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)

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.

Value of a Signature of Immune-Related Genes in Predicting the Prognosis of Melanoma and Its Responses to Immune Checkpoint Blocker Therapies

“…These two closely associated genes both showed up in our model of predicting responses/prognoses, suggesting that IL-2-related pathways and the function of macrophages are important in melanoma. But the application of ibrutinib, a drug that targets IL-2 inducible kinase (which is highly expressed in melanoma), did not deliver any clinical benefits in patients with metastatic melanoma whose PD-1 treatment was failed [ 49 ]. Our model provided more insights into this by revealing another inflammation-related gene indicative of immunotherapy response and closely related to the prognosis: PTAFR.…”

Ibrutinib Modulates Proliferation, Migration, Mitochondrial Homeostasis, and Apoptosis in Melanoma Cells

“…Despite the promising data presented here, recently, a phase II single-arm clinical trial involving 18 patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors did not find an effective antitumor response to the use of Ibrutinib. The authors discuss the reported outcome as a possible consequence of the combination of several factors, including the ability of Ibrutinib to inhibit ITK, the relevance of this target for the treatment of melanoma, and the administered dose (840 mg daily) used to treat solid tumors such as melanoma [36]. Although the result seems disappointing, the authors suggest that additional research is needed to better characterize the Ibrutinib's mechanisms of action in different types of melanoma cells.…”

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

“…However, preliminary clinical data of several trials show no or limited clinical benefit of ibrutinib and acalabrutinib at improving the objective response rates (ORRs), progression-free survival (PFS) or overall survival (OS) in patients with several solid tumors (Table 2). These include ibrutinib plus durvalumab in R/R non-small cell lung cancer (NSCLC), breast cancer and pancreatic cancer (NCT02403271); acalabrutinib in recurrent glioblastoma (NCT02586857); ibrutinib in refractory metastatic cutaneous melanoma (NCT02581930) (52); acalabrutinib in combination with pembrolizumab in advanced head and neck squamous cell carcinoma (HNSCC) (NCT02454179), non-small cell lung cancer (NCT02448303) and platinum-refractory metastatic urothelial carcinoma (NCT02351739) (55); acalabrutinib alone or in combination with pembrolizumab in refractory ovarian cancer (NCT02537444) and metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (NCT02362048) (53); ibrutinib in combination with Nab-paclitaxel and gemcitabine in metastatic pancreatic cancer (NCT02436668) and (NCT02562898) (54); and ibrutinib alone in advanced carcinoid and pancreatic neuroendocrine tumors (Table 2) (www.clinicaltrials.com). Nonetheless, peripheral reductions in MDSCs and increases in proliferating CD8 T cell subsets are observed in some of these cases (53,55).…”