In Pre-Clinical Studies Ibrutinib Enhances Anti-tumor Activity When Combined With An Anti-PD-L1 Antibody

Pharmacyclics, Inc.

today highlighted findings from a pre-clinical study published in the Proceedings of the National Academy of Sciences (www.pnas.org/cgi/doi/10.1073/pnas.1500712112) that showed when ibrutinib (IMBRUVICA^®) was combined with an anti-PD-L1 antibody (a checkpoint inhibitor), suppression of tumor growth was enhanced suggesting a greater response might be achieved when treating certain hematologic cancers and solid tumors with the combination. IMBRUVICA is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. The paper's senior author, Ronald Levy, M.D., a professor of medicine and director of the lymphoma program at the Stanford University School of Medicine, and colleagues found the combination of an anti-PD-L1 antibody and ibrutinib resulted in suppression of tumor growth and extension of survival in a mouse model of lymphoma. The study found while some of the mice responded to anti-PD-L1 treatment alone, the response eventually diminished over time. When ibrutinib was added to anti-PD-L1 treatment, half of the mice were cured and the other half experienced delays of tumor growth and prolonged survival. The researchers also chose two solid tumor models to investigate the novel combination – triple negative breast cancer and colon cancer, which do not express BTK (Bruton's tyrosine kinase) and have low levels of the PD-L1 protein. When ibrutinib and the PD-L1 antibody were given as single agents neither had any effect on tumor growth. However, the combination reduced the size of the primary tumors, improved survival and resulted in fewer metastases in both breast and colon cancer. Specifically, in the case of the colon cancer tumor model, approximately 30% of the mice were cured. Most importantly, the researchers tested whether the mice cured from colon cancer had developed long-term immune memory, specific memory T cells, from the novel combination. These mice were re-exposed to colon cancer cells 90 days post cure and after seven days of tumor growth, all the mice cleared the tumor by day 17 without any additional dosing of the ibrutinib and PD-L1 combination. Programmed death-ligand (PD-L1) is a protein that may suppress the ability of the immune system to fight diseases. In certain cancers, PD-L1 may play a role in inhibiting the ability of T cells (necessary to help the body fight disease) to function properly, which results in the proliferation of tumors in the human body. Anti-PD-L1 antibody therapies have been shown to block the negative effect that PD-L1 can have on T cells, allowing certain cancers to be successfully treated. Recent pre-clinical studies have also demonstrated that ibrutinib, which has been shown to be effective in treating B-cell mediated cancers, can also inhibit interleukin-2-inducible T-cell kinase (ITK), an enzyme important in regulating T-cell effector function. This activity may be relevant to the mechanism by which ibrutinib enhances the efficacy of check point inhibitors. "These findings are very encouraging and support our pursuit of a clinical development strategy that combines ibrutinib with anti-PD-L1 antibodies or other checkpoint inhibitors to maximize the effect that both drugs could have in treating cancer," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics. "Based on what we've seen pre-clinically, we are optimistic that combinations such as these may help to produce new treatment paradigms for patients with cancer." While no conclusions about the safety of this combination were drawn, the authors noted while ibrutinib and anti-PD-L1 antibodies have each been well tolerated as single agents, additional study of the combination of these two agents is necessary to fully understand the appropriate dosing, timing and sequencing of combination treatment. IMBRUVICA will be evaluated with AstraZeneca's investigational anti-PD-L1 immune checkpoint inhibitor, MEDI4736 in patients with several hematologic and solid tumor cancers, all of which are investigational uses for both compounds. IMBRUVICA also will be studied with Bristol-Myers Squibb's human programmed death receptor-1 (PD-1) blocking antibody OPDIVO^® (nivolumab) in several hematologic cancers. These clinical studies are expected to begin enrollment in the coming months.