IMBRUVICA® (ibrutinib) Data in Chronic Lymphocytic Leukemia (CLL) Show up to Seven Years of Progression-free Survival (PFS) in 80 Percent of Previously Untreated Patients, the Longest Follow-up for a Bruton's Tyrosine Kinase Inhibitor to Date

- With up to seven years of treatment, sustained PFS rates with ibrutinib in CLL/small lymphocytic lymphoma (SLL) at 80 percent for previously untreated patients

- Nearly nine out of 10 (89 percent) CLL/SLL patients at time of the seven-year analysis treated with ibrutinib achieved a clinical response rate with stable or improved complete response rates

- These long-term follow-up data were featured at ASH 2018 (abstract #3133)

News provided by

AbbVie

Dec 02, 2018, 12:00 ET

NORTH CHICAGO, Ill., Dec. 2, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced the results of up to seven years of clinical trial follow-up for IMBRUVICA^® (ibrutinib) monotherapy in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the longest follow-up for a Bruton's tyrosine kinase (BTK) inhibitor to date. The updated Phase 1b/2 data demonstrated durable responses in CLL/SLL patients with an overall response rate (ORR) of 89 percent. Evaluated patients included those with high-risk genomic factors such as complex karyotype and unmutated IGHV, and more than 70 patients with three to 12 prior lines of therapy. Progression-free survival (PFS) rates were also sustained (estimated seven-year rates of 80% for previously untreated patients; 32% in the highly pre-treated relapsed/refractory [R/R] groups). The analysis also found that PFS trended better for R/R patients when treated with ibrutinib in earlier lines of therapy (after one or two prior lines of therapy versus three or more lines of prior therapy).

These data were presented today at the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego, CA (Abstract #3133). IMBRUVICA is a once-daily, first-in-class BTK inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"With up to seven years of follow up, IMBRUVICA monotherapy continues to show long-lasting responses and survival benefits in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These results help demonstrate that the benefits of IMBRUVICA can be sustained for many years, which were seen in patients with CLL and SLL that are typically more difficult to treat due to high-risk genomic factors."

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

"The long-term follow-up data with ibrutinib continues to look promising, with remissions that suggest patients are able to live many years beyond what was previously expected," said John C. Byrd, M.D., Warren Brown Chair of Leukemia Research, Professor of Medicine at the Ohio State University and the lead investigator of the seven-year follow-up study. "These data also suggest that starting treatment with ibrutinib as early as possible for CLL and SLL provides the best efficacy over the long-term – an important factor that treating physicians should consider."

About Abstract #3133: Up to 7 Years of Follow-up of Single-Agent Ibrutinib in the Phase 1b/II PCYC-1102 Trial of First Line and Relapsed/Refractory Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Poster presentation: Sunday, December 2 at 6:00 p.m. PST

In the PCYC-1102 and PCYC-1103 studies, newly diagnosed and R/R CLL/SLL patients, including those with high-risk features, received IMBRUVICA with up to seven years of follow up (n=132).

ORR was 89 percent for all patients (complete response [CR], 15%), with similar rates in previously untreated (87%) and R/R patients (89%). CR rates were higher in previously untreated patients (32%) than in R/R patients (10%). Median duration of response (DOR) was not reached (95% confidence interval [CI]: 0+-85+) for newly diagnosed patients but was 57 months (95% CI: 0+-85+) for R/R patients. Median PFS was not reached (95% CI: NE-NE) for newly diagnosed patients and was 51 months (95% CI: 37-70) for R/R patients. Estimated seven-year PFS rates were 80 percent and 32 percent for newly diagnosed and R/R patients, respectively. Median overall survival (OS) was not reached in newly diagnosed (95% CI: 80-NE months) or R/R patients (95% CI: 63-NE months), with estimated seven-year OS rates of 75 percent and 52 percent, respectively.

High grade adverse events (AEs) were reported in 74 percent of newly diagnosed patients and 89 percent of R/R patients. Hypertension (newly diagnosed, 32%; R/R, 26%), diarrhea (newly diagnosed, 16%; R/R, 4%) and hyponatremia (newly diagnosed, 10%; R/R, 0%) were among the most common grade 3 or higher treatment-emergent AEs. Major hemorrhage and grade 3 or higher atrial fibrillation, thrombocytopenia, anemia and arthralgia were observed in 11 percent or less of newly diagnosed and R/R patients. In addition, infection (newly diagnosed, 23%; R/R, 55%) was more common in R/R patients. No new or unexpected AEs were observed, and the occurrence of most grade 3 or higher AEs and serious AEs decreased over time, with the exception of hypertension.

Additional presentation on ibrutinib monotherapy in CLL at ASH 2018

Additional data presented at ASH include a sub-analysis derived from patients with R/R CLL enrolled in the RESONATE™ trial. The sub-analysis assessed the effects of ibrutinib versus ofatumumab on T-cell function (including degranulation and cytokine release) and proliferation. CLL is a B-cell malignancy that is also characterized by profound immune dysregulation, including dysfunctional T cells. These data will also be presented at ASH on December 2 (abstract #3114).

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.

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 December 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.