PMID- 34132450 OWN - NLM STAT- MEDLINE DCOM- 20211025 LR - 20220423 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 26 IP - 10 DP - 2021 Oct TI - A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors. PG - e1844-e1853 LID - 10.1002/onco.13860 [doi] AB - BACKGROUND: GSK2849330, 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 AND METHODS: 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. RESULTS: 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). CONCLUSION: 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. IMPLICATIONS FOR PRACTICE: 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. CI - (c) 2021 GlaxoSmithKline. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press. FAU - Gan, Hui K AU - Gan HK AD - Department of Medical Oncology, Austin Health and Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. AD - School of Medicine, Latrobe University School of Cancer Medicine, Melbourne, Victoria, Australia. AD - Department of Medicine, Melbourne University, Melbourne, Victoria, Australia. FAU - Millward, Michael AU - Millward M AD - Linear Clinical Research and University of Western Australia, Perth, Western Australia, Australia. FAU - Jalving, Mathilde AU - Jalving M AD - Department of Medical Oncology, University Medical Centre Groningen, Groningen, The Netherlands. FAU - Garrido-Laguna, Ignacio AU - Garrido-Laguna I AD - Department of Internal Medicine, Oncology Division, University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah, USA. FAU - Lickliter, Jason D AU - Lickliter JD AD - Nucleus Network, Melbourne, Victoria, Australia. FAU - Schellens, Jan H M AU - Schellens JHM AD - Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. FAU - Lolkema, Martijn P AU - Lolkema MP AD - Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. FAU - Van Herpen, Carla L M AU - Van Herpen CLM AD - Radboud University Medical Center, Radboud University, Nijmegen, The Netherlands. FAU - Hug, Bruce AU - Hug B AD - GlaxoSmithKline, Collegeville, Pennsylvania, USA. FAU - Tang, Lihua AU - Tang L AD - Independent Consultant, North Carolina, USA. FAU - O'Connor-Semmes, Robin AU - O'Connor-Semmes R AD - Clinical Pharmacology, Modeling and Simulation, Parexel International, Durham, North Carolina, USA. FAU - Gagnon, Robert AU - Gagnon R AD - GlaxoSmithKline, Collegeville, Pennsylvania, USA. FAU - Ellis, Catherine AU - Ellis C AD - GlaxoSmithKline, Collegeville, Pennsylvania, USA. FAU - Ganji, Gopinath AU - Ganji G AD - GlaxoSmithKline, Collegeville, Pennsylvania, USA. FAU - Matheny, Christopher AU - Matheny C AD - Candel Therapeutics, Needham, Massachusetts, USA. FAU - Drilon, Alexander AU - Drilon A AD - Department of Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210721 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (GSK2849330) SB - IM MH - Antibodies, Monoclonal, Humanized MH - *Carcinoma, Non-Small-Cell Lung MH - Humans MH - *Lung Neoplasms MH - Maximum Tolerated Dose MH - *Neoplasms/drug therapy MH - Prospective Studies PMC - PMC8488777 OTO - NOTNLM OT - Biomarkers OT - GSK2849330 OT - HER3 OT - NRG1 fusion OT - Neuregulin-1 OT - Pharmacokinetics COIS- Disclosures of potential conflicts of interest may be found at the end of this article. EDAT- 2021/06/17 06:00 MHDA- 2021/10/26 06:00 PMCR- 2021/10/01 CRDT- 2021/06/16 09:28 PHST- 2020/11/13 00:00 [received] PHST- 2021/05/14 00:00 [accepted] PHST- 2021/06/17 06:00 [pubmed] PHST- 2021/10/26 06:00 [medline] PHST- 2021/06/16 09:28 [entrez] PHST- 2021/10/01 00:00 [pmc-release] AID - ONCO13860 [pii] AID - 10.1002/onco.13860 [doi] PST - ppublish SO - Oncologist. 2021 Oct;26(10):e1844-e1853. doi: 10.1002/onco.13860. Epub 2021 Jul 21.