of Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USAen
dc.identifier.affiliationDepartment of Medicine, Melbourne University, Melbourne, Victoria, Australiaen
dc.identifier.affiliationDepartment of Internal Medicine, Oncology Division, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USAen
dc.identifier.affiliationGlaxoSmithKline, Collegeville, Pennsylvania, USAen
dc.identifier.affiliationIndependent Consultant, North Carolina, USAen
dc.identifier.affiliationClinical Pharmacology, Modeling and Simulation, Parexel International, Durham, North Carolina, USAen
dc.identifier.affiliationCandel Therapeutics, Needham, Massachusetts, USAen
dc.identifier.affiliationMedical Oncologyen
dc.identifier.affiliationSchool of Medicine, Latrobe University School of Cancer Medicine, Melbourne, Victoria, Australiaen
dc.identifier.affiliationLinear Clinical Research and University of Western Australia, Perth, Western Australia, Australiaen
dc.identifier.affiliationNucleus Network, Melbourne, Victoria, Australiaen
dc.identifier.affiliationDepartment of Medical Oncology, University Medical Centre Groningen, Groningen, The Netherlands..en
dc.identifier.affiliationDepartment of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands..en
dc.identifier.affiliationDepartment of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands..en
dc.identifier.affiliationRadboud University Medical Center, Radboud University, Nijmegen, The Netherlands..en
dc.identifier.affiliationOlivia Newton-John Cancer Research Instituteen
dc.identifier.pubmedid34132450, Hui K
item.fulltextNo Fulltext-
item.openairetypeJournal Article-
item.openairecristype Oncology- Newton-John Cancer Wellness and Research Centre-
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