Pharmacology Update

Ibrutinib Capsules (Imbruvica™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco.
Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

An inhibitor of bruton’s tyrosine kinase (btk) has been recently approved for the treatment of chronic lymphocytic leukemia (CLL) for patients who have previously been treated. Ibrutinib, approved in November for mantle cell lymphoma (MCL), was approved under the FDA’s accelerated approval process for treatment of CLL. It is marketed by Pharmacyclics, Inc., and Janssen Biotech as Imbruvica.

Indications

Ibrutinib is indicated for the treatment of MCL and chronic lymphocytic leukemia in patients who have received at least one prior therapy.1

Dosage

The recommended dose is 560 mg orally once daily for MCL and 420 mg once daily for CLL. It is available as 140 mg capsules. The dose should be reduced if co-administered with a moderate 3A4 inhibitor that is clinically necessary.¹ The dose should be modified for adverse events.

Potential Advantages

Ibrutinib as monotherapy was able to achieve an overall response rate of 66% in MCL and 58% in CLL in previously treated patients.

Potential Disadvantages

Approximately one-half of patients experience some grade of bleeding with 5-6% grade 3 or higher. About 40% have grade 3 or higher cytopenia and about 30% have grade 3 infections. Common adverse events (> 25%) include diarrhea, nausea, constipation, fatigue musculoskeletal pain, and dyspnea. Other malignancies have been reported in 5% of MCL patients and 10% of CLL patients treated with ibrutinib, mostly skin cancers. Ibrutinib should not be given with a strong or moderate CYP3A4 inhibitor or strong CYP3A4 inducer.¹

Comments

Ibrutinib is an irreversible inhibitor of BTK that acts as a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways.^1,2 Its safety and efficacy was evaluated in 111 subjects with MCL and 48 subjects with CLL in open-label trials. Subjects with MCL were previously treated (median of three treatments), aged 68 years (40–84), median time since diagnosis was 42 months, 39% had at least one tumor 5 cm or larger, 49% had bone marrow involvement, and 54% had extranodal involvement. Ibrutinib was administered at 560 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was investigator assessed overall response rate (ORR). ORR was 65.8% (95% confidence interval [CI], 56.2, 74.5). The complete response was 17.1% and partial response was 48.6%. The median time to response was 1.9 months with a duration of response of 17.5 months. For CLL, 48 subjects had a median time from diagnosis of 80 months and a median number of prior treatments of four, and 46% had at least one tumor of 5 cm or larger at baseline. Ibrutinib was administered as a once-daily dose of 420 mg. ORR (all partial) was 58.3% (95% CI, 43.2, 72.4). Transient increase in lymphocyte count (> 50%) occurred in 77% of CLL subjects and 33% of MCL subjects. The onset occurred in the first few weeks to first month of treatment and resolved by a median of 23 weeks in CLL subjects and 8 weeks in MCL subjects.

Clinical Implications

MCL is a rare form of non-Hodgkin lymphoma (NHL) representing 5-9% of new NHL.² It is a male predominant disease with allogeneic stem cell transplantation as the most effective therapy. For those in which this is not an option, other FDA-approved drugs include bortezomib (Velcade) and lenalidomide (Revlimid). Bortezomide showed an ORR of 31% and duration of response (DOR) of 9.3 months, while lenalidomide had an ORR of 26% and DOR of 16.6 months.³ Ibrutinib provides an active therapy for relapsed and refractory disease. CLL is also a rare blood and bone marrow disease characterized by an increase in B-lymphocytes. Current therapy includes fludarabine, cyclophosphamide, and rituximab. For untreated patients, the ORR was 95%.⁴ This combination is not recommended for relapsed/refractory disease. Preferred treatment includes combination chemotherapy.⁵ Ibrutinib offers a single-agent option in those patients. The wholesale cost of treatment of MCL is $10,933 for 30 days and $8,200 for CCL for 30 days.

References

1. Imbruvica Prescribing Information. Sunnyvale, CA: Pharmacyclics, Inc.; February 2014.
2. Wang ML, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507-517.
3. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205552Orig1s000SumR.pdf. Accessed March 25, 2014.
4. Keating MJ, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005;23:4079-4088.
5. https://www5.medicine.wisc.edu/~williams/nhl.pdf.
   Accessed March 25, 2014.