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)

Stergios J. Moschos, Zeynep Eroglu, Nikhil I. Khushalani, Kari L. Kendra, George Ansstas, Gino K. In, Peng Wang, Glenn Liu, Frances A. Collichio, Paul B. Googe, Craig C. Carson, Karen McKinnon, Hsing Hui Wang, Nana Nikolaishvilli-Feinberg, Anastasia Ivanova, Christy C. Arrowood, Nancy Garrett-Mead, Kathleen C. Conway, Sharon N. Edmiston, David W. OllilaJonathan S. Serody, Nancy E. Thomas, S. Percy Ivy, Lokesh Agrawal, Elizabeth C. Dees, James L. Abbruzzese

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Pages (from-to)162-172
Number of pages11
JournalMelanoma Research
DOIs
StateAccepted/In press - 2021

Keywords

  • CD19
  • IL-2 inducible kinase
  • MAPK inhibitor refractory
  • PD-1 inhibitor refractory
  • PTEN
  • ibrutinib
  • metastatic cutaneous melanoma
  • p16
  • tumor-infiltrating lymphocytes

Fingerprint

Dive into the research topics of '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)'. Together they form a unique fingerprint.

Cite this