Ibrutinib Gains FDA Approval for the Treatment of CLL

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Richard Pazdur, MD

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

The accelerated approval was based specifically on 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 approval considered neither the 34 patients enrolled in the trial who received daily ibrutinib at 840 mg nor the 3 patients with small lymphocytic lymphoma (SLL) who received the 420 mg dose, due to small sample size.

“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.”

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 approval, patients had received a median of 4 prior therapies. The median age of the population was 67 years. To date, 85.4% of patients in the trial remain alive without progressive disease.

According to a median 26-month, investigator-assessed analysis of all 85 patients in the PCYC-1102-CA study published inThe 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 in the trial 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 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.