Ibrutinib is a first-in-class, small-molecule inhibitor of Bruton’s Tyrosine Kinase (BTK). Based on the results of the RESONATE trial, a phase III study, the Committee for Medicinal Products for Human Use formulated a positive recommendation on the 24th of July 2014 to grant market authorisation for the treatment of adult patients with chronic lymphatic leukaemia (CLL) who have received at least one prior therapy, or in first-line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.

The RESONATE trial compared ibrutinib to ofatumumab in 391 previously treated patients with relapsed or refractory CLL or small lymphocytic lymphoma. The median progression-free survival, the primary outcome, was not yet reached in the ibrutinib group at a follow-up of 9.4 months, but was 8.1 months in the ofatumumab group, yielding a hazard ratio of 0.22. This finding was consistent in subgroups associated with a more aggressive disease such as chromosomal abnormality del(17p). Also in terms of overall survival, patients treated with ibrutinib group had a 57% reduction in the risk of death in comparison to the ofatumumab group. Partial responses were achieved in 43% in the ibrutinib group and in 4% in the ofatumumab group.
Most frequent adverse events associated with ibrutinib were diarrhoea, fatigue, fever, and nausea. At least one serious adverse event was observed in 57% in the ibrutinib group, compared to 47% in the ofatumumab group. Cutaneous second primary malignancies (basal-cell and squamous-cell carcinomas) occurred in 4% and 2%, and non-skin cancers in 3% and 1% respectively.

New treatment options for CLL, primarily for difficult-to-treat patients with relapsed or refractory disease or with poor prognostic characteristics such as del(17p) or p53 mutations are needed. Ibrutinib therapy will offer a new alternative for these patients. Open questions remain if combination therapies may achieve deeper remissions and result in the development of resistance to the BTK inhibitor, but also regarding the long-term side effects associated with continued treatment. In addition, even though unknown, costs can be expected to be high.