Stergios J Moschos1,2, Zeynep Eroglu3, Nikhil I Khushalani3, Kari L Kendra4, George Ansstas5, Gino K In6, Peng Wang7, Glenn Liu8, Frances A Collichio1,2, Paul B Googe9, Craig C Carson9, Karen McKinnon10,11, Hsing-Hui Wang11, Nana Nikolaishvilli-Feinberg12, Anastasia Ivanova2,13, Christy C Arrowood14,15, Nancy Garrett-Mead14,15, Kathleen C Conway2,9, Sharon N Edmiston2,9, David W Ollila2,16, Jonathan S Serody1,2,9,11, Nancy E Thomas2,9, S Percy Ivy16, Lokesh Agrawal16, Elizabeth C Dees1,2,17, James L Abbruzzese1,15. 1. Department of Medicine, The University of North Carolina at Chapel Hill. 2. The University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina. 3. Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida. 4. Department of Medicine, The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio. 5. Department of Medicine, Washington University School of Medicine Siteman Cancer Center, Saint Louis, Missouri. 6. Department of Medicine, The University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California. 7. Department of Medicine, University of Kentucky Albert Chandler Medical Center, Zion, Illinois. 8. Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. 9. Department of Dermatology. 10. Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill. 11. Immunogenomics Facility, Lineberger Comprehensive Cancer Center. 12. The University of North Carolina Translational Pathology Laboratory. 13. Department of Biostatistics, The University of North Carolina Gillings School of Global Public Health, Chapel Hill. 14. Department of Medicine, Duke Cancer Institute, Durham, North Carolina. 15. UM1 Consortium, National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network, Bethesda, Maryland. 16. Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland, USA. 17. Department of Surgery, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Abstract
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.
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.
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