In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On November 13, 2013, ibrutinib (Imbruvica) was granted accelerated approval for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.1,2 Approval was based on a multicenter, international, single-arm phase II trial with a primary endpoint of overall response rate.2,3
This indication is based on overall response rate; improvement in survival or disease-related symptoms has not been established. As a condition of accelerated approval, the sponsor is required to submit 24-month follow-up data for all patients in the single-arm trial and the results of a randomized controlled trial comparing ibrutinib plus bendamustine (Treanda)/rituximab (Rituxan) vs bendamustine/rituximab without ibrutinib in patients with newly diagnosed mantle cell lymphoma.
In the study, 111 patients with at least one prior treatment received ibrutinib at 560 mg/d. Patients had a median age of 68 years (range, 40–84 years), 77% were male, 92% were Caucasian, 89% had Eastern Cooperative Oncology Group performance status of 0 or 1, median time from diagnosis was 42 months, 39% of subjects had at at least one tumor ≥ 5 cm, 49% had bone marrow involvement, and 54% had extranodal involvement. Patients had a median of three prior treatments (range, 1–5), including rituximab in 89%, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone in 30%, lenalidomide (Revlimid) in 24%, and stem cell transplantation in 11%.
Median follow-up was 15.3 months, and median treatment duration was 8.3 months. The overall response rate was 65.8% (95% confidence interval [CI] = 56.2%–74.5%), with complete response in 17.1% of patients and partial response in 48.6%. Median duration of response was 17.5 months (95% CI = 15.8 months to not reached).
How It Works
Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways implicated in the pathogenesis of B-cell cancers. Ibrutinib forms a covalent bond with a cysteine residue in the Bruton’s tyrosine kinase active site, leading to inhibition of Bruton’s tyrosine kinase enzymatic activity.
Bruton’s tyrosine kinase signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Preclinical studies indicate that ibrutinib inhibits malignant B-cell proliferation and survival in vivo and cell migration and substrate adhesion in vitro.
How It Is Given
The recommended dose of ibrutinib is 560 mg (four 140-mg capsules) orally once daily. Ibrutinib treatment should be interrupted for any grade 3 or higher nonhematologic toxicity, grade 3 or higher neutropenia with infection or fever, and grade 4 hematologic toxicity. Once toxicity has resolved to grade 1 or baseline, treatment can be reinitiated at the starting dose.
If toxicity recurs, the dose should be reduced by one capsule (140 mg/d) with a second reduction by 140 mg considered as needed. If toxicities persist or recur after two dose reductions, ibrutinib should be discontinued.
Coadministration of ibrutinib with strong or moderate CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole), and strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) should be avoided. Ibrutinib can be interrupted if short-term treatment (≤ 7 days) with a strong CYP3A inhibitor is necessary, and the dose can be reduced to 140 mg/d if a moderate CYP3A inhibitor must be used.
Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity. Ibrutinib should be avoided in patients with hepatic impairment.
The most common adverse events of any grade in the clinical trial were thrombocytopenia (57%), diarrhea (51%), neutropenia (47%), anemia (41%), fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%).
The most common grade 3 or 4 adverse events were neutropenia (29%), thrombocytopenia (17%), anemia (9%), pneumonia (7%), and diarrhea, abdominal pain, skin infections, and fatigue (5% each). Overall, 25% of patients had grade 3 or higher infections and 5% had grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Bleeding events of any grade, including bruising of any grade, occurred in 48% of patients.
Ibrutinib carries warnings/precautions for hemorrhage, infections, myelosuppression, renal toxicity, second primary malignancies (including skin cancers and other carcinomas), and embryo-fetal toxicity. Patients must be monitored for bleeding and for fever and infections. Complete blood counts should be performed monthly. Renal function must be monitored and adequate hydration maintained. Women should be advised of potential fetal risk and to avoid pregnancy during therapy.
Ibrutinib is estimated to cost approximately $10,900 per month of recommended therapy and $130,000 per year. ■
1. U.S. Food and Drug Administration: Ibrutinib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm374857.htm.
2. IMBRUVICATM (ibrutinib) capsules prescribing information. Pharmacyclics, Inc, November 2013. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/205552lbl.pdf.
3. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507-516, 2013.
Report Adverse Events
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 http://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).