IMBRUVICA® (ibrutinib) Receives Regular Approval by U.S. FDA in Chronic Lymphocytic Leukemia (CLL) and CLL patients with del 17p
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The update to the IMBRUVICA label is based on data from the Phase 3 RESONATE™ study, which demonstrated IMBRUVICA significantly improved progression-free survival (PFS) and overall survival (OS) versus ofatumumab in patients with previously treated CLL or small lymphocytic leukemia (SLL).[3]
IMBRUVICA was initially approved in
"The RESONATE data expands our understanding of the efficacy and safety of IMBRUVICA to an even greater degree," said
CLL is a slow-growing blood cancer of white blood cells called lymphocytes, most commonly B cells.[4] CLL is predominantly a disease of the elderly, with a median age of diagnosis of 72.[4] In CLL, the genetic mutation del 17p occurs when part of chromosome 17 has been lost. CLL patients with del 17p have poor treatment outcomes.[2] Del 17p is reported in seven percent of treatment-naive CLL cases,[5] with approximately 20 to 40 percent of relapsed/refractory patients harboring the mutation.[6]
"We're very pleased this approval came swiftly," said
IMBRUVICA in CLL[1]
The safety and efficacy of IMBRUVICA in CLL were evaluated in the randomized, international, multi-center, open-label Phase 3 PCYC-1112 (RESONATE) trial in 391 patients with CLL or SLL, who had received at least one prior therapy. Thirty-two percent of patients in the trial had del 17p. Patients were administered either 420 mg oral ibrutinib (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). Data showed single-agent, once-daily IMBRUVICA significantly prolonged PFS (median not reached vs. 8.1 months; HR 0.22, 95% CI, 0.15 to 0.32; P<0.0001) and OS (HR 0.43; 95% CI, 0.24 to 0.79; P=0.05) versus intravenous ofatumumab in previously treated patients with CLL or SLL. The OS results represent a 57 percent statistically significant reduction in the risk of death in patients receiving IMBRUVICA versus those in the ofatumumab arm.
PFS was the primary endpoint of the RESONATE study, with OS, ORR and safety as key secondary endpoints. PFS, as assessed by an independent review committee according to modified
The Warnings and Precautions for IMBRUVICA include hemorrhage, infections, cytopenias, atrial fibrillation, second primary malignancies and embryo-fetal toxicity.[1] For more information about Warnings and Precautions, please see below in this release.
After an 8.6 month median duration of therapy, the most common Grade 3 or 4 adverse event (AE) was pneumonia* (10%). The most commonly occurring non-hematologic side effects during the RESONATE trial (AEs in 20 percent or more of patients) were diarrhea (48%), fatigue (28%), musculoskeletal pain* (28%), nausea (26%), pyrexia (fever; 24%) and rash* (24%). Hematologic adverse events included (all grades) platelet decrease (52%), neutrophil decrease (51%) and hemoglobin decrease (36%).1 *Includes multiple ADR terms.
Approximately five percent of patients receiving IMBRUVICA in the Phase 3 RESONATE (PCYC-1112-CA) and Phase 1b/2 PCYC-1102-CA studies discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately six percent of patients.[1]
The recommended dose of IMBRUVICA for CLL is 420 mg (three 140 mg capsules) orally once daily.[1]
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage - Grade 3 or higher bleeding events (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 anti-platelet or anti-coagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.
Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 26 to 29%), thrombocytopenia (range, 10 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with 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, 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. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification.
Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).
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®. 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.
ADVERSE REACTIONS
The most common adverse reactions (> 20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.
DRUG INTERACTIONS
CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.
CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.
SPECIFIC POPULATIONS
Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.
For the full prescribing information, visit http://www.imbruvica.com/.
About IMBRUVICA
IMBRUVICA was one of the first therapies to receive U.S. approval via the
This includes a YOU&i Access™ Instant Savings program, which provides co-pay support and benefits information to eligible commercially-insured patients. Patients can access the program by contacting 1-877-877-3536, option 1 or by visiting http://www.imbruvica.com.
About
In oncology, our goal is to fundamentally alter the way cancer is understood, diagnosed, and managed, reinforcing our commitment to the patients who inspire us. In looking to find innovative ways to address the cancer challenge, our primary efforts focus on several treatment and prevention solutions. These include a focus on hematologic malignancies, prostate cancer and lung cancer; cancer interception with the goal of developing products that interrupt the carcinogenic process; biomarkers that may help guide targeted, individualized use of our therapies; as well as safe and effective identification and treatment of early changes in the tumor microenvironment.
(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 unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of
†Disclaimer: Dr. Byrd serves as national principal investigator of the Pharmacyclics-sponsored clinical study forming the basis for the IMBRUVICA FDA approval. He has served as an unpaid advisor to both Pharmacyclics and
[1] IMBRUVICA Prescribing Information, July 2014
[2] NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkins Lymphomas. Version 1.2014. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed
[3]
[4]
[5] Schnaiter A, Stilgenbauer S. 17p deletion in chronic lymphocytic leukemia: risk stratification and therapeutic approach. Hematol Oncol Clin North Am. 2013;27:289-301.
[6] Stilgenbauer S, Zenz T. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010: 481-8.
[7] Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed
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