The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending a change to the terms of the marketing authorisation for ibrutinib (Imbruvica) in the European Union, to indicate the treatment of adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy.¹

Ibrutinib is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics, Inc. Janssen affiliates market ibrutinib in EMEA (Europe, Middle East and Africa) as well as the rest of the world, except for the United States, where Janssen Biotech, Inc. and Pharmacyclics co-market it.

Ibrutinib is already approved in Europe for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), or adult patients with chronic lymphocytic 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.²

If approved by the European Commission, ibrutinib would become the first approved treatment for WM across the EU.

It has also recently been approved in WM by the US FDA.

WM is a slow-growing and rare type of blood cancer.^{3, 4}

WM originates from B cells, a type of white blood cell (lymphocyte), and develops in the bone marrow.3,4 The median age at diagnosis is 63-68 years^{5, 6} and incidence rates among men and women in Europe are approximately 7.3 and 4.2 per million persons, respectively.⁶

Genome sequencing of patients with WM has revealed a common mutation in the MYD88 gene.

This mutation triggers the activation of the enzyme Bruton’s tyrosine kinase (BTK), which is a key component needed to regulate immune cell proliferation and cell survival which plays a part in B-cell malignancies, such as WM.⁷

Ibrutinib forms a strong covalent bond with BTK, thereby inhibiting the enzyme and blocking the transmission of cell survival signals within the malignant B cells.⁸

The Phase 2 multi-centre study on which the CHMP recommendation was based evaluated the efficacy and tolerability of ibrutinib 420 mg once daily in 63 patients with previously treated WM (median age of 63; range, 44-86 years old).

Updated results from the study were published on 8 April, 2015 in an online edition of The New England Journal of Medicine.⁹

The overall response rate using criteria adopted from the International Workshop on WM was 90.5 percent, 57 out of 63 patients.

Eleven patients (17 percent) achieved a minor response, 36 patients (57 percent) achieved a partial response (PR) and 10 patients (16 percent) achieved a very good PR.

The median times to at least minor and partial responses were four weeks and eight weeks, respectively.⁹

Secondary endpoints included progression free survival (PFS) and the safety and tolerability of ibrutinib in symptomatic patients with relapsing/remitting WM.

The estimated two–year PFS and overall survival (OS) rates among all patients were 69.1 percent and 95.2 percent respectively.⁹

The most commonly occurring adverse reaction in the WM trial (14 patients, or 22 percent) was neutropenia (decreased amount of neutrophils in the blood).

Thrombocytopenia (decrease in platelets in the blood) occurred in nine patients (14 percent), and other adverse events occurred in less than five patients (<10 percent) each.

Four patients (six percent) in the WM trial receiving ibrutinib discontinued treatment due to neutropenia or thrombocytopenia.

Additionally these two adverse events lead to dose reduction in three patients (five percent).⁹

References

1.  European Medicines Agency. Committee for Medicinal Products for Human Use: Summary of opinion. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/003791/WC500187054.pdf. Last accessed May 2015.

2.  European Medicines Agency. Committee for Medicinal Products for Human Use: Summary of opinion. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003791/WC500170191.pdf. Last accessed March 2015.

3.  American Cancer Society. Detailed guide: Waldenstrom macroglobulinemia. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003148-pdf.pdf Last accessed March 2015.

4.  Leukemia and Lymphoma Society. Waldenström macroglobulinemia facts. Available at http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/waldenstrommacroglobulinemia.pdf. Last accessed March 2015.

5.  Fonseca R, Hayman S. Waldenström macroglobulinaemia. Br J Haematol. 2007;138:700-20.

6.  Buske C, Leblond V, Dimopoulos M, et al. Waldenström’s macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl. 6):vi155–vi159.

7.  Yang G, Xu L, Zhou Y, et al. Participation of BTK in MYD88 signaling in malignant cells expressing the L265P mutation in Waldenstrom’s macroglobulinemia, and effect on tumor cells with BTK-inhibitor PCI-32765 in combination with MYD88 pathway inhibitors. J Clin Oncol. 2012;30(Suppl.):abstract 8106.

8.  O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15:48-58.

9.  Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015;372:1430-40.

10.  European Medicines Agency. How is the medicine expected to work? http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2012/06/human_orphan_001058.jsp&mid=WC0b01ac058001d12b

Source: Janssen