The Janssen Pharmaceutical Companies of
The study demonstrated superior progression-free survival (PFS) of a once-daily, all-oral, fixed-duration regimen of I+V versus Clb+O as first-line treatment of CLL; the study also showed improved duration of remission and significantly improved depth of remission.[1] With I+V, undetectable minimal residual disease (uMRD) in peripheral blood (PB) was sustained by 85 percent of patients one year after end of treatment.1 The safety and tolerability profile of I+V was consistent with CLL treatment in an older population with comorbidities.1 These data were featured in the
'In the GLOW study, two very active blood cancer treatments are combined to create a complementary therapeutic regimen with the hope that deep responses might enable treatment-free remission for patients,' said
The GLOW study evaluated the efficacy and safety of first-line fixed-duration I+V versus Clb+O in elderly patients with CLL/SLL, or patients ages 18-64 with a cumulative illness rating scale (CIRS) score of greater than six or creatinine clearance less than 70 mL/min.1 The CIRS score measures comorbidity, or concurrent non-CLL illness, in patients across multiple body systems.[2] GLOW excluded patients with del(17p) or known TP53 mutations. Randomization to fixed-duration I+V or a standard six 28-day cycle of Clb+O was stratified by immunoglobulin heavy chain variable region gene (IgHV) mutational status and del(11q) status.1 Patients in the I+V arm received three months of IMBRUVICA lead-in therapy followed by 12 months of combination I+V therapy, and all patients stopped therapy regardless of MRD status.1 In the study, 106 patients received I+V and 105 received Clb+O (n=211; median age, 71 years).1
At a median follow-up of 27.7 months, independent review committee (IRC)-assessed PFS for fixed-duration I+V was superior to Clb+O [
Responses to fixed-duration I+V were sustained after EOT; 84.5 percent (49/58) of patients maintained peripheral blood uMRD from EOT+3 to the assessment 12 months after EOT (EOT+12).1 Thereby, with a median follow-up of 27.7 months, time to next anti-cancer therapy was extended with I+V vs. Clb+O [HR, 0.143; 95 percent CI, 0.05-0.41].1
The most common Grade 3 or higher treatment-emergent adverse events (TEAEs) for fixed-duration I+V were neutropenia/neutrophil count decrease (34.9 percent), infections (17 percent), and diarrhea (10.4 percent) and neutropenia/neutrophil count decrease (49.5 percent), thrombocytopenia (20 percent), and infections (11.4 percent) for Clb+O.1 Deaths during treatment occurred in seven patients on fixed-duration I+V and two patients on Clb+O.1 At time of analysis, overall survival was immature; there were eleven deaths in the fixed-duration I+V arm and twelve in the Clb+O arm.1
Data from the Fixed-Duration Cohort of the Phase 2 CAPTIVATE (PCYC-1142) Study of IMBRUVICA-Based Combination Regimen in Previously Untreated Patients with CLL (Abstract #S147)
GLOW is part of a comprehensive development program exploring the potential of IMBRUVICA-based fixed-duration therapy in previously untreated CLL. This includes the fixed-duration cohort from the Phase 2 CAPTIVATE study in young, fit patients that was recently presented at the 2021
The safety profile of the I+V regimen in CAPTIVATE was consistent with known safety profiles of IMBRUVICA and venetoclax.4 Of note, 21 percent of patients were at risk for tumor lysis syndrome (TLS) based on high tumor burden at baseline, and this was reduced to one percent after three cycles of IMBRUVICA lead-in therapy.[3] AEs were primarily Grade 1/2.4 The most common Grade 3/4 AEs were neutropenia (33 percent), infections (eight percent), hypertension (six percent), and neutrophil count decrease (five percent).4 Discontinuations due to AEs were infrequent (three percent for IMBRUVICA).4
'IMBRUVICA and venetoclax have complementary mechanisms of action, and the promising results from the CAPTIVATE and GLOW studies show that this all-oral regimen that many patients can take at home may provide an effective, flexible treatment option for patients with CLL/SLL seeking a fixed-duration therapy,' said
About IMBRUVICA
IMBRUVICA (ibrutinib) is a once-daily oral medication that is jointly developed and commercialized by
IMBRUVICA is approved in more than 100 countries, and, to date, is the only BTK inhibitor that has been used to treat more than 230,000 patients worldwide.
IMBRUVICA was first approved by the
Accelerated approval was granted for MCL and MZL 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 is the most comprehensively studied BTKi, with more than 150 active clinical trials in several blood cancers and other serious diseases.
IMBRUVICA IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Fatal bleeding events have occurred in patients who received IMBRUVICA. Major hemorrhage (Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and postprocedural hemorrhage) occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA, respectively.
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. Across clinical trials, 3.1% of 2,838 patients who received 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 21% of 1,476 patients who received 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: In 645 patients with B-cell malignancies who received IMBRUVICA as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 3%, based on laboratory measurements.
Monitor complete blood counts monthly.
Cardiac Arrhythmias and Cardiac Failure: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4%, and Grade 3 or greater cardiac failure occurred in 1% of 1,476 patients who received 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.
At baseline and then periodically, monitor patients clinically for cardiac arrhythmias and cardiac failure. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias and cardiac failure appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.
Hypertension: Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 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%), occurred among the 1,476 patients who received 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. 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period.
ADVERSE REACTIONS
B-cell malignancies: The most common adverse reactions (30%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (54.5%), diarrhea (43.8%), fatigue (39.1%), musculoskeletal pain (38.8%), neutropenia (38.6%), rash (35.8%), anemia (35.0%), and bruising (32.0%).
The most common Grade 3 adverse reactions (5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (20.7%), thrombocytopenia (13.6%), pneumonia (8.2%), and hypertension (8.0%).
Approximately 9% (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).
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 hepatic impairment. In patients with mild or moderate impairment, reduce recommended IMBRUVICA dose and monitor more frequently for adverse reactions of IMBRUVICA.
About the Janssen Pharmaceutical Companies of
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Cautions Concerning Forward-Looking Statements
This press release contains 'forward-looking statements' as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of IMBRUVICA (ibrutinib). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of
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