Ibrutinib (IMBRUVICA®) Significantly Improved Progression-Free and Overall Survival Versus Chlorambucil in Patients with Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

ORLANDO, Fla. and RARITAN, N.J., Dec. 6, 2015 /PRNewswire/ -- Data from the investigational, randomized, multi-center, open-label Phase 3 RESONATE™-2 (PCYC-1115) clinical trial show ibrutinib (IMBRUVICA^®) was superior to chlorambucil in all efficacy endpoints measured in patients with treatment-naive chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) aged 65 or older, Janssen Research & Development, LLC announced today. Ibrutinib significantly prolonged progression-free survival (PFS), the study's primary endpoint, and overall survival (OS), a key secondary endpoint, and also improved other hematologic measures. Notably, ibrutinib was associated with a 98 percent OS rate versus 85 percent for chlorambucil at 24 months. These data will be included in a presentation today during the official press program at the 2015 American Society of Hematology (ASH) meeting in Orlando, FL and simultaneously published in The New England Journal of Medicine. IMBRUVICA is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.

These data will be presented in full by RESONATE-2 study investigator Alessandra Tedeschi, M.D., Medical Director, Azienda Ospedaliera Niguarda Ca Granda, Milan, Italy, during the "CLL: Therapy, Excluding Transplantation: Upfront CLL Therapy Excluding Transplantation" session on Monday, December 7 at 7:30 a.m. ET.

"The ibrutinib data represent some of the most compelling results I've seen during my career. These data may change how we clinicians treat patients with CLL or SLL in the front-line setting," said Jan Burger, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas and study lead investigator. "The results showcase the clinical utility of ibrutinib in this setting and the value it may bring as an appropriate treatment option for these patients."

The Independent Review Committee (IRC) found ibrutinib significantly prolonged PFS compared with chlorambucil. The hazard ratio (HR) was 0.16 (95 percent CI, 0.09-0.28; P<0.001), which represents a reduction in the risk of progression or death by 84 percent versus chlorambucil (median not reached vs. 18.9 months); the PFS rate at 18 months was 90 percent for ibrutinib versus 52 percent for chlorambucil. Ibrutinib also significantly prolonged OS (HR=0.16: 95 percent CI, 0.05, 0.56; P=0.001) with a 24-month survival rate of 98 percent, compared to 85 percent for patients in the chlorambucil arm. Additionally, ibrutinib was associated with a significantly higher ORR (86 percent vs. 35 percent; P<0.001) as assessed by the IRC and significantly increased the rate of sustained improvements in both hemoglobin and platelets.

"RESONATE-2 is the first Phase 3 head-to-head trial to evaluate the efficacy and safety of ibrutinib monotherapy versus traditional chemotherapy in patients with treatment-naive CLL. These data have now been submitted to the FDA to broaden the ibrutinib prescribing information," said Craig Tendler, M.D., Vice President, Late-Stage Development and Global Medical Affairs for Oncology, Janssen Research & Development. "We continue to see clinically meaningful improvements in progression-free and overall survival in CLL patients with single-agent ibrutinib that have not been seen before and this suggests that long-term benefits of ibrutinib in the front-line setting may be quite impactful."

The safety of ibrutinib in this patient population was consistent with previously reported studies. It is worth noting that exposure to treatment and adverse event (AE) follow-up was nearly 2.5 times longer for ibrutinib compared with chlorambucil and 87 percent of patients randomized to ibrutinib were still on therapy at the time of analysis. Overall, AEs leading to treatment discontinuation were less frequent with ibrutinib than with chlorambucil (9 percent vs. 23 percent, respectively). The most common AEs (≥ 20 percent) of any Grade in the RESONATE-2 trial for ibrutinib were diarrhea (42 percent), fatigue (30 percent), cough (22 percent) and nausea (22 percent); AEs for chlorambucil included nausea (39 percent), fatigue (38 percent), neutropenia (23 percent) and vomiting (20 percent). Hypertension occurred at a higher rate in the ibrutinib arm (14 percent; Grade 3 in 4 percent, no Grade 4 or 5). All six patients with Grade 3 hypertension were managed with hypertensive medication and did not require ibrutinib dose reduction or discontinuation. Four ibrutinib patients experienced Grade 3 hemorrhage and one experienced Grade 4 hemorrhage. Atrial fibrillation occurred in eight patients (six percent) in the ibrutinib arm and was primarily Grade 2 in six patients and Grade 3 in two patients. It was managed with discontinuation in two patients and without a dose modification in remaining patients.

