TY - JOUR
T1 - Targeting the IL-2 inducible kinase in melanoma; A phase 2 study of ibrutinib in systemic treatment-refractory distant metastatic cutaneous melanoma
T2 - Preclinical rationale, biology, and clinical activity (NCI9922)
AU - Moschos, Stergios J.
AU - Eroglu, Zeynep
AU - Khushalani, Nikhil I.
AU - Kendra, Kari L.
AU - Ansstas, George
AU - In, Gino K.
AU - Wang, Peng
AU - Liu, Glenn
AU - Collichio, Frances A.
AU - Googe, Paul B.
AU - Carson, Craig C.
AU - McKinnon, Karen
AU - Wang, Hsing Hui
AU - Nikolaishvilli-Feinberg, Nana
AU - Ivanova, Anastasia
AU - Arrowood, Christy C.
AU - Garrett-Mead, Nancy
AU - Conway, Kathleen C.
AU - Edmiston, Sharon N.
AU - Ollila, David W.
AU - Serody, Jonathan S.
AU - Thomas, Nancy E.
AU - Ivy, S. Percy
AU - Agrawal, Lokesh
AU - Dees, Elizabeth C.
AU - Abbruzzese, James L.
N1 - Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
KW - CD19
KW - IL-2 inducible kinase
KW - MAPK inhibitor refractory
KW - PD-1 inhibitor refractory
KW - PTEN
KW - ibrutinib
KW - metastatic cutaneous melanoma
KW - p16
KW - tumor-infiltrating lymphocytes
UR - http://www.scopus.com/inward/record.url?scp=85102482674&partnerID=8YFLogxK
U2 - 10.1097/CMR.0000000000000726
DO - 10.1097/CMR.0000000000000726
M3 - Article
C2 - 33661190
AN - SCOPUS:85102482674
SN - 0960-8931
VL - 31
SP - 162
EP - 172
JO - Melanoma Research
JF - Melanoma Research
IS - 2
ER -