SAN DIEGO AND RARITAN, N.J., Dec. 3, 2016 /PRNewswire/ -- Today, Janssen Research & Development, LLC (Janssen) announced the longest follow-up results to date of patients treated with IMBRUVICA® (ibrutinib) for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), showing high and lasting responses through five years. These updated Phase 1b/2 data demonstrated an overall response rate (ORR) of 89%, including patients with genetic mutations associated with poor outcomes. A complete response (CR) was observed in 29% of patients treated in the first-line setting. Progression-free survival (PFS) was improved with earlier initiation of therapy across treatment-naïve (TN) and relapsed/refractory (r/r) patients. These data (abstract #233) were presented today in an oral presentation at the 58th Annual American Society of Hematology (ASH) Meeting and Exposition in San Diego, Calif.1
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Additional follow-up data in patients with CLL/SLL treated with IMBRUVICA through 29 months from the Phase 3 RESONATE-2 trial will also be presented today (abstract #234).2 IMBRUVICA, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.
"These longer-term results demonstrate that ibrutinib can help patients keep chronic lymphocytic leukemia and small lymphocytic lymphoma in a remission for an extended period of time, through five years, without chemotherapy," said Susan O'Brien, M.D., Associate Director for Clinical Science, Chao Family Comprehensive Cancer Center at UC Irvine Health, Medical Director, Sue and Ralph Stern Center for Clinical Trials & Research, and an investigator and presenter of the PCYC-1102 and PCYC-1103 trials.* "In addition, these data indicate the time without disease progression is longer for patients when treatment with ibrutinib is started as early as possible in the course of the disease."
Abstract #233: Five-Year Experience With Single-Agent Ibrutinib In Patients With Previously Untreated And Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia
Oral presentation: Saturday, December 3, 2016, 5:00 PM PT
In these studies (PCYC-1102 and PCYC-1103), with five years of follow-up, the ORR in patients treated with IMBRUVICA was 89%, with 14% of patients achieving complete responses (CR) [87% ORR with 29% CR in TN patients (n=31) and 89% ORR with 10% CR in r/r patients (n=101)]. Median time on study was 62 months (1-67) for TN patients and 49 months (1-67) for r/r patients. Overall survival (OS) at five years was 92% for TN patients and 57% for r/r patients, with a PFS rate of 92% and 43%, respectively. Median OS and median duration of response (DOR) was not reached. Median PFS was not reached in TN patients and was 52 months for r/r patients.1
Findings were consistent in r/r patients with high-risk CLL/SLL, and risk factors traditionally associated with poor outcomes, including those with deletion 11q (del11q; n=28), deletion 13q (del13q; n=13), deletion 17p (del17p; n=34) and unmutated immunoglobulin heavy-chain variable-region (IGHV; n=79).3 Median PFS was 55 months (31-NE) for those with del11q, 26 months (95% CI, 18-37) for those with del17p, 43 months (95% CI, 32-NE) for those with unmutated IGHV, and was not reached for those with del13q. Results indicated PFS and OS were higher when IMBRUVICA treatment was started earlier. Median PFS was not reached in TN patients and was 63 months for r/r patients who received one to two prior regimens, 59 months for those who had three prior regimens and 39 months for those who had four or more prior regimens.1
"We continue to learn about the full potential that IMBRUVICA may offer patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. The longer-term data through five years add strong evidence about the extended use of IMBRUVICA across a wide spectrum of patients," said Craig Tendler, M.D., Vice President, Late-Stage Development and Global Medical Affairs for Oncology, Janssen Research & Development. "We are very encouraged to see such improvements in long-term clinical outcomes for the ibrutinib-treated CLL population, especially for those patients with poor prognostic risk factors."
No new safety signals emerged in the study. The onset of most grade 3 or higher treatment-emergent adverse events (TEAEs) among all patients was highest in the first year and decreased over time. The most frequent adverse events (AEs) were hypertension (26%), pneumonia (22%), neutropenia (17%) and atrial fibrillation (9%).1
The Phase 1b/2 PCYC-1102 trial evaluated safety and efficacy of single-agent ibrutinib in 132 patients with CLL/SLL: 31 patients were TN; 101 were r/r. Patients received either 420 mg or 840 mg once daily until disease progression or unacceptable toxicity. Among r/r patients, 34% had del17p, 35% del11q, 47% had del13q, and 78% unmutated IGHV. Primary endpoint was ORR, with secondary endpoints of DOR and PFS in addition to safety. PCYC-1103 is the long-term extension study.1 Primary results from this trial were published in the New England Journal of Medicine in June 2013 and were the basis for the initial approval of IMBRUVICA in CLL in February 2014.
