BEERSE, Belgium, December 9, 2014 /PRNewswire/ --
Data confirms consistency of IMBRUVICA as an effective treatment option for patients with these challenging blood cancers
- Note: This press release corresponds to ASH abstracts 3331 and 4453
Janssen-Cilag International NV (Janssen) is pleased to announce the presentation of new longer term follow-up data from two IMBRUVICA® (ibrutinib) studies at the American Society of Hematology (ASH) meeting in San Francisco, CA. IMBRUVICA is a first-in-class, once-daily, oral Bruton's tyrosine kinase (BTK) inhibitor. The first set of data detailed a 16-month follow-up study on the Phase 3 RESONATE™ trial, which showed IMBRUVICA significantly improved progression-free survival (PFS) and overall survival (OS) versus ofatumumab in patients with relapsed or refractory (RR) chronic lymphocytic leukaemia (CLL) regardless of baseline cytogenetics, or number of prior therapies. The second longer-term follow-up presentation reported two-year data from the Phase 2 PCYC-1104 study in patients with RR mantle cell lymphoma (MCL).
IMBRUVICA is co-developed by Cilag GmbH International (a member of the Janssen Pharmaceutical Companies) and Pharmacyclics Switzerland GmbH. Janssen affiliates market IMBRUVICA 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, Inc. co-market it.
In the RESONATE study with a median follow-up of 16-months, the investigator-assessed PFS was significantly longer in patients with RR CLL receiving IMBRUVICA versus ofatumumab (median PFS not reached vs. 8.1 months respectively, an 89.4 percent reduction in the risk of progression or death [HR 0.106, 95 percent CI, 0.073-0.153, P<0.0001]). At 12 months, 84 percent of the IMBRUVICA patients continued progression-free compared to 19 percent in patients randomised to receive ofatumumab. The OS for patients randomised to receive IMBRUVICA was significantly longer than for patients in the ofatumumab arm, with 18-month survival rates of 85 percent versus 78 percent, despite 62 percent of ofatumumab patients crossing over to receive IMBRUVICA. The data were detailed in a poster presentation by Jennifer Brown, M.D., Ph.D., Director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute; Associate Professor of Medicine, Harvard Medical School on Sunday, December 7 [Abstract 3331].
"The investigator-assessed, progression-free survival rate in the IMBRUVICA RESONATE follow-up analysis clearly demonstrates the impact this treatment is already having on the lives of patients with relapsed or refractory chronic lymphocytic leukaemia," said Brown.* "What was compelling about this study was IMBRUVICA improved progression-free survival, versus ofatumumab, regardless of baseline cytogenetics or number of prior therapies."
In two-year follow-up data from the PCYC-1104 study, IMBRUVICA was associated with a median PFS of 13 months and median OS of 22.5 months. Almost one-third of RR MCL patients (31 percent) remain progression-free at two years and almost half (47 percent) of the 111 patients in the study remain alive. The data were presented at ASH by Michael Wang, M.D., Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center and lead investigator for the pivotal registration trial PCYC-1104 on Monday, December 8 [Abstract 4453].
"The safety and efficacy over time seen with the use of single-agent IMBRUVICA in people with relapsed or refractory mantle cell lymphoma are very encouraging," said Wang.† "These data further confirm the longer-term potential of IMBRUVICA as a treatment option, directly making a positive impact on our MCL patients."
"The sustained responses seen in the longer-term treatment of patients with MCL and CLL are a positive development for people living with these rare and complex blood cancers," said Thomas Stark Vice President Medical Affairs, Janssen Europe, Middle East and Africa (EMEA). "Janssen continues to work to better understand the full benefit of IMBRUVICA, and is encouraged by these results which demonstrate the potential of IMBRUVICA as an effective treatment option for both of these challenging blood cancers."
Abstract 3331: Phase 3 RESONATE Follow-up
Sixteen-month follow-up data from the randomised, multicentre, open-label Phase 3 RESONATE trial (N= 391), showed an investigator-assessed PFS at 12 months of 84 percent. After a median follow-up of 16 months, the investigator-assessed PFS was significantly longer in patients taking IMBRUVICA versus ofatumumab (not reached vs. 8.1 months [HR 0.106, 95 percent CI, 0.073-0.153, P<0.0001]). Treatment with ibrutinib demonstrates an 89.4 percent reduction in the risk of progression or death versus ofatumumab. The median OS in patients receiving IMBRUVICA has not yet been reached; the overall comparison showed OS for patients taking IMBRUVICA was significantly better than for patients in the ofatumumab arm, with 18-month OS rates of 85 percent and 78 percent respectively, despite 62 percent of patients randomised to ofatumumab who crossed over to receive IMBRUVICA and were censored at that time. The overall investigator-assessed response rate was 90 percent in patients taking IMBRUVICA (versus 25 percent in ofatumumab patients; P<0.0001), including eight percent of patients who achieved a partial response with lymphocytosis.
In an exploratory analysis, Brown showed that patients who had received only one versus two or more prior therapies before IMBRUVICA had a higher PFS (94 percent at 12 months versus 82 percent; P= 0.01). An additional analysis also showed the rates of ORR and PFS were similar in patients with or without del17p, indicating that the high risk del17p mutation did not confer a worse outcome for patients receiving IMBRUVICA.
Overall, at a median follow-up of 16 months, seventy-six percent of people randomised to IMBRUVICA continued on treatment in the study.
