Ibrutinib Receives Additional Breakthrough Designation for CLL

Adrian Wiestner, MD, PhD

After receiving breakthrough therapy designation from the FDA for the treatment of two B-cell malignancies earlier this year, ibrutinib has received an additional breakthrough designation for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with deletion of the short arm of chromosome 17.

Ibrutinib is a selective tyrosine kinase inhibitor of the Bruton’s tyrosine kinase enzyme, which is associated with apoptosis, cell adhesion, cell migration, and other cellular processes that can help a tumor survive. In addition to CLL/SLL, ibrutinib is being investigated in multiple myeloma, follicular lymphoma, and diffuse large B-cell lymphoma. In February, ibrutinib received breakthrough designation for Waldenström’s macroglobulinemia and mantle cell lymphoma.

Patients with CLL with this chromosome 17 deletion (del 17p) often have poor outcomes if they receive treatment with chemotherapy.

According to the 2012 FDA Safety and Innovation Act (FDASIA), breakthrough therapy designation is assigned to drugs designed to treat a life-threatening condition when “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”

The purpose of the breakthrough designation is to expedite the review process for ibrutinib for CLL/SLL by allowing for more meetings during the development process, potentially reducing the number of patients required for clinical trial enrollment, and shortening the time needed to conduct those clinical trials.

Ibrutinib is being co-developed and co-commercialized through a collaborative agreement between Janssen Biotech, Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, and Pharmacyclics. The manufacturers are still allowed to seek fast-track designation, accelerated approval, and priority review for ibrutinib for this indication during the review process.

“Ibrutinib continues to demonstrate promise for patients living with B-cell malignancies, and we are pleased that the FDA has recognized its potential for people living with CLL and the del17p mutation,” said Peter F. Lebowitz, MD, PhD, head of Global Oncology Therapeutic Area at Janssen, in a statement. “This third breakthrough therapy designation reflects the potential importance of ibrutinib for patients diagnosed with a 17p deletion chromosomal abnormality in CLL/SLL, and we are committed to working with Pharmacyclics and the FDA to expedite development and review of ibrutinib as quickly as possible.”

The news of the additional breakthrough designation comes on the same day that new data on ibrutinib’s effectiveness for the treatment of CLL were presented at the American Association of Cancer Research (AACR) Annual Meeting 2013, held in Washington, DC.

In the ongoing phase II study, 53 patients with CLL were divided into two cohorts, with 29 patients with del 17p and 24 patients without del 17p who were at least 65 years old. Patients received 420 mg of ibrutinib daily, and their responses were evaluated at six months and every six months thereafter until disease progression.

At 12 months, the estimated event-free survival rate was 94%. After six months, at least a 50% reduction in lymph node disease was observed in 95% of patients, with a median reduction in lymph node size of 73%. A median decrease of 82% in tumor infiltration in bone marrow was observed in patients who received a bone marrow biopsy. All patients showed a reduction in spleen enlargement, with a median reduction of 55%.

The drug was also well tolerated, with most adverse events reported as mild, with nonhematologic toxicities that were grade 3 or higher occurring in less than 13% of patients. Two patients on the study died, but their deaths were not related to the treatment.

“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status,” said Adrian Wiestner, MD, PhD, investigator and head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) in Bethesda, MD, in a statement. “Responses appear to be durable, and the drug is effective against the disease in lymph nodes, spleen, and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach will greatly improve the lives of patients with this disease.”

Wiestner A, Herman S, Mustafa R, et al. Potent single agent activity of Ibrutinib (PCI-32765) in patients with chronic lymphocytic leukemia (CLL): clinical and translational results from an ongoing phase II study. Presented at: AACR Annual Meeting 2013; April 6—10; Washington, DC. Abstract LB-141.