12.04.16 Press Release

Favorable Response Rates Suggest Promise of Ibrutinib (IMBRUVICA®) Combination Therapy in Two Common Types of Non-Hodgkin's Lymphoma

NORTH CHICAGO, Ill., Dec. 4, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced encouraging efficacy and safety findings from two separate studies evaluating ibrutinib (IMBRUVICA®) as a combination therapy in two of the most common types of non-Hodgkin's lymphoma: diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). 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.

In a Phase 1b study of patients with relapsed/refractory (R/R) DLBCL, the investigational combination of ibrutinib, rituximab, and escalating doses of lenalidomide were tested (abstract #473). Preliminary efficacy results demonstrated the highest response rate was observed in patients with the worst prognosis subtype (non-GCB) and in patients with transformed disease.1 These data will be presented today in an oral presentation at the 58th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, CA.

"Though standard therapy can cure over half of patients with diffuse large B-cell lymphoma (the most common form of aggressive lymphoma), patients with relapsed or refractory disease do overall poorly with only less than a quarter of patients efficiently salvaged with current strategies including stem cell transplantation," said Andre Goy, M.D., Chairman and Executive Director at John Theurer Cancer Center at Hackensack University Medical Center in New Jersey and lead investigator of the study.* "We are encouraged by these results in a heavily pretreated and refractory population and look forward to further evaluating the efficacy of ibrutinib combination therapy with rituximab and lenalidomide in the Phase 2 portion of the study." 

Separately at the meeting, data from a Phase 2 multicenter study showed that the combination of ibrutinib and rituximab produced favorable response rates in patients with previously untreated FL (abstract #1804). At a median time on study of 22 months, the overall response rate (ORR) was 85%, with 35% of patients achieving a complete response (CR).2 The data were presented in a poster presentation on Saturday, December 3.

"We are highly encouraged by this longer-term data showing strong and durable responses that appear to improve with an extended treatment duration," said Nathan Fowler, M.D., Associate Professor, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX and lead investigator of the study.* "The results of the study to date suggest that the addition of ibrutinib to rituximab in the front-line follicular lymphoma setting provides enhanced outcomes over rituximab alone."

DLCBL is an aggressive B-cell lymphoma and the most common subtype of non-Hodgkin's lymphoma. Despite 50-60% of patients being cured with standard chemo-immunotherapy, patients who relapse have poor outcomes.3 FL is the most common subtype of indolent non-Hodgkin's lymphoma. It is often slow-growing, but is considered incurable in advanced stages. Over time, about one-third of FL cases advance to the fast-growing DLBCL.4 

"The response rates observed with ibrutinib combination therapy in treatment-naïve follicular lymphoma and relapsed/refractory diffuse large B-cell lymphoma show promise for patients with two different types of non-Hodgkin's lymphoma," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics LLC, an AbbVie company. "We pioneered the development of BTK inhibition with ibrutinib, and we continue to progress our robust development program. Based on the encouraging Phase 2 study results in FL, we are initiating a Phase 3 study of the combination of ibrutinib and rituximab in the first-line setting."

About the Studies

Abstract #473: A multicenter, open-label phase 1b/2 study of ibrutinib in combination with lenalidomide and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma (Oral Presentation;Sunday, December 4, 4:30 PM PT)

Subjects with R/R DLBCL were treated with the investigational combination of ibrutinib 560 mg once daily, rituximab 375 mg/m2 on day one for six cycles and escalating doses of lenalidomide. Preliminary data for 45 patients showed responses on 15 mg, 20 mg, and 25 mg lenalidomide, with responses for patients with the non-GCB subtype (response-evaluable population) seen in more than half of the subjects. Patients with transformed disease also showed favorable responses. Overall, the treatment combination was tolerable. The most frequent Grade 3 or 4 adverse events (AEs) were neutropenia (38%), thrombocytopenia (11%), and maculopapular rash (11%). Based on safety data from this portion of the study, the Phase 2 portion of the trial is being initiated.1

Abstract #1804: Ibrutinib combined with rituximab in treatment-naïve patients with follicular lymphoma: Arm 1 + arm 2 results from a multicenter, open-label phase 2 study (Poster Presentation; Saturday, December 3, 5:30 PM – 7:30 PM PT)

Updated data were presented for 80 patients with FL receiving two different administration schedules of ibrutinib and rituximab (Arm 1, 60 patients; Arm 2, 20 patients). In Arm 1 at a median time on study of 22 months, the ORR was 85%, with 35% CR. Median time to best response was 2.7 months. With a median time on study of 15 months in Arm 2, ORR was 75%, with 35% CR. Median time to best response was 4.3 months. Median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were not reached in either arm.2

In Arm 1, patients received ibrutinib 560 mg once daily until disease progression or unacceptable toxicity and rituximab 375 mg/m2 once weekly for four weeks. In Arm 2, patients received ibrutinib 560 mg once daily for eight weeks, then concurrent rituximab once weekly for four weeks, followed by ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DOR, PFS and OS.2

Treatment was well tolerated, with no new safety signals with longer follow up. AEs were primarily Grade 1 or 2. The most common AEs included fatigue (68%), diarrhea (52%), nausea (47%), headache (30%), cough, myalgia, maculopapular rash (28% each), and muscle spasms (23%) in Arm 1, and fatigue (80%), diarrhea (60%), nausea (55%), myalgia (45%), maculopapular rash (35%), and headache, cough and muscle spasms (25% each) in Arm 2. Common Grade 3 or 4 AEs in either Arm 1 or 2 included maculopapular rash (5% and 10%, respectively), fatigue (7% and 5%), pyrexia (3% and 10%) and diarrhea (2% and 10%).2

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.5,6 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.5

IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with mantle cell lymphoma who have received at least one prior therapy and patients with Waldenström's macroglobulinemia. 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.5

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. Goy and Dr. Fowler served as investigators of Pharmacyclics-sponsored clinical studies as noted. Dr. Goy and Dr. Fowler do not have a financial interest in the company.

1 Goy A, et al., A multicenter open-label phase 1b/2 study of ibrutinib in combination with lenalidomide and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma.  ASH 2016 Abstract #473.
2 Fowler N, et al. Ibrutinib combined with rituximab in treatment-naïve patients with follicular lymphoma: Arm 1 + Arm 2 results from a multicenter, open-label phase 2 study. ASH 2016 Abstract #1804.
3 Vaidya  R, Witzig TE. Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era. Annals of Oncology 2014; 25: 2124–2133. 
4 American Cancer Society. Types of non-Hodgkin lymphoma. Available from: http://www.cancer.org/cancer/non-hodgkinlymphoma/detailedguide/non-hodgkin-lymphoma-types-of-non-hodgkin-lymphoma Accessed November 2016.
5 IMBRUVICA US Prescribing Information, June 2016.
6 Genetics Home Reference. Isolated growth hormone deficiency. Available from: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed November 2016.

SOURCE AbbVie

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