IMBRUVICA® (ibrutinib) Phase 3 Combination Data with Obinutuzumab Finds Significant Improvement in Progression-Free Survival (PFS) Over Standard Chemoimmunotherapy of Chlorambucil Plus Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

- These data were included in the recent sNDA accepted by the U.S. FDA, which received Priority Review, and could lead to the first chemotherapy-free anti-CD20 combination approved for first-line CLL treatment

- Phase 3 iLLUMINATE study's safety and efficacy results have the potential to add to data supporting IMBRUVICA as an effective treatment for CLL/SLL, alone and in combination with other therapies

- Results highlighted at ASH 2018 in an oral presentation (abstract #691) and simultaneously published in The Lancet Oncology

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AbbVie

Dec 03, 2018, 14:17 ET

NORTH CHICAGO, Ill., Dec. 3, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced results from the Phase 3 iLLUMINATE (PCYC-1130) trial, evaluating the chemotherapy-free, anti-CD20 combination of IMBRUVICA^® (ibrutinib) plus obinutuzumab (Gazyva^®) in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). At a median follow-up of 31 months, study results showed IMBRUVICA plus obinutuzumab significantly prolonged progression-free survival (PFS) (median not reached [NR] vs. 19 months) with a 77 percent reduction in risk of progression or death versus chlorambucil plus obinutuzumab, the current National Comprehensive Cancer Network guidelines Category 1 treatment regimen (hazard ratio [HR] 0.23; 95% confidence interval [CI]: 0.15-0.37; P<0.0001).

The data were presented today in an oral session at the 2018 American Society of Hematology (ASH) Annual Meeting (abstract #691) and were simultaneously published in The Lancet Oncology. Based on these data, a supplemental New Drug Application (sNDA) was recently accepted for Priority Review by the U.S. Food and Drug Administration (FDA) to expand the use of IMBRUVICA in combination with obinutuzumab in previously untreated CLL/SLL. IMBRUVICA is a once-daily, first-in-class Bruton's tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"iLLUMINATE represents one of three IMBRUVICA Phase 3 studies in chronic lymphocytic leukemia being presented at this year's ASH. Results from the iLLUMINATE study support the use of IMBRUVICA as a chemotherapy-free, anti-CD20 combination treatment option versus the current National Comprehensive Cancer Network guidelines Category 1 treatment of chlorambucil plus obinutuzumab," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These latest findings, in addition to seven-year long-term data and a Late-Breaker at this year's ASH, add to the robust amount of data supporting the use of IMBRUVICA as backbone therapy in CLL and SLL."

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).¹ While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 20,000 newly diagnosed patients every year.²^,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 Both CLL and SLL are predominately diseases of the elderly, with a median age at diagnosis ranging from 65-70 years.⁵

"For years, we had to rely on chemotherapy as the only treatment option for patients with previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma," said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and lead study investigator of iLLUMINATE. "We're pleased to share results from iLLUMINATE that help show that it is possible to provide efficacious treatment for patients with CLL and SLL without the use of chemotherapy."

About Abstract #691: Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab as First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE

Oral presentation: Monday, December 3 at 10:30 a.m. PST

In the Phase 3 iLLUMINATE (PCYC-1130) study, newly diagnosed CLL patients were randomized to receive IMBRUVICA 420 milligrams (mg) once daily continuously in combination with obinutuzumab 1000 mg intravenously over six cycles (n=113); or chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle plus obinutuzumab 1000 mg intravenously over six cycles (n=116). The primary endpoint was PFS, as assessed by an Independent Review Committee (IRC). The study also evaluated: PFS for patients with high-risk features (unmutated IGHV, del11q, del17p or TP53 mutation); rate of undetectable minimal residual disease (MRD); overall response rate (ORR); overall survival (OS); and safety.

