Ibrutinib Granted Breakthrough Designation for Chronic GVHD

The FDA has granted a breakthrough therapy designation to ibrutinib (Imbruvica) has a potential treatment for patients with chronic graft-versus-host-disease (cGVHD) after failure of one or more lines of systemic therapy, according to statements from the manufacturers of the BTK inhibitor, Janssen and AbbVie/Pharmacyclics.

The designation was based on findings from a phase Ib/II study, in which single-agent ibrutinib demonstrated an objective response rate (ORR) of 55% for patients with steroid-dependent or refractory cGVHD. Moreover, responses to ibrutinib appeared durable, with a biomarker analysis indicating activity in B and T cells.

"We are excited to learn if the mechanism of action for ibrutinib may allow its use beyond its current indications in hematologic malignancies," Sen Zhuang, MD, PhD, vice president, Clinical Development, Hematology for Janssen Research & Development, said in a statement. "Chronic GVHD is a debilitating condition with limited treatment options. We're hopeful ibrutinib can make a difference and look forward to working with the FDA and our strategic partner, Pharmacyclics, on this development program."

Ibrutinib was first approved in 2013 as a treatment for patients with mantle cell lymphoma (MCL), and has since gained further indications for chronic lymphocytic leukemia and Waldenström's macroglobulinemia (WM). Preclinical models have shown that ibrutinib can reduce the severity of GVHD, through the blockade of BTK and the IL-2 inducible T-cell kinase (ITK).

The phase Ib/II study exploring ibrutinib for cGVHD had enrolled 28 patients at the time of the data cutoff for an April 2016 presentation at the European Society for Blood and Marrow Transplantation. All patients had undergone a stem cell transplant and had received ≤3 prior regimens for cGVHD, had a >25% BSA erythema, or an NIH mouth score of >4.

The median age of patients was 57 years (range, 27-70). The median duration of cGVHD prior to entering the study was 15.8 months (range, 1.4-63.2). Patients had received a median of 2 prior regimens for cGVHD. The primary endpoint of the study was cGVHD response per 2005 NIH consensus response criteria.

At the time of the analysis, 6 patients were not assessable for responses. Of the remaining 22 patients, 12 had responded to treatment with ibrutinib. Responses consisted of 1 complete response and 11 partial responses. Responses continued for 49 weeks for 3 patients in the study, and an additional 3 patients were treated and responded for 23 weeks, showing early signs of durability. A majority of responders (92%) were able to reduced (n = 10) or discontinue (n = 1) corticosteroids.

A biomarker analysis showed promising signs of B- and T-cell signaling pathway inhibition. Serum BAFF levels decreased with ibrutinib, suggesting activity for the agent in B-cell—driven cGVHD. Additionally, ibrutinib was capable of decreasing ITK expression, as measured by CD4 T cell pPLC γ 1-Tyr783 levels.

"Two key kinase enzymes are believed to be involved in the cell signaling associated with chronic graft-versus-host-disease: Bruton's tyrosine kinase and interleukin-2-inducible T-cell kinase, known as BTK and ITK respectively," noted Zhuang.

The most common all grade adverse events (AEs) in the trial were fatigue (50%), bruising (25%), diarrhea (25%), and nausea (21%). The most frequently observed grade ≥3 AEs were fatigue, which occurred in 5 patients, and diarrhea, pneumonia, and headache (2 patients each). Six patients discontinued therapy due to an AE, specifically fatigue (n = 2), atrial fibrillation, brain abscess, oral pain, and tongue ulceration (1 patient each). Three patients discontinued after developing progressive cGVHD.

"This fourth breakthrough therapy designation from the FDA shows the promise of Imbruvica and its unique mechanism of action as a potential therapy beyond blood cancers, including chronic graft-versus-host-disease, a severe inflammatory condition with currently no approved therapies specifically for these patients," Danelle James, MD, MS, head of Oncology at Pharmacyclics, said in a statement. "We are committed to continuing to evaluate the potential benefit ibrutinib may offer in treating blood cancers, solid tumors and other health conditions with unmet medical needs."

Ibrutinib continues to be explored across a number of settings for patients with hematologic malignancies, including novel combinations with nivolumab (Opdivo) and venetoclax (Venclexta). Additionally, studies are looking at the agent as a treatment for patients with solid tumors, including lung cancer (NCT02321540) and pancreatic cancer (NCT02436668).

Miklos D, Cutler C, Arora M, et al. Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid-Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD). Presented at: 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation, Valencia, Spain; April 3-6, 2016. Abstract P124.