Extended Follow-up Phase 3 Data Underscore Sustained Efficacy and Safety of IMBRUVICA® (ibrutinib) in the Treatment of Chronic Lymphocytic Leukemia (CLL)

NORTH CHICAGO, Ill., Dec. 7, 2019 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced results from an extended follow-up analysis of the Phase 3 E1912 clinical study - designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), which is part of the National Institutes of Health. Study results showed superior progression-free survival (PFS) and overall survival (OS) in patients with chronic lymphocytic leukemia (CLL) new to treatment.

These results demonstrated the benefits of IMBRUVICA(®) (ibrutinib) plus rituximab compared to a standard chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab (FCR) for previously untreated patients with CLL aged 70 years or younger. These results were featured today in the CLL Therapy Oral Presentation Session at the American Society of Hematology (ASH) Annual Meeting, and served as the basis of the recent supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) to expand further the IMBRUVICA prescribing label in CLL.

Additionally, a new integrated analysis of up to six years of long-term follow-up from the Phase 3 RESONATE(TM) and RESONATE-2 studies will be presented on December 8 at the ASH Annual Meeting, evaluating the use of IMBRUVICA monotherapy in previously untreated patients. Results showed better PFS, OS and overall response rate (ORR), with good tolerability compared to use in the relapsed/refractory (R/R) setting.

"These latest findings add to the extensive clinical evidence supporting the use of IMBRUVICA, the most comprehensively studied BTK inhibitor in CLL, as both a single-agent and as a combination regimen to improve patient outcomes in early lines of treatment, which has previously been reserved for chemoimmunotherapy," said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company. "We're pleased to present extended follow-up results from the Phase 3 E1912 and RESONATE/RESONATE-2 studies at this year's ASH Annual Meeting - all of which are landmark clinical trials that have uniquely changed our understanding of CLL."

"Phase 3 RESONATE and RESONATE-2 trials have proven to be cornerstone studies that have significantly advanced the treatment of CLL among a variety of patients - and the latest data presented at this year's ASH Annual Meeting demonstrate using IMBRUVICA alone and earlier in CLL treatment results in improved patient outcomes," said Paul M. Barr, M.D., study investigator of the Phase 3 RESONATE and RESONATE-2 trials, and Associate Professor of Medicine, Hematology/Oncology at the Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York. "These results reaffirm the sustained disease control and safety profile of IMBRUVICA and further support its use as a chemotherapy-free option for previously untreated patients living with this common form of adult leukemia."

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.

Abstract #33: E1912 extended follow-up of IMBRUVICA plus rituximab compared to FCR in patients with CLL/SLL aged 70 or younger

Oral Presentation: Saturday, December 7, 2019 at 7:30 a.m. EST

Longer-term outcomes data from the Phase 3 E1912 clinical trial - designed and conducted by ECOG-ACRIN and sponsored by the NCI - were presented today in an oral session. As previously reported in earlier data readouts, the study evaluated 354 previously untreated patients with CLL aged 70 years or younger who were randomly assigned to receive IMBRUVICA and rituximab or six courses of intravenous FCR chemoimmunotherapy every 28 days. The study met the primary endpoints of PFS and OS.

At a median follow-up of 48 months, 73 percent of patients in the IMBRUVICA plus rituximab treatment arm remained on IMBRUVICA with median time on treatment of 43 months (range of 0.2 to 61 months). The median time to progression or death after discontinuing IMBRUVICA was 23 months. Superior PFS benefits were sustained for the IMBRUVICA plus rituximab arm compared to the FCR treatment arm (hazard ratio [HR]: 0.39; 95 percent confidence interval [CI], 0.26-0.57; p<0.0001). OS also continued to favor the IMBRUVICA plus rituximab arm (HR=0.34, 95 percent CI, 0.15-0.79; p=0.009). Grade 3 and above treatment-related adverse events (AEs) were observed in 70 percent of patients in the IMBRUVICA plus rituximab arm versus 80 percent in the FCR arm (odds ratio [OR]: 0.56; 95 percent CI, 0.34 - 0.90; p=0.013).