At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab significantly prolonged the IRC-assessed PFS compared to chlorambucil plus obinutuzumab, with a 77 percent reduction in risk of progression or death (median NR vs. 19 months; hazard ratio [HR] 0.23; 95% CI: 0.15-0.37; P<0.0001). At 30 months, the IRC-assessed PFS rates were 79 percent and 31 percent with ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab, respectively. The investigator-assessed PFS was also significantly improved with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab (median NR vs. 21.9 months; HR 0.26; 95% CI: 0.16-0.42; P<0.0001).

The PFS in the IMBRUVICA plus obinutuzumab arm in the high-risk population, including those with unmutated IGHV, del11q, del17p, or TP53 mutation was assessed, with an 85 percent reduction in risk of progression or death (median not reached vs. 14.7 months; HR 0.15; 95% CI: 0.09-0.27; P<0.0001). In addition, IRC-assessed ORR was higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (88% vs. 73%); complete response (CR)/complete response with incomplete blood recovery (CRi) rates were also higher with 19 percent versus eight percent, respectively. The investigator-assessed ORR was also higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (91% vs. 81%); CR/CRi rates were also higher with 41 percent versus 16 percent, respectively. Depth of remission as reflected by undetectable MRD in blood and/or bone marrow was greater in patients with ibrutinib plus obinutuzumab, with 35 percent of patients showing undetectable MRD compared to 25 percent of patients with chlorambucil plus obinutuzumab. OS rates at 31 months were 86 percent for the ibrutinib arm compared to 85 percent for the chlorambucil arm.

Most common Grade 3 or higher adverse events (AEs) in the ibrutinib plus obinutuzumab arm versus chlorambucil plus obinutuzumab arm were neutropenia (43% vs. 63%), thrombocytopenia (35% vs. 25%), diarrhea (34% vs. 10%), cough (27% vs. 12%), infusion-related reactions (25% vs. 58%), arthralgia (22% vs. 10%), pyrexia (19% vs. 26%), anemia (17% vs. 25%), and nausea (12% vs. 30%). Ibrutinib plus obinutuzumab also seemed to decrease the risk of infusion reactions related to the use of obinutuzumab.

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH 2018, please visit: https://ash.confex.com/ash/2018/webprogram/start.html

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting 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.⁶ IMBRUVICA blocks signals that tell malignant B-cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).⁷

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.

Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.⁸ IMBRUVICA was one of the first medicines to receive 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 more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, more than 135,000 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 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA^® in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% 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 post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA^® therapy. Grade 3 or greater infections occurred in 24% of 1,011 patients exposed to IMBRUVICA^® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA^®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA^®.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA^® therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,011 patients exposed to IMBRUVICA^® in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA^® treatment and follow dose modification guidelines.

Hypertension: Hypertension has occurred in 12% of 1,011 patients treated with IMBRUVICA^® in clinical trials with a median time to onset of 5 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 anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients treated with IMBRUVICA^® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (e.g., 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. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA^® in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA^® in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA^® dose.

Please click here for full Prescribing Information.

About AbbVie
AbbVie is a global, research and development-based biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, LinkedIn or Instagram.

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.

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1} American Society of Hematology. Leukemia. http://www.hematology.org/Patients/Cancers/Leukemia.aspx Accessed December 2018.
² IMS Database [Data on File].
³ National Cancer Institute. Cancer Stat Facts: Leukemia - Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html. Accessed December 2018.
⁴ Leukaemia Foundation. Small lymphocytic lymphoma. https://www.leukaemia.org.au/disease-information/lymphomas/non-hodgkin-lymphoma/other-non-hodgkin-lymphomas/small-lymphocytic-lymphoma/. Accessed December 2018.
⁵ Shanafelt, et al. Age at Diagnosis and the Utility of Prognostic Testing in Patients with Chronic Lymphocytic Leukemia (CLL). Cancer. 2010; 116(20): 4777–4787.
⁶ Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed November 2018.
⁷ IMBRUVICA U.S. Prescribing Information, August 2018.
⁸ U.S. Food and Drug Administration. Fact Sheet: Breakthrough Therapies. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htm. Accessed December 2018.