IMBRUVICA® (ibrutinib) Patient-Reported Outcomes Data Detail Long-Term Improvement in Treatment Outcomes and Quality of Life Experience in Chronic Lymphocytic Leukemia (CLL) Patients

NORTH CHICAGO, Ill., Dec. 9, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced new three-year follow-up data from the RESONATE™-2 study (PCYC-1115/1116), which found that previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients reported sustained improvements in measures of well-being with IMBRUVICA® (ibrutinib) versus chemotherapy with chlorambucil. These new data provide the longest quality of life follow up for ibrutinib to date using patient-reported outcomes (PRO). Patients reported their quality of life outcomes for fatigue, mobility, self-care, usual activities, pain/discomfort and anxiety/depression. At 30 months, ibrutinib was also associated with a greater progression-free survival (PFS) rate of 85 percent versus chlorambucil, which had a PFS rate of 28 percent.

The new RESONATE-2 data will be presented at the 59^th American Society of Hematology (ASH) Annual Meeting and Exposition on Dec. 9 in Atlanta (abstract #1746). IMBRUVICA is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"In the RESONATE-2 study, patients who were treated with ibrutinib reported greater and sustained improvements in overall health and well-being and experienced decreased disease-related symptoms," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "For patients with chronic lymphocytic leukemia, a disease that affects primarily older patients, quality of life is an important consideration that should be factored into treatment choices initially and throughout long-term use."  

CLL is the most common form of leukemia in adults and is a type of cancer that can form from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes). While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S.¹ with approximately 19,000 newly diagnosed patients every year.² SLL is a slow-growing lymphoma, biologically similar to CLL, in which too many immature white blood cells cause lymph nodes to become larger than normal.³ CLL/SLL are predominately diseases of the elderly, with a median age of 71 at diagnosis.

About the Presentation

Abstract #1746: Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study
Poster Presentation; Saturday, December 9, 5:30 – 7:30 p.m. ET

At a median follow up of three years, ibrutinib treatment resulted in significantly longer PFS (median, not reached versus 15 months with chlorambucil), with an 87% reduction in risk of progression or death versus chlorambucil (HR 0.130; 95% CI: 0.081, 0.208). The PFS rate for ibrutinib was 85% versus 28% with chlorambucil. Greater and sustained improvements in PROs were observed with ibrutinib, resulting in significantly greater improvements over time versus chlorambucil (via FACIT-F and EQ-5D-5L Visual Analogue Scale by repeated measures).

In chlorambucil patients with progressive disease, PROs improved after crossing over to ibrutinib. Approximately 87% of patients on ibrutinib (versus 52% on chlorambucil) had decreased/normalized lymphadenopathy within 2 months, which was sustained through 36 months, and disease symptoms, including fatigue and night sweats, improved more frequently for patients on ibrutinib. A greater proportion of patients with baseline cytopenia showed sustained hematologic improvement with ibrutinib versus chlorambucil for hemoglobin (90% versus 45%) and platelets (83% versus 46%).

Patients 65 years and older (median age 73) were randomized to receive 420mg ibrutinib once daily until progressive disease or chlorambucil for up to 12 months. Median treatment duration was 34.1 months on ibrutinib versus 7.1 months on chlorambucil. Further data showed the burden of hematologic support medical resource utilization was less with ibrutinib versus chlorambucil in the first year and subsequently continued to decrease.

The most common adverse events (AEs) of any grade with ibrutinib were diarrhea (47%), fatigue (33%), and cough (30%). Eight Grade 3 or higher AEs had a prevalence of less than 3% in ibrutinib patients and generally decreased or were stable over time. During the first year of treatment, patients on ibrutinib versus chlorambucil experienced less Grade 3 or higher neutropenia (8% and 18%), anemia (6% and 8%), and thrombocytopenia (2% and 5%); other common Grade 3 or higher AEs were pneumonia (5% and 2%), hypertension (4% and 0%), and infections as combined term (17% and 8%). Grade 3 or higher bleeding occurred in 7% of ibrutinib patients over the 3-year follow up. AEs leading to treatment discontinuation occurred in 16% with ibrutinib over 3 years versus 23% for chlorambucil over 7 months of therapy, respectively.

Additional Presentation on RESONATE-2 at ASH 2017

A separate presentation at ASH this year will also discuss the RESONATE-2 clinical trial (with a median follow up of 35.7 months) as part of a cross-trial comparison. The data compares ibrutinib as a single-agent therapy and six different chemoimmunotherapy regimens from additional Phase 3 studies in patients with CLL as a first-line therapy, reviewing results in PFS, overall survival (OS) and safety measures. The six chemoimmunotherapy regimens included as part of the cross-trial comparison are fludarabine, cyclophosphamide and rituximab (FCR); bendamustine and rituximab (BR); obinutuzumab and chlorambucil; rituximab and chlorambucil; and ofatumumab and chlorambucil. This data will also be presented at ASH on Dec. 9 (abstract #1750).

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH 2017, which includes 12 oral presentations, please click here.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking a protein called Bruton's tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells as well as other serious, debilitating conditions.⁴ IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host-disease (cGVHD).⁵

• IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
• Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
• IMBRUVICA was approved for adult patients with WM in January 2015.
• In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously-treated CLL/SLL.
• In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
• In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.

Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.⁶ IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 90,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical 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 post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies 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 (e.g., 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 anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 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, 2 to 13%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (e.g., 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. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%), muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%), and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%), pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA® in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

DRUG INTERACTIONS

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

CYP3A Inhibitors: Dose adjustment may be recommended.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose.

About AbbVie
AbbVie is a global, research-driven biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook or LinkedIn.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2015 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

IMBRUVICA® is a registered trademark of Pharmacyclics LLC.

1 IMS Database [Data on File].
2 American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed December 2017.
3 American Cancer Society. Leukemia – chronic lymphocytic. http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Accessed December 2017.
4 Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed December 2017.
5 Janssen Biotech, Inc., Pharmacyclics LLC. IMBRUVICA U.S. prescribing information.  https://www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing_information.pdf. Accessed December 2017.
6 U.S. Food and Drug Administration. Fact sheet: breakthrough therapies. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htm. Accessed December 2017.

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SOURCE AbbVie Inc.