There were three deaths in the ibrutinib arm and 17 deaths on the chlorambucil arm over the median follow-up of 18.4 months. None of the patients who progressed in the ibrutinib arm died during the subsequent follow-up period. 

The RESONATE-2 results are the basis for a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for treatment-naive patients with CLL, which was filed on September 14, 2015. More information about the study can be found on www.clinicaltrials.gov.

RESONATE-2 is a Pharmacyclics-sponsored trial and its protocol and specific performance goals were established in a special protocol assessment (SPA) with the U.S. FDA. An SPA is an agreement with the FDA that an ongoing Phase 3 clinical trial design, its clinical endpoints and other statistical analyses are acceptable to the Agency to support an approval. The trial enrolled 269 patients with CLL/SLL aged 65 years or older without prior treatment in the U.S., EU and other regions. CLL patients with deletion of the short arm of chromosome 17 (del 17p CLL) were excluded from the trial, as single-agent chlorambucil is not recognized as an appropriate therapy in this patient population. Patients were randomized to receive either ibrutinib 420 mg orally, once daily until progression or toxicity or chlorambucil 0.5 to 0.8 mg/kg on days 1 and 15 of each 28-day cycle for up to 12 cycles. The primary endpoint of the study was PFS as assessed by the IRC according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included ORR, OS, rate of hematologic improvement and safety.

About IMBRUVICA^® (ibrutinib)
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).¹ 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.^1,2 IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread.¹ For more information, visit www.IMBRUVICA.com.

Additional Information about IMBRUVICA^®
INDICATIONS
IMBRUVICA^® is indicated to treat people with:

• 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.
• Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
• Chronic lymphocytic leukemia (CLL) with 17p deletion
• Waldenström's macroglobulinemia (WM)

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA®. 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 antiplatelet or anticoagulant 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^® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA^®. Monitor patients for fever and infections and evaluate promptly.

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%) 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 (e.g., 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 14%) including non-skin 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 11%).

Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA^® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g., high tumor burden).

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 (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%**, NA***), bruising (30%, 12%**, 16%**), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%**, 22%**).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

**Includes multiple ADR terms.

***Not applicable; no associated ADRs.

The most common Grade 3 or 4 non-hematological 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 events.

Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. 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 moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA^® dose.

Please see full Prescribing Information: http://www.imbruvica.com/downloads/Prescribing_Information.pdf

About Chronic Lymphocytic Leukemia
Chronic Lymphocytic Leukemia is a slow-growing blood cancer that most commonly arises from B cells, a type of white blood cell (lymphocyte) that originates in the bone marrow.^3,4 CLL is predominantly a disease of the elderly, with a median age of 71 at diagnosis.⁵

About Janssen Research & Development, LLC
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Research & Development, LLC; Janssen Products, LP; and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit http://www.janssen.com for more information.

Janssen 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. Please visit http://www.janssen.com for more information. 

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 and uncertainties inherent in new product development, including the uncertainty of clinical success and of obtaining regulatory approvals; 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 December 28, 2014, 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.

¹ IMBRUVICA Prescribing Information, January 2015
² Genetics Home Reference. Isolated growth hormone deficiency. Available at: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed December 2015.
³ American Cancer Society. Detailed guide: what is chronic lymphocytic leukemia. Available from: http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Accessed December 2015.
⁴ Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol. 2002;2(12):920-932.
⁵ American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? Available from: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed: December 2015

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