Idelalisib and Ibrutinib 2 Promising B-Cell Receptor–Signaling Inhibitors for B-Cell Malignancies

October 2013, Vol 4, No 8

New York, NY—Targeted therapy to the B-cell receptor signaling is paying off in chronic lymphocytic leukemia (CLL) and in other B-cell lymphomas. Two novel oral agents—the PI3K inhibitor idelalisib and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib—show great promise for these malignancies. These drugs have been studied in phase 3 trials, and current studies are focusing on combination strategies and new schedules to improve outcomes. In addition, both drugs have recently been submitted for review by the US Food and Drug Administration (FDA).

“These drugs are breakthrough drugs” in the treatment of B-cell malignancies, said Jeffrey Jones, MD, MPH, Assistant Professor of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, at the National Comprehensive Cancer Network congress on hematologic malignancies. The FDA has designated each of these drugs as a “breakthrough drug” earlier this year.

The B-cell receptor is present on the surface of normal cells and cancer cells. Abnormal B-cell receptor signaling is implicated in B-cell malignancies, promoting leukemia-cell survival and proliferation. Therefore, B-cell receptor signaling has become a therapeutic target for new therapies in development.

PI3K Inhibitors

The oral PI3K inhibitor idelalisib achieves rapid regression in lymph node volume, accompanied by a concomitant rise in absolute lymphocyte count. Many patients treated with the drug do not achieve complete response, because of the rise in absolute lymphocyte count and lymphocytosis.

The toxicity profile is good, with relatively little grade 3 and 4 toxicity, with the exception of pneumonitis (in approximately 24% of patients) and neutropenia (in approximately 18%) reported in clinical trials. Hematologic toxicity is easily managed.

Combination strategies are being studied to improve response rates in relapsed and/or refractory CLL, relapsed non-Hodgkin lymphoma (NHL), and mantle-cell lymphoma (MCL). Also, idelalisib is currently being studied in combination with rituximab (Rituxan) for the treatment of patients with CLL.

On September 11, 2013, Gilead Sciences (the drug manufacturer) submitted a New Drug Application (NDA) to the FDA for idelalisib for the treatment of patients with indolent NHL based on the results of a phase 2 clinical trial in this setting in patients with indolent NHL that is refractory to alkylating-agent-containing chemotherapy and to rituximab.

A second PI3K inhibitor—IPI-145—is less well studied. The drug has achieved excellent responses in indolent lymphomas and NHL. The major toxicity is risk of pneumocystic pneumonia, suggesting that patients should receive prophylaxis.

Approval of idelalisib is expected shortly, and IPI-145 is about to enter phase 3 testing.

BTK Inhibitors

The majority of the clinical data on BTK inhibitors, which also have a role in B-cell receptor signaling, are related to ibrutinib. In CLL, response rates were high—68% in treatment-naïve patients and 71% in high-risk patients with relapsed and/or refractory disease, based on recently published results (Byrd JC, et al. N Engl J Med. 2013;369:32-42).

Ibrutinib achieves excellent responses even in patients with high-risk cytogenetics, such as chromosome deletions of 17p/13.1 and deletions of 11q/22.r.

Stable remission has been achieved in patients with these genetic abnormalities.

Ibrutinib causes mainly mild adverse events, such as diarrhea, nausea, and fatigue.

In addition, ibrutinib combined with rituximab achieves a marked reduction in lymphocytosis in previously untreated high-risk CLL or small-cell leukemia (SCL). However, longer-term follow-up is needed to determine the value of this strategy.

Higher doses of ibrutinib achieve overall response rates of more than 70% in patients with MCL, and the response continues to improve with longer treatment. Ibrutinib is also being studied in combination with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen in large-cell lymphoma.

On August 27, 2013, the FDA accepted the NDA submitted by Pharmacyclics (the drug manufacturer) for ibrutinib for 2 indications in B-cell malignancies—CLL and SCL.

Studies of the oral BTK inhibitor CC-292 BTK have not been as promising as those of ibrutinib.

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