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Published on 2 June 2014

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Ibrutinib 3-year follow-up of single-agent and combination study results in chronic lymphocytic leukaemia

Janssen announced results in chronic lymphocytic leukaemia that show ibrutinib monotherapy continued to produce high overall response rates (ORRs) (78% for all treated patients, with the median duration of response not achieved after almost 30 months and 25 months for patients with del 17p).

Moreover, the rate of Grade 3 or higher adverse events (AEs) and serious adverse events or those leading to hospitalisation decreased after 1 year on treatment.

Janssen announced results in chronic lymphocytic leukaemia that show ibrutinib monotherapy continued to produce high overall response rates (ORRs) (78% for all treated patients, with the median duration of response not achieved after almost 30 months and 25 months for patients with del 17p).

Moreover, the rate of Grade 3 or higher adverse events (AEs) and serious adverse events or those leading to hospitalisation decreased after 1 year on treatment.

Three-year follow-up data from the phase Ib/2 PCYC-1102 trial of monotherapy ibrutinib showed continued durable responses in patients with treatment-naïve (TN) or relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to data from an analysis that will be discussed at the American Society of Clinical Oncology (ASCO) 50th annual meeting. Ibrutinib is an investigational compound in the EU within a class of medicines called Bruton’s tyrosine kinase (BTK) inhibitors.

Ibrutinib is defined as an investigational compound as it is not yet approved by any regulatory authority in the EU. On 30 October 2013, Janssen submitted a New Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for ibrutinib for the treatment of adult patients with relapsed or refractory CLL/SLL or relapsed or refractory mantle cell lymphoma (MCL).

Ibrutinib is marketed as IMBRUVICA® in the US, where it received approval from the U.S. Food and Drug Administration (FDA) for the treatment of patients with MCL who have received at least one prior therapy(1) and for the treatment of patients with CLL who have received at least one prior therapy.(2)

In a separate poster presentation, data suggest the combination of single-agent ibrutinib administered orally once-daily with ofatumumab, a CD20-directed cytolytic monoclonal antibody administered intravenously, is tolerable in patients with previously treated relapsed or refractory CLL/SLL.

In 2011, Janssen and Pharmacyclics Inc. entered into an agreement to jointly develop and commercialise ibrutinib.

Three-year follow-up of single agent ibrutinib in phase Ib/2 trial

Three-year follow-up from the initial phase Ib/2 PCYC-1102 trial of single-agent ibrutinib showed continued durable responses in patients with treatment-naïve (TN) (n=31) or relapsed or refractory CLL or SLL (n=101). Ibrutinib was associated with a 78% ORR, with durable responses regardless of prior treatment history (83.9% in treatment-naïve patients; 76.2% in relapsed or refractory patients; 55.9% in relapsed or refractory patients with a deletion of the short arm of chromosome 17 [del 17p]). In addition, five patients with relapsed or refractory CLL and two with del 17p achieved a partial response (PR) with lymphocytosis as best response. Patients received either single-agent ibrutinib once-daily at either 420mg or 840mg daily. ORR was assessed based on International Working Committee on Chronic Lymphocytic Leukemia (IWCLL) criteria. The median time on study was 29.4 months (range 0.7–38.1 months).

The median duration of response was not achieved for the full set of patients (n=132) evaluated for the analysis. For relapsed or refractory patients with del 17p, the median duration of response was 25 months (range 4.8–34.3 months).

“These results suggest significantly extended response to ibrutinib in patients with CLL three years after starting treatment,” said Professor Ulrich Jäger, Medical University of Vienna, Department of Medicine, Division of Haematology and Hemostaseology. “We are especially encouraged to see that patients showed durable responses to treatment with ibrutinib monotherapy regardless of their treatment history.”

Grade 3 or 4 AEs in the pooled analysis related to ibrutinib (investigator-assessed) decreased from 24% to 4% after 3 years of follow-up. Grade 3 or higher serious AEs (SAEs) related to ibrutinib also decreased over time from 8% in the first year to 1% after 3 years of treatment. No new safety signals were observed in long-term follow-up and 64% of patients remain on treatment with ibrutinib. The rate of Grade 3 or higher adverse events or those leading to hospitalisation decreased after one year on treatment with ibrutinib.

Combination data

Separately, data from the phase Ib/2 PCYC-1109 study to be presented at ASCO, showed treatment with monotherapy ibrutinib administered once-daily in combination with ofatumumab administered intravenously is tolerated and highly active in patients with relapsed or refractory CLL/SLL (n=71). The combination produced an 83% ORR in patients across all three dosing regimens studied, including a 100% ORR (n=27) in patients who started with one cycle of ibrutinib therapy followed by ofatumumab; additionally, two patients in the study achieved a PR with lymphocytosis. Additionally, at 12 months, the average progression-free survival (PFS) across all patients was approximately 88%, with 64% of patients continuing on monotherapy ibrutinib in a long-term extension study. Three patients with Richter’s transformation receiving ibrutinib and ofatumumab achieved disease control followed by progression after Day 471, 168 and 137, respectively.

The most common Grade 3 or 4 AE in the study (occurring in 10% or more of patients) was neutropenia (17%). The most frequent AEs (occurring in 20% or more of patients) were diarrhoea (68%), infusion-related reaction (45%), peripheral sensory neuropathy (nerve damage; 42%) and stomatitis (inflammation of the mouth and lips; 37%). Six patients (8%) experienced AEs leading to discontinuation of treatment with ibrutinib. Nine patients (12.7%) died within 30 days of the last dose and two died within the follow-up period.

CLL is a usually slow-growing blood cancer that most commonly originates from B cells, a type of white blood cell (lymphocyte) that develops in the bone marrow. B cells are part of the immune system and play an important role in fighting infection in the body. CLL is the most common adult leukaemia in the Western world, with the median age at diagnosis being primarily those over 70 years old. The incidence rates among men and women in Europe are approximately 5.87 and 4.01 cases per 100,000 persons per year, respectively. CLL is a chronic disease; median overall survival ranges between 18 months and more than 10 years according to the stage of disease. When cancer cells are located mostly in the lymph nodes, the disease is called SLL.(3–7)

  1. U.S. Food and Drug Administration. Press Announcement: FDA approves Imbruvica for rare blood cancer. Nov 2013. Available at: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm374761.htm (accessed May 2014).
  2. U.S. Food and Drug Administration. Press Announcement: FDA approves Imbruvica to treat chronic lymphocytic leukemia. Feb 2014. Available at: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm385764.htm (accessed May 2014).
  3. Parker, T. Chronic lymphocytic leukemia: prognostic factors and impact on treatment. Discovery Medicine. 2011;57.
  4. American Cancer Society. Detailed guide: what is chronic lymphocytic leukemia. Available at: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-what-is-cll (accessed 6 March 2014).
  5. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010;116:3724–34.
  6. Cancer Research UK. The most common types of non-Hodgkins lymphoma. Available at: http://www.cancerresearchuk.org/cancer-help/type/non-hodgkins-lymphoma/about/types/the-most-common-types-of-non-hodgkins-lymphoma (accessed 14 March 2014).
  7. Sagatys EM, Zhang L. Clinical and laboratory prognostic indicators in chronic lymphocytic leukemia. Cancer Control. 2012;19:18–25.


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