European Commission Approves Ibrutinib for MCL, CLL

Peter Hillmen, MD, PhD

Ibrutinib (Imbruvica) has been approved by the European Commission for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) and adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy or as a first-line therapy for those with 17p deletion or TP53 mutations in patients unsuitable for chemo-immunotherapy. Janssen-Cilag International NV, the company co-developing the drug with Pharmacyclics Switzerland GmbH, made the announcement.

This action follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in July and triggers an $80 million payment to Pharmacyclics from Janssen. The approval of ibrutinib was based on data from 3 trials: the phase II PCYC-1104 trial in MCL and the phase III RESONATE trial and phase Ib/II PCYC-1102 trial in CLL.

"MCL and CLL with 17p deletion are usually challenging and difficult-to-treat blood cancers that do not respond well to conventional therapies. They usually rapidly progress during or soon after chemotherapy leaving patients with very limited treatment options and poor survival," Peter Hillmen, MD, PhD, from St. James's University Hospital, Leeds, and investigator on the RESONATE trial, said in a statement. "Being able to use Imbruvica as a single agent offers a new option and gives renewed hope for physicians and their patients."

In the phase II PCYC-1104 trial of 111 previously treated patients with relapsed or refractory MCL, ibrutinib demonstrated an overall response rate (ORR) of 68%, complete response rate of 21%, and a median duration of response of 17.5 months.

In the phase III RESONATE trial presented at the 2014 ASCO Annual Meeting, 391 patients with CLL or small lymphocytic lymphoma (SLL) were randomized to receive ibrutinib or ofatumumab. Ibrutinib extended progression-free survival by 78% and overall survival by 57%.

The phase Ib/II PCYC-1102 trial was a single-arm, 48-patient study of ibrutinib in CLL. At a median 15.6-month follow-up, the ORR was 58.3% (all partial responses) with duration of response of up to 24.2 months.

The most common adverse events reported with ibrutinib in CLL and MCL are diarrhea, musculoskeletal pain, upper respiratory tract infection, bruising, rash, nausea, fever, neutropenia, and constipation. The most common grade 3/4 adverse reactions are anemia, neutropenia, pneumonia, and thrombocytopenia.

"We are delighted the European Commission has approved Imbruvica as a new treatment approach, which could prolong the lives of patients with these complex blood cancers," Jane Griffiths, PhD, Company Group Chairman, Janssen, Europe, Middle East and Africa (EMEA), said in a statement. "This is a positive step forward for patients, and Janssen is committed to looking into further areas of unmet need in blood cancers where Imbruvica could improve outcomes."

The FDA approved ibrutinib for the treatment of patients with MCL who have received at least 1 prior therapy in November 2013 and for the treatment of patients with CLL who have received at least 1 prior therapy in February 2014. Ibrutinib received full FDA approval for CLL in July 2014.

Ibrutinib is still being investigated in other settings of CLL and MCL, as well as other types of blood cancer, including Waldenström's macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma.