IMBRUVICA® (ibrutinib) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma 5-Year Analysis and Long-Term RESONATE-2 Follow-up Data at ASH 2016 Show Lasting Efficacy

NORTH CHICAGO, Ill., Dec. 3, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced long-term follow-up results evaluating up to five years of IMBRUVICA® (ibrutinib) use in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this analysis, 89% of treatment-naïve (TN) and relapsed/refractory (R/R) patients with CLL/SLL, including those with high-risk disease, show a complete or partial response. Further, almost one-third of patients (29%) who received ibrutinib as their first treatment for the disease achieved a complete response (CR), and patients lived without disease progression longer when treatment was started earlier in the course of the disease (abstract #233). 

These data from the Phase 1b/2 PCYC-1102 trial and PCYC-1103 extension study of single-agent ibrutinib will be presented today in an oral presentation at the 58^th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, CA. Additional ibrutinib data in CLL/SLL to be presented include longer-term efficacy and safety analyses of IMBRUVICA (abstract #234). IMBRUVICA, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company and Janssen Biotech, Inc.

"These five-year results suggest that both previously treated or untreated CLL/SLL patients may achieve robust and long-lasting responses with single-agent ibrutinib, with more patients developing a complete response over time," said Susan O'Brien, M.D., Associate Director for Clinical Science, Chao Family Comprehensive Cancer Center at University of California Irvine Health and lead investigator of the study.* "Our data also suggest that starting treatment with ibrutinib as early as possible in CLL/SLL has promising clinical potential for long-term progression-free and overall survival."   

CLL is a type of cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow. The cancer (leukemia) cells start in the bone marrow but then go into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S.² with approximately 19,000 newly diagnosed patients every year.³ 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.⁴ CLL/SLL are predominately a disease of the elderly, with a median age of 71 at diagnosis.³

"These long-term data, coupled with other ibrutinib studies presented at ASH, add to the evidence that extended treatment with IMBRUVICA may benefit a wide range of CLL/SLL patients, even those with genetic mutations such as deletion 11q that make their disease difficult to control with chemoimmunotherapy," said Danelle James, M.D., M.S., Head of Oncology, Pharmacyclics LLC, an AbbVie company. "We are excited about the potential for this first-in-class BTK inhibitor to continue to reshape treatment expectations and survival benefits in CLL/SLL."

About the Studies

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

With five years of follow-up, the overall response rate (ORR) in patients treated with IMBRUVICA was 89%, with 14% of patients achieving 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 for TN patients and 49 months for R/R patients. At five years, progression-free survival (PFS) was 92% in TN patients and 43% in R/R patients, and overall survival (OS) was 92% for TN patients and 57% for R/R patients. Median PFS was not reached in the TN group and was 52 months for previously treated R/R patients. Median OS was not reached for TN or R/R patients.¹

These results were observed in the subgroup of R/R patients with genetic alterations that put them at high risk for poor outcomes, typically not experiencing durable responses to standard chemotherapies. In these patients, median PFS was 55 months for those with deletion 11q (del11q), 26 months for those with deletion 17p (del17p), 43 months for those with unmutated IGVH, and was not reached for those with deletion 13q (del13q). Additionally, PFS and OS was higher when treatment with IMBRUVICA was started in earlier lines of therapy. Median PFS was not reached in TN patients; 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  

Among all patients, the onset of most Grade 3 or higher treatment-emergent adverse events (TEAEs) was highest in the first year and decreased over time. With about 5 years of follow up, the most frequent Grade 3 or higher adverse events (AEs) were hypertension (26%), pneumonia (22%), neutropenia (17%), thrombocytopenia (9%), and atrial fibrillation (8%).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 and 101 patients 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% had del11q, 47% had del13q, and 78% had unmutated IGVH. The primary endpoint was ORR, and secondary endpoints included duration of response, PFS, and safety. PCYC-1103 is the long-term extension study. Primary results from this trial were published in The New England Journal of Medicine in June 2013⁵ and were the basis for the initial approval of IMBRUVICA in CLL via Breakthrough Therapy Designation 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 results from the pivotal Phase 3 RESONATE-2 trial (PCYC-1115) showed that IMBRUVICA continued to be efficacious as first-line therapy in CLL/SLL at a median 29 months of follow-up. IMBRUVICA reduced the risk of progression or death by 88% compared with chlorambucil, a commonly used chemotherapy agent. 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). Of note, in the high-risk del11q subgroup ibrutinib was associated with a 99% reduction in risk of progression or death compared to chlorambucil (HR= 0.014; 95% CI (0.002-0.108); p<0.0001) and 82% reduction for those without del11q (HR=0.180, 95% CI (0.106-0.303), p<0.0001). With longer follow-up, investigator-assessed ORR was 92% with ibrutinib and 36% with chlorambucil; in the ibrutinib arm, CR or CR with incomplete bone marrow recovery (Cri) improved from 11% at 18.4 months to 18%. In ibrutinib-treated patients, ORR was 100% for patients with del11q and 90% for those without the genetic alteration.⁶

Safety was consistent with the primary analysis of the study and showed that Grade 3 or higher AEs decreased over time. Most AEs that led to discontinuation occurred in the first year of treatment.² The most frequent AEs were neutropenia (12%), pneumonia (7%), anemia (7%) and hypertension (5%). These data will be presented at an oral presentation on Saturday, December 3.

RESONATE-2 is a 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). ⁷  

Results from RESONATE-2 were first presented in an oral session at the ASH meeting in December 2015 and simultaneously published in The New England Journal of Medicine.⁹ The results were also part of the official press program at ASH 2015.

Additional Phase 3 ibrutinib data to be presented at ASH that reinforce its safety and efficacy across patient types in CLL/SLL include: ^8,9

• 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 Three Randomized Phase 3 Studies
  • Poster Presentation: Saturday, December 3, 2016, 5:30 PM - 7:30 PM PT

"The data gathered on ibrutinib's role in treating chronic and small lymphocytic leukemia patients with 11q deletion are encouraging for these patients. As physicians we always want patients to understand that they have options and for our part it's a matter of understanding how to adjust treatment for them," said Thomas J. Kipps, M.D., Ph.D., University of California San Diego, Moores Cancer Center and lead investigator of the study.*

About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits 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.^10,11 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.¹⁰

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström's macroglobulinemia (WM). Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.¹⁰

IMBRUVICA was one of the first medicines to receive U.S. 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 nearly 30 (n=27) company-sponsored trials underway, 14 of which are Phase 3. In addition, there are more than 40 (n=44) investigator-sponsored trials taking place around the world. To date, more than 65,000 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 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 IMBRUVICA^®. 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.

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

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.

SPECIFIC POPULATIONS

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 AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. Together with its wholly-owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

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.

*Disclaimer: Dr. O'Brien and Dr. Kipps served as investigators of Pharmacyclics-sponsored clinical studies as noted. Dr. O'Brien and Dr. Kipps do not have a financial interest in the company.

SOURCE AbbVie

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