Targeting the IL-2 inducible kinase in melanoma; a phase 2 study of ibrutinib in systemic treatment-refractory distant metastatic cutaneous melanoma: preclinical rationale, biology, and clinical activity (NCI9922).

Autor:	Moschos SJ; Department of Medicine, The University of North Carolina at Chapel Hill.; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina., Eroglu Z; Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida., Khushalani NI; Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida., Kendra KL; Department of Medicine, The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio., Ansstas G; Department of Medicine, Washington University School of Medicine Siteman Cancer Center, Saint Louis, Missouri., In GK; Department of Medicine, The University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California., Wang P; Department of Medicine, University of Kentucky Albert Chandler Medical Center, Zion, Illinois., Liu G; Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin., Collichio FA; Department of Medicine, The University of North Carolina at Chapel Hill.; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina., Googe PB; Department of Dermatology., Carson CC; Department of Dermatology., McKinnon K; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill.; Immunogenomics Facility, Lineberger Comprehensive Cancer Center., Wang HH; Immunogenomics Facility, Lineberger Comprehensive Cancer Center., Nikolaishvilli-Feinberg N; The University of North Carolina Translational Pathology Laboratory., Ivanova A; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.; Department of Biostatistics, The University of North Carolina Gillings School of Global Public Health, Chapel Hill., Arrowood CC; Department of Medicine, Duke Cancer Institute, Durham, North Carolina.; UM1 Consortium, National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network, Bethesda, Maryland., Garrett-Mead N; Department of Medicine, Duke Cancer Institute, Durham, North Carolina.; UM1 Consortium, National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network, Bethesda, Maryland., Conway KC; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.; Department of Dermatology., Edmiston SN; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.; Department of Dermatology., Ollila DW; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.; Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland, USA., Serody JS; Department of Medicine, The University of North Carolina at Chapel Hill.; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.; Department of Dermatology.; Immunogenomics Facility, Lineberger Comprehensive Cancer Center., Thomas NE; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.; Department of Dermatology., Ivy SP; Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland, USA., Agrawal L; Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland, USA., Dees EC; Department of Medicine, The University of North Carolina at Chapel Hill.; The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.; Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Abbruzzese JL; Department of Medicine, The University of North Carolina at Chapel Hill.; UM1 Consortium, National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network, Bethesda, Maryland.
Jazyk:	angličtina
Zdroj:	Melanoma research [Melanoma Res] 2021 Apr 01; Vol. 31 (2), pp. 162-172.
DOI:	10.1097/CMR.0000000000000726
Abstrakt:	Background: IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses. Methods: We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930). Results: Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets. Conclusion: Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis. (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
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