IMBRUVICA® (Ibrutinib) Phase 3 RAY Data Show Significant Reductions in Disease Progression versus Temsirolimus in Relapsed/Refractory Mantle Cell Lymphoma Patients

NORTH CHICAGO, Ill., Dec. 7, 2015 /PRNewswire/ -- Today AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced results from the Phase 3 RAY (MCL3001) trial, which showed IMBRUVICA^® (ibrutinib) significantly prolonged progression-free survival (PFS; the primary endpoint) and improved overall response rates (ORR; a key secondary endpoint) in patients with relapsed or refractory mantle cell lymphoma (MCL), compared with temsirolimus. Notably, IMBRUVICA was associated with a 57% reduction in the risk of 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 57^th Annual American Society of Hematology (ASH) Meeting and Exposition in Orlando, FL. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc.

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.^1,2  MCL is more prevalent in men than women.¹ The majority of patients are in their mid-60s at diagnosis and the median overall survival rate is three to four years.^1,3

"MCL patients typically achieve only short-term remissions with conventional therapies, so the positive results seen with IMBRUVICA in this Phase 3 trial are particularly striking," said Simon Rule, M.D., Consultant Haematologist, Department of Haematology, and Head of the Lymphoma Service, Derriford Hospital, Plymouth, UK, and RAY study investigator. "As clinicians, we strive to ensure our patients receive safe and effective treatment options. The RAY data show IMBRUVICA was associated with an improved risk-benefit profile compared to temsirolimus."

IMBRUVICA significantly improved PFS as determined by an Independent Review Committee (IRC) compared to treatment with temsirolimus, resulting in a reduction in the risk of disease progression or death by 57% after a median follow-up of 20 months (HR 0.43 [95% CI, 0.32-0.58; P<0.0001]). The median PFS for IMBRUVICA-treated patients was 14.6 months compared to 6.2 months for patients treated with temsirolimus. IMBRUVICA was associated with a significantly higher ORR versus temsirolimus as assessed by an IRC (72% vs. 40%, respectively; difference 31.­5% [95% CI, 20­.5–42.­5]; p<0­0001). Twenty-six patients who received IMBRUVICA (19%) achieved a complete response (CR), while only two patients who received temsirolimus experienced a CR (1%). Of note, the median treatment duration was four times longer in patients taking IMBRUVICA than those receiving temsirolimus (14.4 months vs. 3.0 months, respectively). Median overall survival was not reached with IMBRUVICA, as compared to 21.3 months with temsirolimus (HR, 0.76; [95% CI, 0.53-1.09).

These findings are consistent with results from previous single-arm Phase 2 studies evaluating the safety and efficacy of IMBRUVICA in patients with MCL.

"These data confirm results from an earlier Phase 2 study, which formed the basis of an accelerated approval of IMBRUVICA for MCL patients who have received at least one prior therapy in the U.S.," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics. "We are pleased to see these results confirm the benefit of IMBRUVICA for patients with this aggressive form of blood cancer."

The most common treatment-emergent adverse events (AEs >20%) observed in IMBRUVICA, included diarrhea (29%), cough (22%) and fatigue (22%); AEs observed in temsirolimus, included thrombocytopenia (56%), anemia (43%), diarrhea (31%), fatigue (29%), neutropenia (26%), epistaxis (24%), cough (22%), peripheral edema (22%) nausea (22%), pyrexia (21%) and stomatitis (21%). The most common hematological AEs (>10%) were thrombocytopenia (18% vs. 56%), anemia (18% vs. 43%) and neutropenia (16% vs. 26%).  

Overall, 7% of IMBRUVICA patients and 26% of temsirolimus patients discontinued treatment due to AEs. After a median follow-up of 20 months, 42% of IMBRUVICA patients died and 45% of patients who received temsirolimus died.

About the RAY Study 
RAY is a Janssen-sponsored Phase 3, open-label trial which 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 in accordance with the approved product 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 IRC-assessed PFS; secondary endpoints included ORR, OS and safety, among others.

About IMBRUVICA 
IMBRUVICA is currently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients who have del 17p and patients with Waldenstrom's macroglobulinemia.⁴ IMBRUVICA is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.⁴ 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.⁴

IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK).⁴ IMBRUVICA was one of the first medicines to receive a U.S. FDA approval after being granted a Breakthrough Therapy Designation, and IMBRUVICA is one of the few therapies to receive three separate designations.

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.^4,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.⁴

IMBRUVICA is being studied alone and in combination with other treatments in several blood cancers. More than 6,100 patients have been treated in clinical trials of IMBRUVICA conducted in 35 countries by more than 800 investigators. Currently, 16 Phase 3 trials have been initiated with IMBRUVICA and 67 trials are registered on www.clinicaltrials.gov.

To learn more about the medical terminology used in this news release, please visit http://stedmansonline.com/.

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
• Waldenstrom's macroglobulinemia

Patients taking IMBRUVICA for CLL or WM should take 420 mg taken orally once daily (or three 140 mg capsules once daily).

Patients taking IMBRUVICA for MCL should take 560 mg taken orally once daily (or four 140 mg capsules once daily).

Capsules should be taken orally with a glass of water. Capsules should be taken whole. Do not open, break, split or chew the capsules.

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 Pharmacyclics, An AbbVie Company 
Pharmacyclics LLC, a wholly-owned subsidiary of AbbVie (NYSE: ABBV), is focused on developing and commercializing innovative small-molecule drugs for the treatment of cancer and immune-mediated diseases. Pharmacyclics' mission is to develop and commercialize novel therapies intended to improve quality of life, increase duration of life and resolve serious unmet medical needs.

Pharmacyclics markets IMBRUVICA and has two product candidates in clinical development and several preclinical molecules in lead optimization. Pharmacyclics is committed to high standards of ethics, scientific rigor and operational efficiency as it moves each of these programs toward commercialization. To learn more, please visit www.pharmacyclics.com.

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, the likelihood that the transaction is consummated, the expected benefits of the transaction, 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.

*Disclaimer: Dr. Rule served as an investigator for the RAY study. He has served as an unpaid advisor to both Pharmacyclics and Janssen in developing the compound ibrutinib. He does not have a financial interest in either company.

IMBRUVICA is a registered trademark of Pharmacyclics LLC

¹ Leukemia and Lymphoma Society. Mantle Cell Lymphoma Facts. http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/mantlecelllymphoma.pdf. Accessed November 2015. 
² Cancer Research UK. What is mantle cell lymphoma. 
http://www.cancerresearchuk.org/cancer-help/type/non-hodgkins-lymphoma/about/types/mantle-cell-lymphoma. Accessed November 2015. 
³ Goy A, Bernstein SH, Kahl B, et al. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol. 2009;20:520-525. 
⁴ IMBRUVICA Prescribing Information, January 2015 
⁵ Genetics Home Reference. Isolated growth hormone deficiency. Available at: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed November 2015.

SOURCE AbbVie

Related Links

http://www.abbvie.com