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 July 28, 2014, the approved use of ibrutinib (Imbruvica) in previously treated chronic lymphocytic leukemia (CLL) was expanded to patients with CLL involving the chromosome 17p deletion.1,2 Ibrutinib received a Breakthrough Therapy designation for this use. Ibrutinib has new labeling reflecting demonstration of improved progression-free survival in patients with CLL and in those with CLL with the 17p deletion.
The drug received accelerated approval for treatment of CLL in February 2014 based on response rate in a small single-arm study. Ibrutinib also previously received accelerated approval for treatment of patients with Mantle cell lymphoma who have received at least one prior treatment.
Supporting Trial
The new approval and labeling were based on the results of a phase III trial in which 391 patients with previously treated CLL (n = 273) or small lymphocytic lymphoma (n = 18), including 127 with the 17p deletion, were randomly assigned to receive ibrutinib at 420 mg daily (n = 195, 63 with 17p deletion) or ofatumumab (Arzerra) at an initial dose of 300 mg followed 1 week later by a dose of 2,000 mg weekly for seven doses and then every 4 weeks for four additional doses (n = 196, 64 with 17p deletion).2,3
Patients had a median age of 67 years, 68% were male, 90% were Caucasian, and all had Eastern Cooperative Oncology Group performance status of 0 or 1. Median time since diagnosis was 91 months and median number of prior treatments was 2 (range, 1 to 13). At baseline, 58% of patients had at least one tumor ≥ 5 cm. A total of 29% of patients in the ofatumumab group crossed over to ibrutinib following disease progression.
The trial was stopped early, after an interim analysis showed that median progression-free survival assessed by an independent review committee was significantly longer in the ibrutinib group (not reached vs 8.1 months, hazard ratio [HR] = 0.22, 95% confidence interval [CI] = 0.15–0.32). Median overall survival was significantly prolonged (HR = 0.43, 95% CI = 0.24–0.79) and overall response rate was higher (42.6% vs 4.1%, all partial responses) in the ibrutinib group. Among the 127 patients with the 17p deletion, median progression-free survival was significantly prolonged with ibrutinib (not reached vs 5.8 months, HR = 0.25, 95% CI = 0.14–0.45). The objective response rate was 47.6% vs 4.7%.
Lymphocytosis consisting of a ≥ 50% increase in absolute lymphocyte count from baseline and to > 5,000/µL occurred in 77% of patients. The isolated lymphocytosis occurred during the first month of treatment and resolved by a median of 23 weeks (range, 1 to > 104 weeks).
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. Bruton’s tyrosine kinase activity via signaling through the B-cell surface receptor results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. 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. Preclinical studies have shown 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 in CLL is 420 mg once daily. Ibrutinib treatment should be interrupted for grade 3 or higher nonhematologic toxicities, grade 3 or higher neutropenia with fever, and grade 4 hematologic toxicities. With resolution of toxicity to grade 1 or baseline status, treatment can be reinitiated at the starting dose. The dose may be reduced to 280 mg and then to 140 mg for recurrent toxicity.
Coadministration of ibrutinib with strong or moderate CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole) should be avoided. If a strong inhibitor is to be used for ≤ 7 days, interruption of ibrutinib during this period should be considered. If a moderate inhibitor must be used, the ibrutinib dose should be reduced to 140 mg. Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity.
Since ibrutinib is metabolized in the liver, significant increases in exposure are expected in patients with hepatic impairment, and patients with aspartate transaminase or alanine transaminase at least 3.0 times the upper limit of normal were excluded from clinical trials. Use of ibrutinib should be avoided in patients with hepatic impairment; there are insufficient data to recommend a dose in such patients.
Ibrutinib exposure is not altered in patients with creatinine clearance > 25 mL/min. There are no data in patients with severe renal impairment or on dialysis.
Safety Profile
In the phase III trial, the most common clinical adverse events of any grade in ibrutinib patients were diarrhea (48% vs 18% in ofatumumab patients), fatigue (28% vs 30%), musculoskeletal pain (28% vs 18%), and nausea (26% vs 18%), and the only grade 3 or 4 event occurring in > 2% of patients was pneumonia (10% vs 9%). Neutropenia, thrombocytopenia, and anemia of any grade occurred in 51% vs 57%, 52% vs 45%, and 36% vs 21% of patients, respectively, and grade 3 or 4 events occurred in 23% vs 26%, 5% vs 10%, and 0% vs 0%, respectively.
In the phase III study and the single-arm trial (n = 48) that supported the earlier accelerated approval of ibrutinib, adverse events led to ibrutinib dose reduction in 6% of patients and to discontinuation in 5%, with reasons for discontinuation including infection, subdural hematoma, and diarrhea.
Ibrutinib carries warnings/precautions for hemorrhage, infection, cytopenias, atrial fibrillation, second primary malignancies (including skin cancers and other carcinomas), and embryo-fetal toxicity. Patients must be monitored for bleeding, fever, infection, and atrial fibrillation. Complete blood counts should be monitored monthly. Women must be advised of potential fetal risk and counseled to avoid pregnancy while taking ibrutinib. ■
References
1. U.S. Food and Drug Administration: FDA expands approved use of Imbruvica for chronic lymphocytic leukemia. Available at www.fda.gov/newsevents/newsroom/pressannouncements/ucm406916.htm.
2. IMBRUVICA® (ibrutinib) capsules prescribing information, Pharmacyclics, Inc, and Janssen Biotech, Inc, July 2014. Available at www.imbruvica.com/downloads/Prescribing_Information.pdf.
3. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 2014.
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 www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).