There were no new safety findings with the most common Grade 3 or 4 AEs in the RESONATE trial analysis (occurring in five percent or more of IMBRUVICA patients) were neutropenia (18 percent), pneumonia (9 percent), thrombocytopenia (low platelets in the blood; 6 percent), anaemia (6 percent) and hypertension (6 percent). The most frequently reported AEs of any grade were diarrhoea (37 percent), nausea (24 percent), fatigue (18 percent) and atrial fibrillation (7 percent). Forty-seven people (24 percent) discontinued IMBRUVICA: 17 due to progressive disease (9 percent), 13 due to AEs (7 percent) and 10 (5 percent) due to death. Notably, the incidence of treatment-emergent AEs decreased over time.
Abstract 4453: 2-year follow-up of IMBRUVICA in relapsed/refractory MCL
Patients in the Phase 2 multicentre, open-label, PCYC-1104 study received 560mg IMBRUVICA once daily until disease progression or unacceptable toxicity, and were eligible to continue on therapy via a long-term extension study (N=111 treated patients). Fifty-one patients (46 percent) were treated for more than one year and 29 patients (26 percent) who continued on treatment and follow-up in the extension study were treated for more than two years. Importantly, two-year (median of 26.7 months) follow-up data from the trial confirmed nearly one-third of patients (31 percent) were still progression-free and almost half of the 111 treated patients (47 percent) remain alive today. The median PFS was 13 months and the median OS was 22.5 months. Investigator-assessed ORR (primary endpoint) was 67 percent, with a complete response (CR) in 22.5 percent of patients. Additionally, the median time to response was 1.9 months.
The most common Grade 3 or greater adverse events (AEs) in the study were infection (28 percent), diarrhoea (5 percent) and bleeding (6 percent). Grade 3 or greater AEs occurred in 81 percent of people and serious AEs (SAEs) of any grade occurred in 63 percent of patients. The most frequently reported (occurring in >30 percent of IMBRUVICA patients) AEs of any grade were infection (78 percent), diarrhoea (54 percent), bleeding (50.5 percent), fatigue (49.5 percent), nausea (33 percent) and dyspnoea (shortness of breath; 32 percent). Treatment discontinuation due to AEs was reported in 11 percent of patients.
NOTES TO EDITORS
IMBRUVICA (ibrutinib) is a Bruton's tyrosine kinase (BTK) inhibitor, which works by forming a strong covalent bond with BTK to block the transmission of cell survival signals within the malignant B cells. By blocking this BTK protein, IMBRUVICA helps kill and reduce the number of cancer cells. It also slows down the worsening of the cancer.
IMBRUVICA received European Commission approval in October 2014 for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), and 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 (del17p CLL) or TP53 mutation in patients with CLL who are unsuitable for chemo-immunotherapy. This approval allows for the marketing of IMBRUVICA in all 28 countries of the European Union. In addition, a Type II variation application was submitted to the European Medicines Agency (EMA) in November to expand the marketing authorisation for IMBRUVICA (ibrutinib), to include a new therapeutic indication, the treatment of adult patients with Waldenström's macroglobulinemia (WM).
Investigational uses for ibrutinib, alone and in combination with other treatments, are underway in several blood cancers including CLL, MCL, Waldenström's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and multiple myeloma (MM); IMBRUVICA is approved for the treatment of CLL and MCL; regulatory approval for additional uses has not yet been granted.
In most patients, CLL is generally a slow-growing blood cancer of the white blood cells called B-lymphocytes. The median age at diagnosis is 72 years, and 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. The disease eventually progresses in the majority of patients, and patients are faced with fewer treatment options each time. Patients are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.
Deletion 17p (del17p) and TP53 mutation are associated with aggressive, treatment-resistant disease. The abnormality results in the loss of function of a key gene, TP53. TP53 senses the presence of abnormal DNA and triggers either DNA repair mechanisms or cell death and is important in tumour suppression and the action of cytotoxic chemotherapy. Approximately five to eight percent of patients receiving first-line treatment have del17p at diagnosis. However, incidence of del17p and/or TP53 mutation rises to 29 to 52 percent in patients who have relapsed or refractory disease. The median predicted survival for patients with the del17p mutation or TP53 mutation is just two to three years.
CLL cells are found in both the lymphatic system and the blood. When the cancer cells are located mostly in the lymph nodes, the disease is called small lymphocytic lymphoma (SLL). Both CLL and SLL are considered different manifestations of the same entity, as classified in the fourth edition of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues.
MCL is considered a rare disease, characterised by high unmet need and small patient populations impacting fewer than 0.45 in 100,000 people in Europe and with a median age at diagnosis of 65., MCL is much more predominant in men than women and accounts for six percent of all non-Hodgkin's lymphomas., Median overall survival is typically three to four years, and only one to two years in patients following the first relapse. MCL typically involves the lymph nodes, but can spread to other tissues, such as the bone marrow, liver, spleen and gastrointestinal tract. This challenging disease is associated with poor prognoses.
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(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges inherent in new product development, including obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes in behaviour and spending patterns or financial distress of purchasers of health care products and services; changes to laws and regulations and domestic and foreign health care reforms; general industry conditions, including trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 29, 2013, including in Exhibit 99 thereto, and subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at http://www.sec.gov, http://www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statements as a result of new information or future events or developments.)
*Disclaimer: Dr. Brown has served as an unpaid advisor to both Pharmacyclics and Janssen in developing the compound ibrutinib. Dr. Brown does not have a financial interest in either company.
[†]Disclaimer: Dr. Wang serves as national principal investigator of this Pharmacyclics-sponsored clinical study. He has served as an unpaid advisor to both Pharmacyclics and Janssen in developing the compound ibrutinib. Dr. Wang does not have a financial interest in either company
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