On December 5, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported efficacy and safety findings from a Phase 2 study demonstrating that nearly half (48%) of patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL) had a complete or partial response with single-agent ibrutinib (IMBRUVICA), as assessed by Independent Review Committee (IRC) investigators (Press release, AbbVie, DEC 5, 2016, View Source [SID1234516940]). The median duration of response was not reached.1 These data will be presented today in an oral presentation at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, CA (abstract #1213). IMBRUVICA, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor, is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.
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MZL is a diverse group of slow-growing non-Hodgkin’s lymphomas arising from white blood cells (lymphocytes) at the edges of lymphoid tissue.2 MZL accounts for approximately 12% of all cases of non-Hodgkin’s lymphoma in adults and the median age at diagnosis is 65 years old.3 There are currently no approved treatments or standards of care specifically indicated for patients with MZL in the United States.
"We are pleased with the 48% response rate seen with ibrutinib in this trial, as the hematology-oncology community has a need for effective new therapies to treat marginal zone lymphoma," said Ariela Noy, M.D., Hematologic Oncologist at Memorial Sloan Kettering Cancer Center in New York and lead investigator of the study.* "In particular, a non-chemotherapy targeted oral option like ibrutinib could represent an important step forward for patients with MZL to keep this incurable type of cancer under control."
In this multicenter, open-label trial, 63 MZL patients (including splenic MZL [SMZL], nodal MZL [NMZL] and extranodal MZL [EMZL] subtypes) received one or more prior therapies including at least one CD20-directed regimen (chemo-immunotherapy or rituximab monotherapy). In the study, 79% of patients experienced some tumor reduction (50 out of 63 patients) and overall response rates (ORR) was 48%, implying that BTK signaling is an important growth and survival factor in MZL. The median time to initial response was 4.5 months.1
Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies. The most common adverse events (AEs) included fatigue (44%), diarrhea (43%), anemia (33%), nausea (25%), thrombocytopenia, peripheral edema and arthralgia (24% each), cough (22%), dyspnea and URTI (21% each). Grade 3 or 4 AEs occurred in 63% of patients. The most frequent were anemia (14%), pneumonia (8%) and fatigue (6%). Grade 1 and 2 atrial fibrillation occurred in four (6%) patients.1
"These findings contribute to the growing body of evidence exploring the use of ibrutinib in different types of hematologic cancers, including marginal zone lymphoma and its three sub-types," said Darrin Beaupre, M.D., Ph.D., Head of Early Development and Immunotherapy at Pharmacyclics LLC, an AbbVie company. "Results from this study support the recent submission of a supplemental New Drug Application to include more patients who may benefit from treatment with ibrutinib."
About the Study
The Phase 2 study evaluated the safety and efficacy of ibrutinib in patients with R/R MZL. The primary objective of the trial was ORR as assessed by an IRC. Duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety were secondary objectives.1 Data from this study were submitted to the U.S. Food and Drug Administration (FDA) in September 2016 as part of a supplemental New Drug Application (sNDA) to expand the current indication for IMBRUVICA.
About IMBRUVICA
IMBRUVICA is a first-in-class, oral, once-daily therapy that inhibits 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.4,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.4
IMBRUVICA is approved to treat patients with CLL/SLL including patients with 17p deletion, patients with mantle cell lymphoma who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.4
IMBRUVICA was one of the first medicines to receive U.S. 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 nearly 30 (n=27) company-sponsored trials underway, 14 of which are Phase 3. In addition, there are more than 40 (n=44) investigator-sponsored trials taking place around the world. To date, more than 65,000 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 postsurgery depending upon the type of surgery and the risk of bleeding.
Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.
Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.
Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed 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 antihypertensive medications and/or initiate antihypertensive treatment as appropriate.
Second Primary Malignancies – Other malignancies (range, 5% 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, 4% to 13%).
Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, 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.
ADVERSE REACTIONS
The most common adverse reactions (?20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia** (64%), thrombocytopenia** (63%), diarrhea (43%), anemia** (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).
**Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
The most common Grade 3 or 4 non-hematologic adverse reactions (?5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).
Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.
Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.
DRUG INTERACTIONS
CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.
CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.
SPECIFIC POPULATIONS
Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.
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