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FDA Approves Ibrutinib for Chronic Lymphocytic Leukemia

Silas Inman
Published Online: Wednesday, February 12, 2014
Dr. Richard Pazdur

Richard Pazdur, MD

The FDA has expanded the approval of ibrutinib (Imbruvica) to include the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one previous therapy, based on a single-arm clinical trial demonstrating a durable improvement in overall response rates (ORR).

The accelerated approval was supported specifically by 48 patients in the phase Ib/II PCYC-1102-CA study who received single-agent ibrutinib at 420 mg daily. In these select patients, at a median 15.6-month follow-up, the ORR was 58.3% (all partial responses) with duration of response of up to 24.2 months, according to the FDA. The analysis used for the approval did not include data from 34 patients enrolled in the trial who received daily ibrutinib at 840 mg nor 3 patients with small lymphocytic lymphoma (SLL) who received the 420 mg dose.

“Today’s approval provides an important new treatment option for CLL patients whose cancer has progressed despite having undergone previous therapy,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “The FDA completed its review of Imbruvica’s new indication under the agency’s accelerated approval process, which played a vital role in rapidly making this new therapy available to those who need it most.”

The phase III RESONATE study will act as the confirmation for the accelerated approval. This study compared the 420 mg dose of ibrutinib to ofatumumab in 391 patients with relapsed or refractory CLL or SLL following treatment with one prior therapy. In January, this study was stopped early after demonstrating a significant improvement in the primary endpoint of progression-free survival and the secondary endpoint of overall survival for patients treated with ibrutinib compared with ofatumumab. Full data from this investigation have not yet been released.

Ibrutinib is an irreversible small-molecule inhibitor of Bruton's tyrosine kinase (BTK). The agent works by blocking B-cell activation and signaling, which prevents the growth of malignant B cells that overexpress BTK.

In November 2013, ibrutinib was approved as a treatment for patients with mantle cell lymphoma (MCL). This initial approval followed multiple Breakthrough Therapy designations from the FDA in early 2013 as a treatment for CLL/SLL, MCL, and Waldenström's Macroglobulinemia.

In the independently-reviewed analysis, which was the basis for the CLL approval, patients had received a median of 4 prior therapies. The median age of the population was 67 years. At the 15.6-month analysis, 85.4% of patients in the trial remained alive without progressive disease.

According to a median 26-month, investigator-assessed analysis of all 85 patients in the PCYC-1102-CA study published in The New England Journal of Medicine, the ORR was 71% for patients treated with ibrutinib at all doses. The estimated progression-free survival rate was 75% with an overall survival rate of 83%. Data show that responses were equivalent across doses and were independent of clinical and genomic risk factors present before treatment, such as 17p deletions.

The most commonly occurring adverse reactions for patients with CLL were thrombocytopenia (71%), diarrhea (63%), bruising (54%), neutropenia (54%), anemia (44%), and upper respiratory tract infection (48%). The most common grade 3/4 non-hematological adverse reactions were pneumonia (8%), hypertension (8%), dehydration (6.4%), atrial fibrillation (6.3%), and sinusitis (6%). Additionally, ibrutinib-related grade 3/4 cytopenias were reported in 35% of patients. Five patients in the trial discontinued treatment due to adverse reactions.

"Rarely does a drug come along with so much potential to help CLL patients," John C. Byrd, MD, the director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center and lead investigator of the PCYC-1102 trial, said in a statement. "I have been impressed with the promising and durable response rates we have seen in patients. It is particularly gratifying to see the difference that Imbruvica has made for patients in the clinical trials."

Ibrutinib is being explored as monotherapy in untreated patients with CLL and SLL in several settings. Additionally, the agent is under investigation in combinations with bendamustine and rituximab for patients with relapsed or refractory CLL.

In a 14-month update of a phase II trial of ibrutinib plus rituximab for 40 patients with high-risk CLL, the combination resulted in a 95% response rate. Moreover, the overarching collection of clinical trial results seems to indicate that responses to ibrutinib are achieved for patients with 17p deletions, which traditionally indicates a worse prognosis.

Ibrutinib is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. The approval in CLL triggers a $60 million payment from Janssen to Pharmacyclics, as part of the collaboration.


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.


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