ABBV AbbVie Inc

NORTH CHICAGO, Ill., Dec. 7, 2019 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced results of a 7.5-year pooled analysis showing earlier treatment with IMBRUVICA^® (ibrutinib) monotherapy compared to later lines of therapy (LOT) extended progression-free survival (PFS) and increased the likelihood of a complete response (CR) in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) – demonstrating that some patients achieved a disappearance of any signs of disease.

The updated pooled analysis includes three clinical trials: Phase 2 SPARK, Phase 3 RAY and Phase 2 PCYC-1104. Patients achieving a CR with IMBRUVICA had a strong response, with a median duration of therapy longer than 5.5 years. These results were presented today at the American Society of Hematology (ASH) Annual Meeting.

"MCL is an aggressive B-cell malignancy in which most patients have poor prognosis and are likely to relapse after their initial line of therapy. For those treated with chemotherapy, progression-free survival generally declines with each successive line of treatment," said Simon Rule, M.D., Professor in Haematology, Peninsula Medical School, University of Plymouth, United Kingdom. "These extended follow-up results from the pooled analysis of ibrutinib compared to prior regimens are very encouraging for patients with relapsed or refractory MCL – as they showed treatment with ibrutinib at first relapse versus later lines of therapy resulted in a median progression-free survival of longer than two years."

"Building on the legacy of IMBRUVICA, these latest pooled data presented at ASH, which represent the longest follow-up to-date in mantle cell lymphoma, add to the unprecedented body of evidence supporting the use of IMBRUVICA monotherapy to treat this rare and aggressive form of non-Hodgkin's lymphoma," said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company. "We continue to be pleased by the proven efficacy and safety profile of this pioneering BTK inhibitor, which has shown to delay disease progression and improve durable responses when used at first relapse."

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 #1538: Long-term outcomes with IMBRUVICA versus the prior regimen: a pooled analysis in relapsed/refractory MCL with up to 7.5 years of extended follow-up

Poster Presentation: Saturday, December 7 at 5:30 p.m. EST

The pooled analysis evaluated 370 patients with R/R MCL (median 2 [range 1-9] prior LOTs) enrolled in the SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) studies who received IMBRUVICA 560 mg orally once daily. For the regimen prior to IMBRUVICA, time to next treatment (TTNT) was used as a surrogate for PFS. Progression of disease (POD) on frontline treatment was categorized as early (TTNT less than 24 months) or late (TTNT of 24 months or longer). The median follow-up and exposure for IMBRUVICA-treated patients were 41 months (0.2 – 92.4) and 11.1 months (0.03 – 92.4), respectively. Treatment duration was three years or more in 22.4 percent of patients.

Results showed overall median PFS on IMBRUVICA was 12.5 months (9.8 – 16.6) compared to median TTNT on the prior regimen of 10.9 months (9.1-12.6). PFS for patients who received IMBRUVICA was longer than TTNT on the prior regimen for 50 percent of patients; for 27 percent of patients, PFS was longer than TTNT on the prior regimen by 12 months or more. At five years, PFS rate was 19 percent and overall survival (OS) rate was 41 percent. In patients with one prior LOT, median PFS was 25.4 months (17.5 – 51.8) and OS was 61.6 months (36.0 – not estimable [NE]). In patients with a CR, median PFS was 67.7 months (51.7 – NE) and OS was not reached (NE-NE).

Additionally, of the 99 patients who received IMBRUVICA in second-line, 43 percent had early frontline POD and 57 percent of them had late frontline POD. In patients with early frontline POD, median PFS with IMBRUVICA (13.8 months) was similar to median frontline TTNT (14.0 months); median duration of response (DOR) and OS on IMBRUVICA were 22.1 and 23.5 months, respectively. In patients with late frontline POD, median PFS with IMBRUVICA (57.5 months) was longer than median frontline TTNT (42.2 months); median DOR and OS on IMBRUVICA were not reached.

With up to 92 months of follow-up, 81.6 percent of patients had Grade 3 or higher treatment-emergent adverse events (TEAEs) and 64.9 percent had serious adverse events (SAEs). The most common Grade 3 or higher TEAEs were neutropenia (17 percent), pneumonia (13.5 percent) and thrombocytopenia (12.4 percent). The most common SAEs were pneumonia (13.2 percent), atrial fibrillation (5.7 percent), and dyspnea (4.3 percent).

About IMBRUVICA

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. By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.

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.

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.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

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.

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%)*, 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.

DRUG INTERACTIONS

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. 

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 Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed October 2019.
² Turetsky, et al. Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor. Scientific Reports. volume 4, Article number: 4782 (2014).
³ de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.
⁴ IMBRUVICA U.S. Prescribing Information, September 2019.

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