New Drug Application Filed for Ibrutinib in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma

The FDA has received a new drug application for ibrutinib as a therapy for previously treated CLL and previously treated MCL.


The FDA has received a new drug application for ibrutinib as a therapy for previously treated chronic lymphocytic leukemia (CLL) and previously treated mantle cell lymphoma (MCL). The new drug application comes after high response rates observed in two clinical trials published last month.

Ibrutinib is a selective Bruton’s tyrosine kinase inhibitor, and if approved, would be the first to receive approval from the FDA. Bruton’s tyrosine kinase is associated with apoptosis, cell adhesion, cell migration, and other cellular processes that can help a tumor survive. Ibrutinib appears to selectively target the implicated enzyme while sparing healthy T cells. The drug is being investigated in multiple hematologic malignancies, including multiple myeloma, follicular lymphoma, and diffuse large B-cell lymphoma.

The announcement of the filing was made by Janssen Research and Development, LLC, and if approved, the drug would be co-commercialized in the United States by Janssen Biotech, Inc. and Pharmacyclics.

“The FDA submission is another important milestone for ibrutinib since we formed our strategic partnership with Pharmacyclics just 18 months ago,” said Peter F. Lebowitz, MD, PhD, Global Oncology Head at Janssen, in a statement. “Both companies recognize that there is great unmet need among these patient populations, and together in close collaboration with the FDA, as part of its Breakthrough Therapy Designation pathway, we have been able to accelerate the ibrutinib development program for the benefit of patients.”

The filing for the indication for CLL was based on the results of a phase Ib/II trial, in which 85 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) received ibrutinib orally once daily, with 51 patients receiving a 420 mg dose and 34 patients receiving an 840 mg dose.1

The overall response rate (ORR) in both treatment groups was 71%, with an additional 20% of patients in the 420 mg dose arm and 15% of patients in the 840 mg dose arm experiencing a partial response with lymphocytosis. After 26 months of follow-up, the estimated rate of progression-free survival (PFS) was 75%, and the rate of overall survival (OS) was 83% for all patients, irrespective of the dose. Side effects were minimal and consisted mostly of grade 1 or 2 transient diarrhea, fatigue, and upper respiratory tract infection.

In the study that looked at patients with MCL, 111 patients with relapsed or refractory disease received a daily dose of 560 mg of ibrutinib. Patients enrolled in this phase II trial were divided into two groups: those who had received ≥2 complete cycles of prior bortezomib therapy and patients who had received <2 complete cycles of the therapy, including those with no prior bortezomib therapy. ORR was the primary endpoint, with duration of response, PFS, OS, and safety serving as secondary endpoints.2

In this study, the ORR was 68%, the complete response rate was 21%, and the partial response rate was 47%, regardless of whether the patients had received prior therapy with bortezomib. After a median follow-up of 15.3 months, the estimated median duration of response was 17.5 months (95% CI, 15.8—not reached), the median PFS was 13.9 months (95% CI, 7.0–not reached), and the median OS was not yet reached. At 18 months, the estimated rate of OS was 58%. Infrequent grade 3 or higher hematologic events were observed and included neutropenia (16%), thrombocytopenia (11%), and anemia (10%).

In 2013, ibrutinib has three separate breakthrough therapy designations from the FDA for the treatment of CLL or SLL with deletion of the short arm of chromosome 17; relapsed or refractory MCL after prior treatment; and Waldenström’s macroglobulinemia. This designation is granted to drugs that demonstrate a substantial improvement over existing therapies, and helps them achieve an expedited review process.


  1. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia [published online ahead of print June 19, 2013].N Engl J Med. doi:10.1056/NEJMoa1215637.
  2. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma [published online ahead of print June 19, 2013].N Engl J Med. doi:10.1056/NEJMoa13056220.