Phase 2 IMBRUVICA® (ibrutinib) Plus VENCLEXTA® (venetoclax) Early Data Show High Rates of Responses in Patients with Previously-Untreated Chronic Lymphocytic Leukemia (CLL)

NORTH CHICAGO, Ill., June 3, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced positive data from the Phase 2 CAPTIVATE (PCYC-1142) study evaluating IMBRUVICA^® (ibrutinib) in combination with VENCLEXTA^® (venetoclax) in previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Early results of the combination oral regimen suggest promising activity in treatment-naïve CLL/SLL with 77 percent of the first 30 patients achieving responses with no detectable minimal residual disease (MRD) after six cycles of the combination therapy. MRD is determined by measuring the number of cancer cells remaining and helps confirm depth of remission. The first 14 CLL/SLL patients to complete the clinical trial combination therapy of 12 cycles (15 cycles of ibrutinib) achieved responses with no detectable MRD in approximately nine out of 10 patients, with 93 percent achieving MRD negativity when measuring in peripheral blood and 86 percent with MRD negativity when measuring in the bone marrow.¹

These data will be presented today as an oral presentation at the 54^th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago (abstract #7502).¹ The results were also selected for the 2018 Best of ASCO Meetings. IMBRUVICA is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"The findings underscore prior data sets that have been reported by external investigators and support the potential benefit of combining these two agents with complementary mechanisms of action, IMBRUVICA and venetoclax, which may work together to deliver deep responses in chronic lymphocytic leukemia," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "The Phase 2 results from the CAPTIVATE study suggest we could be one step closer to advancing treatment without the use of chemotherapy for patients with CLL and SLL."

CLL is the most common form 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). These cancer cells start in the bone marrow and later spread to the blood. The prevalence of CLL is approximately 115,000 patients in the U.S. with approximately 19,000 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 CLL/SLL are predominantly diseases of the elderly, with an average age of 70 at diagnosis.³ Treatment options for CLL vary greatly, depending on the person's age, the disease risk group, and symptoms. Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn't been shown to help people live longer.⁵

"IMBRUVICA demonstrates the progress made in evaluating non-chemotherapy treatments for CLL and the potential for improved outcomes," said William G. Wierda, M.D., Ph.D., D.B. Lane Cancer Research Distinguished Professor, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, TX, and lead investigator of the CAPTIVATE study.* "We are now working with IMBRUVICA on treatments directed at potentially achieving deep remission with undetectable minimal residual disease and anticipate long treatment-free remissions. Early results from the CAPTIVATE study suggest that IMBRUVICA, when used in combination with venetoclax, may be able drive this much-desired outcome – deep undetectable MRD remission."

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASCO 2018, please visit: https://meetinglibrary.asco.org/.

Abstract #7502: Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL)
Oral presentation: Sunday, June 3 at 10:09 – 10:21 a.m. CDT

In the Phase 2 CAPTIVATE (PCYC-1142) study, treatment-naïve CLL/SLL patients received single-agent ibrutinib (420 mg/day) alone for three 28-day cycles before initiating venetoclax ramp-up (standard ramp-up to 400 mg/day). Early data suggest promising activity for the combination oral regimen with undetectable MRD achieved in 77% of the first 30 patients after six cycles of therapy and undetectable MRD in 86% of the first 14 patients after 12 cycles of therapy in both the bone marrow and blood.

CAPTIVATE is a multicenter study that has enrolled 164 treatment-naïve CLL/SLL patients as defined by the International Workshop on Chronic Lymphocytic Leukemia criteria (median age: 58); 15% had del17p, 18% had del11q, and 32% had longest lymph node diameter (LDi) of 5 or more centimeters (cm). The trial was designed to evaluate if remission with undetectable MRD can provide treatment-naïve CLL/SLL patients with treatment holidays (a period of time when a patient is able to stop therapy).

The first 30 patients enrolled for safety run-in completed six or more cycles of ibrutinib and venetoclax (median treatment duration: 10.4 months ibrutinib, 7.6 months venetoclax). In the safety run-in of the first 14 patients who completed 12 cycles of ibrutinib and venetoclax, no dose-limiting toxicities occurred, with an overall response rate of 100% in the 11 patients assessed (6 complete responses, 5 partial responses). Bone marrow was MRD-negative in 12 of 14 assessed patients after 12 cycles of ibrutinib and venetoclax.

The most common AEs (occurring in ≥ 20% patients) were diarrhea (63%), fatigue (27%), nausea (35%), headache (24%), upper respiratory tract infection (24%) and arthralgia (29%). Grade 3 or higher AEs (occurring in ≥ 3% patients) were neutropenia (27%), hypertension (6%), diarrhea (4%) and thrombocytopenia (6%). No clinical tumor lysis syndrome (TLS) occurred and lab TLS was seen in 1 of 164 patients. In treated patients with baseline LDi 5 cm or greater, LDi decreased to less than 5 cm in 43 of 53 patients (81%) after ibrutinib lead-in. TLS risk shifted from high to medium/low in 36 of 40 patients (90%), and overall, the proportion of high-risk TLS decreased from 24% at baseline to 3% after ibrutinib lead-in.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking 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 as well as other serious, debilitating conditions.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 initially 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 previously treated 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.

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, 100,000 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 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 14% to 29% of patients. 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 (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) 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 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. 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 (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 anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 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, 2 to 13%).

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 (62%)*, neutropenia (61%)*, diarrhea (43%), anemia (41%)*, musculoskeletal pain (30%), bruising (30%), rash (30%), fatigue (29%), nausea (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%)*, thrombocytopenia (16%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9 % (WM [6%] 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 adjustment 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-driven 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 or LinkedIn.

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.
SOURCE AbbVie Inc.

*Disclaimer: Dr. Wierda served as lead investigator of this Pharmacyclics-sponsored clinical study. Dr. Wierda does not have a financial interest in the company.

¹ Wierda WG et al. ASCO 2018 Abstract #7502. June 2018.
² IMS Database [Data on File].
³ American Cancer Society. What are the key statistics for chronic lymphocytic leukemia? http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed May 2018.
⁴ American Cancer Society. Leukemia – chronic lymphocytic. http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Accessed May 2018.
⁵ American Cancer Society. Typical Treatment of Chronic Lymphocytic Leukemia. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/treating/treatment-by-risk-group.html. Accessed May 2018.
⁶ Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed May 2018.
⁷ IMBRUVICA U.S. Prescribing Information, February 2018.
⁸ U.S. Food and Drug Administration. Fact sheet: breakthrough therapies. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htm. Accessed May 2018.

SOURCE AbbVie

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