The E1912 study served as the basis of the recent sNDA to the U.S. FDA to expand the IMBRUVICA label to include the combination with rituximab for the first-line treatment of patients with CLL or SLL. The submission is being reviewed by the FDA under the Real-Time Oncology Review pilot program.

Abstract #3054: New RESONATE/RESONATE-2 long-term analysis of ibrutinib monotherapy in earlier lines of CLL treatment

Poster Presentation: Sunday, December 8, 2019 at 6:00 p.m. EST

A new integrated analysis with up to six years of follow-up from the Phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115/1116) studies evaluating IMBRUVICA monotherapy in previously untreated patients (n=136; median age of 73 years) and R/R patients (n=135; median age of 65 years for patients with 1-2 prior lines; median age of 67 years for patients with 3 or more lines) with CLL will be presented. Results reported IMBRUVICA monotherapy demonstrated improved PFS, OS and ORR, with sustained efficacy for the first-line patient group, including patients with high-risk prognostic features, compared to the R/R group.

At up to six years of follow-up (first-line group: median of 59.8 months; 1-2 prior lines: 66.2 months; 3 or more prior lines: 65.1 months), the median PFS was not reached for the first-line or the 1-2 prior lines groups, and median PFS was 40.1 months for the 3 or more prior lines group. A greater portion of patients treated with IMBRUVICA in earlier lines remained progression-free or alive at 60 months (first-line: 70 percent; 1-2 prior lines: 60 percent; 3 or more prior lines: 33 percent), and first-line treatment resulted in a 34 percent reduction in risk of disease progression or death compared to patients who had 1-2 prior lines of therapy (HR: 0.66; 95 percent CI, 0.40 - 1.09). PFS was significantly prolonged for patients receiving first-line treatment compared to those who have received 3 or more prior therapy (HR: 0.32; 95 percent CI, 0.21 - 0.49). Furthermore, median OS for the first-line or 1-2 prior lines group was not reached and was 67.4 months for the 3 or more prior lines group. At 60 months, the ORR was 92 percent (first-line), 96 percent (1-2 prior lines) and 88 percent (3 or more prior lines).

At the time of analysis, 58 percent of patients remain on IMBRUVICA in the first-line group. Overall, 6 percent of patients in the first-line group discontinued due to progressive disease, while it was the most common reason for discontinuation for patients who received 1-2 prior lines of therapy (22 percent) and for those who received 3 or more prior lines (37 percent). Across all three groups, 19 percent of patients discontinued due to AEs (first-line: 21 percent; 1-2 prior: 19 percent; 3 or more prior: 15 percent).


IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works differently than chemotherapy as it blocks a protein called Bruton's tyrosine kinase (BTK). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.(1,2) By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.(3)

Since its launch in 2013, IMBRUVICA has received 10 FDA approvals across six disease areas:
chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström's macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* - and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.(4)

IMBRUVICA is now approved in 95 countries and has been used to treat more than 170,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. 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. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(®)) for CLL recommends ibrutinib (IMBRUVICA(®)) as a preferred regimen for the initial treatment of CLL/SLL and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 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. For more information, visit www.IMBRUVICA.com.

*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.



Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA(®). Major hemorrhage (>= Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA(®) in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA(®).

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA(®) increases the risk of major hemorrhage. In IMBRUVICA(®) clinical trials, 3.1% of patients taking IMBRUVICA(®) without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA(®). Monitor for signs and symptoms 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 1,124 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 1,124 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 of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA(®) in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA(®) and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA(®) as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 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.


B-cell malignancies: The most common adverse reactions (>=20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), 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 (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (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%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (>=5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (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.


CYP3A Inhibitors: Co-administration of IMBRUVICA(®) with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA(®) may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA(®) if strong inhibitors are used short-term (e.g., for <= 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.


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.
SOURCE AbbVie Inc.

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