In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On August 27, 2018, ibrutinib (Imbruvica) was approved for use in combination with rituximab (Rituxan) for the treatment of adult patients with Waldenström’s macroglobulinemia. The approval represents the first approved nonchemotherapy combination option for the treatment of Waldenström’s macroglobulinemia. Ibrutinib was approved as monotherapy for Waldenström’s macroglobulinemia in January 2015.
Supporting Efficacy Data
The current approval is based on findings in the double-blind phase III iNNOVATE trial,1 in which 150 treatment-naive or previously treated patients were randomly assigned to receive ibrutinib at 420 mg daily plus rituximab (n = 75) vs placebo plus rituximab (n = 75) until disease progression or unacceptable toxicity. Rituximab was given at a weekly dose of 375 mg/m2 for 4 consecutive weeks on weeks 1 to 4 followed by a second weekly course for 4 consecutive weeks on weeks 17 to 20. The major efficacy outcome measure was progression-free survival, as assessed by an independent review committee.
Rituximab has boxed warnings for fatal infusion reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy
Patients had a median age of 69 years (range = 36–89 years), 66% were male, 79% were white, 93% had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 45% were treatment-naive. Among previously treated patients, the median number of prior treatments was 2 (range = 1–6). The median baseline serum immunoglobulin M value was 3.2 g/dL (range = 0.6–8.3 g/dL), and MYD88 L265P mutations were present in 77% of patients and absent in 13% of patients (9% not evaluable for mutation status).
Median progression-free survival was not reached in the combination group vs 20.3 months in the rituximab group (hazard ratio [HR] = 0.20, P < .0001). The overall response rate was 72% vs 32%; median duration of response was not reached vs 21.2 months. An exploratory analysis showed sustained hemoglobin improvement (increase ≥ 2 g/dL over baseline for ≥ 8 weeks without blood transfusions or growth factor support) in 65% vs 39%.
How It Is Used
The recommended dose of ibrutinib in Waldenström’s macroglobulinemia as a single agent or in combination with rituximab is 420 mg orally once daily until disease progression or unacceptable toxicity. When administering ibrutinib in combination with rituximab, administration of ibrutinib prior to rituximab should be considered when given on the same day.
Ibrutinib dose modifications for adverse reactions and stepwise dose reductions for recurrent adverse reactions are provided in product labeling. Product labeling provides instructions on dose modification when ibrutinib is used with CYP3A inhibitors and in patients with hepatic impairment. Rituximab prescribing information should be consulted for recommended dosing and dose modifications.
The most common adverse events of any grade in the ibrutinib-plus-rituximab group in iNNOVATE were bruising (37% vs 5% in rituximab group), musculoskeletal pain (35% vs 21%), hemorrhage (32% vs 17%), diarrhea (28% vs 15%), rash (24% vs 11%), arthralgia (24% vs 11%), nausea (21% vs 12%), and hypertension (20% vs 5%). The most common grade 3 or 4 adverse events included hypertension (13% vs 4%), pneumonia (13% vs 3%), neutropenia (12% vs 4%), and atrial fibrillation (12% vs 1%). Grade 3 or 4 infusion-related reactions occurred in 1% of the combination group.
Ibrutinib carries warnings/precautions for hemorrhage, infection, cytopenias, cardiac arrhythmia, hypertension, second primary malignancies (including skin cancers and other carcinomas), tumor-lysis syndrome, and embryofetal toxicity. Patients must be monitored for bleeding, fever and infection, blood pressure, and symptoms of arrhythmia. Complete blood cell counts should be monitored monthly.
Rituximab has boxed warnings for fatal infusion reactions, severe mucocutaneous reactions (some with fatal outcome), hepatitis B virus reactivation (resulting in fulminant hepatitis, hepatic failure, and death in some cases), and progressive multifocal leukoencephalopathy.2 It also carries warnings/precautions for tumor-lysis syndrome, infections, cardiac adverse reactions, renal toxicity, bowel obstruction and perforation, immunizations (live virus vaccinations prior to or during treatment are not recommended), and embryofetal toxicity. ■
1. Imbruvica (ibrutinib) capsules prescribing information, Pharmacyclics LLC, Janssen Biotech, Inc, August 2018. Available at www.imbruvica.com/docs/librariesprovider7/default-document-library/prescribing-information.pdf. Accessed September 10, 2018.
2. Dimopoulos MA, Tedeschi A, Trotman J, et al: Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med 378:2399-2410, 2018.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).