IMBRUVICA® (ibrutinib) Phase 3 RAY Data Show Significant Improvements in Progression-Free Survival Versus Temsirolimus in Patients with Relapsed or Refractory Mantle Cell Lymphoma

Phase 3 IMBRUVICA monotherapy results in mantle cell lymphoma published online in The Lancet and simultaneously presented at the 2015 American Society of Hematology (ASH) Meeting

This release corresponds to abstract #469

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Janssen Biotech, Inc.

Dec 07, 2015, 08:35 ET

ORLANDO, Fla. and HORSHAM, Pa., Dec. 7, 2015 /PRNewswire/ -- Data from the Phase 3 RAY (MCL3001) study, an investigational clinical trial, showed oral IMBRUVICA^® (ibrutinib) significantly improved progression-free survival (PFS; the primary endpoint) versus intravenous temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL). Janssen Biotech, Inc. announced IMBRUVICA was associated with a 57 percent reduction in the risk of disease progression or death with a median follow-up of 20 months. These data were published online in The Lancet today and presented in an oral session at the 2015 American Society of Hematology (ASH) meeting in Orlando, FL. IMBRUVICA is jointly developed and commercialized by Janssen and Pharmacyclics LLC, an AbbVie company.

These results were presented in full by RAY study investigator Simon Rule, M.D., Consultant Haematologist, Department of Haematology, and Head of the Lymphoma Service, Derriford Hospital, Plymouth, UK, during the "Lymphoma: Therapy with Biologic Agents, excluding Pre-Clinical Models: Biologic Agents in B Cell Lymphoma" session on Monday, December 7 at 7:00 a.m. ET.

"Mantle cell lymphoma is an aggressive blood cancer associated with poor prognoses, as patients typically achieve only short-term remissions with conventional chemotherapy," said Dr. Rule. "The benefits seen with IMBRUVICA versus temsirolimus in the Phase 3 RAY trial show that IMBRUVICA provides a treatment option with a favorable efficacy and safety profile for patients living with this disease."

RAY is a Janssen-sponsored, Phase 3, randomized, open-label trial that enrolled 280 patients with relapsed or refractory MCL who were randomized to receive either IMBRUVICA (N=139) or temsirolimus (N=141). Patients were given either oral IMBRUVICA 560 mg per the approved label or intravenous temsirolimus (175 mg on days 1, 8 and 15 of cycle 1; 75 mg on days 1, 8 and 15 of all subsequent 21-day cycles) until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS as assessed by the Independent Review Committee (IRC); secondary endpoints included overall response rate (ORR), overall survival (OS) and safety, among others.

IMBRUVICA significantly improved PFS as determined by the IRC compared with temsirolimus, reducing the risk of disease progression or death by 57 percent after a median follow-up of 20 months (HR 0.43; [95 percent CI, 0.32-0.58]; P<0.0001). The median PFS for patients who received IMBRUVICA was 14.6 months, compared with 6.2 months for those who received temsirolimus. Notably, at two years, patients receiving IMBRUVICA had a 41 percent PFS rate, compared with seven percent in those receiving temsirolimus.

IMBRUVICA demonstrated a significantly higher ORR versus temsirolimus (72 percent vs. 40 percent, respectively; difference 31.5 percent [95 percent CI, 20.5-42.5]; P<0.0001). Twenty-six patients who received IMBRUVICA (19 percent) achieved a complete response (CR), while only two patients who received temsirolimus experienced a CR (1 percent). These findings are consistent with results from previous trials. Treatment with IMBRUVICA significantly lengthened the time to a patient's next treatment. The median time to next treatment was not reached with IMBRUVICA, versus 11.6 months median time to next treatment with temsirolimus (P<0.0001). These data articulate that subsequent treatments were required more frequently following temsirolimus treatment compared to treatment with IMBRUVICA.

In addition, the median treatment duration was four times longer in patients taking IMBRUVICA (14.4 months vs. 3.0 months, respectively). Median OS was not reached with IMBRUVICA, as compared to 21.3 months with temsirolimus.

"We are encouraged by the positive results achieved in the Phase 3 RAY trial, which confirm the clinical benefit seen in the earlier Phase 2 study that was the basis for the initial U.S. Accelerated Approval in relapsed MCL in 2013," said Craig Tendler, M.D., Vice President, Late-Stage Development and Global Medical Affairs for Oncology, Janssen Research & Development. "As we continue to study IMBRUVICA for the treatment of serious blood cancers, we are very encouraged to see the superior benefit/risk profile of this therapy when evaluated against existing treatments in this setting."

Overall, six percent of IMBRUVICA patients and 26 percent of temsirolimus patients discontinued treatment due to adverse events (AEs); the most common treatment-emergent AEs (≥20 percent) of any Grade for IMBRUVICA, were diarrhea (29 percent), cough (22 percent) and fatigue (22 percent); the most common treatment-emergent AEs (>20 percent) of any Grade for temsirolimus, were thrombocytopenia (56 percent), anemia (43 percent), diarrhea (31 percent), fatigue (29 percent), neutropenia (26 percent), epistaxis (24 percent), cough (22 percent), peripheral edema (22 percent), nausea (22 percent), pyrexia (21 percent) and stomatitis (21 percent). The most common hematological AEs (≥10 percent) were thrombocytopenia (18 percent vs. 56 percent), anemia (18 percent vs. 43 percent) and neutropenia (16 percent vs. 26 percent). After a median follow up of 20 months, 42 percent of patients in the IMBRUVICA group had died and 45 percent of patients in the temsirolimus group had died. The most common cause of death associated with IMBRUVICA was disease progression, while deaths in the temsirolimus arm were primarily attributed to AEs. Grade 3 or higher AEs include atrial fibrillation which was reported in five patients (4 percent) treated with IMBRUVICA and in two patients (1 percent) treated with temsirolimus, and major bleeding which was reported in 14 patients (10 percent) treated with IMBRUVICA and in nine patients (6 percent) treated with temsirolimus.

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 Mantle Cell Lymphoma
Mantle cell lymphoma is an aggressive form of blood cancer which arises from B cells, a type of white blood cell (lymphocyte) that originates in the bone marrow.^3,4 MCL is more prevalent in men than women. The majority of patients are in their mid-60s at diagnosis and this challenging disease is associated with poor prognoses.³

About Janssen Biotech, Inc.
Janssen Biotech, Inc. redefines the standard of care in immunology, oncology, urology and nephrology. Built upon a rich legacy of innovative firsts, Janssen Biotech has delivered on the promise of new treatments and ways to improve the health of individuals with serious disease. Beyond its innovative medicines, Janssen Biotech is at the forefront of developing education and public policy initiatives to ensure patients and their families, caregivers, advocates and health care professionals have access to the latest treatment information, support services and quality care.

Janssen Biotech, Inc. and Janssen Research & Development, LLC are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. For more information on Janssen Biotech, Inc. or its products, visit http://www.janssen.com. Follow us on Twitter at www.twitter.com/JanssenUS.

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, Janssen Biotech, Inc. 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 Leukemia and Lymphoma Society. "Mantle Cell Lymphoma Facts." Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/mantlecelllymphoma.pdf. Accessed December 2015.
⁴ Cancer Research UK. "What is mantle cell lymphoma." Available at: http://www.cancerresearchuk.org/cancer-help/type/non-hodgkins-lymphoma/about/types/mantle-cell-lymphoma. Accessed December 2015.