October 17, 2014 Pharmacyclics reported that the European Commission (EC) has granted marketing approval for IMBRUVICA (ibrutinib) throughout the 28 member states of the European Union (EU) (Press release Pharmacyclics, OCT 17, 2014, View Source [SID:1234500842]). IMBRUVICA, a first-in-class, oral, once-daily, non-chemotherapy treatment, now is approved to be marketed in Europe for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), or adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, or in first line CLL patients in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemotherapy.
IMBRUVICA is being jointly developed and commercialized in the U.S. by Pharmacyclics and Janssen Biotech, Inc. (Janssen). Janssen affiliates will hold the marketing authorization and will market IMBRUVICA in EMEA (Europe, Middle East, Africa), as well as the rest of the world, outside the U.S.
The EC approval was based on data from the Phase II study (PCYC-1104) in MCL, the Phase III RESONATE study (PCYC-1112-CA) in CLL and small lymphocytic lymphoma (SLL) and the Phase Ib/II study (PCYC-1102) in CLL/SLL. This approval is based on the IMBRUVICA Marketing Authorization Application (MAA) submitted to the European Medicines Agency (EMA) last year. The EMA is an agency of the EU that administers a centralized procedure for the scientific evaluation of medicines developed by pharmaceutical companies for use in the 28 countries of the EU. In addition to EU markets, a worldwide regulatory filing program for ibrutinib currently is underway.
“We are very pleased that patients with CLL and relapsed or refractory MCL in the European Union will have a first-in-class, oral, single-agent, non-chemotherapy treatment option in IMBRUVICA,” said Bob Duggan, Chairman & CEO of Pharmacyclics. “This approval underscores the compelling safety and efficacy benefits of IMBRUVICA, including statistically significant improvement in overall survival and progression-free survival in CLL and the overall robustness of the data in MCL.”
IMBRUVICA is approved in the U.S. for three indications: for the treatment of patients with MCL and CLL who have received at least one prior therapy, and for the treatment of CLL patients with deletion of the short arm of chromosome 17 (del 17p), including treatment-naive and previously treated del 17p CLL patients. Accelerated approval was granted for the MCL indication based on overall response rate (ORR). Improvements in survival or disease-related symptoms have not been established in MCL. Continued approval for the MCL indication may be contingent upon verification of clinical benefit in confirmatory trials.
The following results are included in the IMBRUVICA Summary of Product Characteristics (SmPC) from EU commission review.
MCL Study Efficacy Results
In a multi-center, single-arm, open-label Phase II study (PCYC 1104), the efficacy of ibrutinib in 111 patients with relapsed or refractory MCL were evaluated. An ORR of 68% was observed, with a complete response rate of 21% and a partial response rate of 47%. With an estimated median follow up of 15.3 months, the estimated median response duration was 17.5 months, and the estimated median progression-free survival (PFS) was 13.9 months.1
CLL Study Efficacy Results
RESONATE (PCYC-1112) is a Phase III, randomized, multi-center, open-label, international, head-to-head study of single-agent, orally-administered ibrutinib versus the intravenously administered monoclonal antibody ofatumumab, targeting the CD-20 antigen. The study enrolled 391 previously treated patients with CLL/SLL.2
At a median follow-up of 9.4 months, single-agent ibrutinib demonstrated a statistically significant improvement in PFS, overall survival (OS), and ORR, regardless of baseline characteristics, as compared with patients treated with ofatumumab.
The PFS results represent a 78% reduction in the risk of progression or death in patients treated with ibrutinib compared to ofatumumab. The OS results represent a 57% reduction in the risk of death in patients receiving ibrutinib versus those in the ofatumumab arm. The efficacy was similar across all of the subgroups examined, including in patients with and without del 17p, a pre-specified stratification factor.
As noted in the market application and reported in The New England Journal of Medicine publication, the RESONATE results were observed despite a total of 57 patients who were initially randomized to ofatumumab crossing over to receive IMBRUVICA prior to the analysis.
MCL and CLL Study Safety Results
The most commonly occurring adverse reactions ( > 20%) were diarrhea, musculoskeletal pain, upper respiratory tract infection, bruising, rash, nausea, pyrexia, neutropenia, and constipation. The most common grade 3/4 reactions ( > 5%) were anemia, neutropenia, pneumonia, and thrombocytopenia.