Abstract #234: Updated Efficacy and Safety From The Phase 3 RESONATE-2 Study: Ibrutinib as First-Line Treatment Option in Patients 65 Years and Older With Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia
Oral presentation: Saturday, December 3, 2016, 5:15 PM PT
Updated findings from the pivotal Phase 3 RESONATE-2 trial (PCYC-1115) demonstrated that at a median of 29 months of follow-up, IMBRUVICA continued to have substantial efficacy as first-line therapy in CLL/SLL. The study found IMBRUVICA reduced the risk of progression or death by 88% compared with commonly used chemotherapy agent chlorambucil. At 24 months, PFS was 89% for patients taking IMBRUVICA and 34% for chlorambucil [HR, 0.121; 95% CI 0.074-0.198; p<0.0001). Investigator-assessed ORR with this longer follow up was 92% with ibrutinib and 36% with chlorambucil; in the ibrutinib arm, CR or CR with incomplete bone marrow recovery (Cri) improved from 15% at 24 months to 18% with longer follow-up of 29 months.2
Safety findings were in line with the primary analysis of the study and found that most Grade 3 or higher AEs decreased over time. Most AEs that led to discontinuation occurred in the first year of treatment. The most frequent (≥5%) Grade ≥ 3 AEs were neutropenia (12%), pneumonia (7%), anemia (7%) and hypertension (5%).2 These data will be presented at an oral presentation on Saturday, December 3.
RESONATE-2 is a continuing Pharmacyclics-sponsored, randomized multi-center, open-label, Phase 3 study, which enrolled 269 TN patients with CLL/SLL aged 65 years or older in the U.S., EU and other regions. Patients were randomized to receive IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The study met its primary endpoint, demonstrating improved PFS, as assessed by an independent review committee (IRC).2
Additional Phase 3 ibrutinib data at ASH that support its utility in different types of CLL/SLL patients include:
Abstract #4383: Integrated and Long-Term Safety Analysis of Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Poster Presentation: Monday, December 5, 2016, 6:00 PM - 8:00 PM PT
Abstract #2042: 11q Deletion (del11q) Is not a Prognostic Factor for Adverse Outcomes for Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated With Ibrutinib: Pooled Data From 3 Randomized Phase 3 Studies
Poster Presentation: Saturday, December 3, 2016, 5:30 PM - 7:30 PM PT
IMBRUVICA was one of the first therapies to receive U.S. approval after having received the FDA's Breakthrough Therapy Designation. IMBRUVICA works by blocking a specific protein called Bruton's tyrosine kinase (BTK).4 The BTK protein transmits important signals that tell B cells to mature and produce antibodies and is needed by specific cancer cells to multiply and spread.5 IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread. To date, more than 65,000 patients have received treatment with IMBRUVICA. For more information, visit www.IMBRUVICA.com.
Additional Information about IMBRUVICA®
IMBRUVICA® is indicated to treat people with:
- Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
- Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion
- Waldenström's macroglobulinemia (WM)
- Mantle cell lymphoma (MCL) who have received at least one prior therapy
- Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.
The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.
Infections - Fatal and nonfatal infections have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICAÒ. Evaluate patients for fever and infections and treat appropriately.
Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA®. Monitor complete blood counts monthly.
Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA® treatment and follow dose modification guidelines.
Hypertension - Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA® with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA®. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.
Second Primary Malignancies - Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).
Tumor Lysis Syndrome - Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA® and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).
*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%). Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.
Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.
CYP3A Inhibitors - Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.
CYP3A Inducers - Avoid coadministration with strong CYP3A inducers.
Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose.
Please see Full Prescribing Information: https://www.imbruvica.com/prescribing-information.
About the Janssen Pharmaceutical Companies
At the Janssen Pharmaceutical Companies of Johnson & Johnson, we are working to create a world without disease. Transforming lives by finding new and better ways to prevent, intercept, treat and cure disease inspires us. We bring together the best minds and pursue the most promising science. We are Janssen. We collaborate with the world for the health of everyone in it. Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenUS and www.twitter.com/JanssenGlobal.
Cautions Concerning Forward-Looking Statements
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 Research & Development, LLC and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges inherent in product research and development, including the uncertainty of clinical success and obtaining regulatory approvals; uncertainty of commercial success for new products or new indications; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. 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 January 3, 2016, including in Exhibit 99 thereto, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.
*Disclaimer: Dr. O'Brien served as an investigator of this Pharmacyclics-sponsored clinical study. Dr. O'Brien does not have a financial interest in the company.
1 O'Brien, S, et al. Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. ASH 2016 Abstract #233.
2 Barr, P, et al. Updated Efficacy and Safety from the Phase 3 Resonate-2 Study: Ibrutinib As First-Line Treatment Option in Patients 65 Years and Older with Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. ASH 2016 Abstract #234.
3 Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol 2013;88:803-816.
4 IMBRUVICA U.S. Prescribing Information, May 2016.
5 Genetics Home Reference. Isolated growth hormone deficiency. Available from:
http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed November 2016.
Satu Kaarina Glawe
Joseph J. Wolk
Pharmacyclics Medical Information:
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