Ibrutinib (Imbruvica) Approved for CLL in US

Zosia Chustecka

February 13, 2014

UPDATED WITH INTERVIEW // Ibrutinib (Imbruvica, Pharmacyclics) has obtained an accelerated approval from the US Food and Drug Administration (FDA) for use in chronic lymphocytic leukemia (CLL) in patients who have received at least 1 previous therapy.

This is an expanded indication for the drug — it was approved for use in mantle cell lymphoma in November 2013.

Ibrutinib is a first-in-class inhibitor of Bruton's tyrosine kinase, developed specifically for the treatment of B-cell cancers, including CLL. The drug has shown "striking" efficacy in both indications, and has stirred up considerable excitement in hematology circles, with experts describing it as a "turning point" in the treatment of CLL, and "a step change" in the treatment of mantle cell lymphoma.

Commenting on the CLL approval, one of the principal investigators involved in the CLL clinical trials, John C. Byrd, MD, director of the division of hematology at Ohio State University Comprehensive Cancer Center in Columbus, said: "I have been impressed with the promising and durable response rates we have seen in patients."

"Rarely does a drug come along with so much potential to help CLL patients," he said in a statement.

The CLL approval has been highly anticipated, after the news last month that a pivotal trial was stopped early. That trial, known as RESONATE, was a phase 3 study conducted at more than 70 clinical sites across 10 countries. It involved 391 patients with relapsed or refractory CLL or small lymphocytic leukemia who had received at least 1 previous therapy. A head-to-head comparison trial, it pitched the oral drug ibrutinib against the intravenous drug ofatumumab (Arzerra, GlaxoSmithKline), which was approved for CLL in 2009. The company said an interim analysis in January showed that patients on ibrutinib had a statistically significant improvement in progression-free survival (the primary end point of the study), as well as in overall survival (a secondary end point), when compared with ofatumumab.

However, that phase 3 study was apparently not considered in the approval process.

The FDA says that it granted accelerated approval of ibrutinib in CLL on the basis of a clinical study of 48 previously treated participants. On average, participants were diagnosed with CLL 6.7 years prior to the study and had received 4 previous therapies. All study participants received ibrutinib 420 mg orally until the treatment reached unacceptable toxicity or the disease progressed.

The results show an overall response rate of nearly 58%. At the time of the study, the duration of response ranged from 5.6 to 24.2 months. An improvement in survival or disease-related symptoms has not been established, the agency notes.

The most common adverse effects observed in the clinical study include thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness.

In addition to undergoing an accelerated approval process, ibrutinib also received priority review and orphan-drug designation, the FDA noted.

Unprecedented Activity

In an interview with Medscape Medical News, Dr. Byrd said, "this is by far the most active drug that I have seen in 16 years of treating CLL patients."

The data on 48 patients with previously treated CLL on which the approval was based come from a larger trial of 85 patients headed by Dr. Byrd that that was published last year in the New England Journal of Medicine (2013;369:32-42). This trial also included patients with small lymphocytic lymphoma, and tested the drug at 2 doses (420 mg and 840 mg daily), Dr. Byrd explained. As both doses were equally efficacious, the approval application was based just on the CLL patients treated with the lower dose.

The primary end point was an overall response rate of 58%, with a median duration of 5.5 to 24.0 months. This is much better than has been seen historically, Dr. Byrd said, when the best that you could hope for would be a response rate of 20% to 30% with a duration response of 6 to 12 months, but you would also see "a lot of side effects," he said. The better efficacy with ibrutinib comes with a good tolerability, he said.

These were heavily pretreated patients who had used a median of 4 previous therapies, he said. Typically, they would have already progressed through ofatumumab, high-dose steroids, and alemtuzumab, and would have few other options left.

Ibrutinib is also active in CLL patients who have not previously been treated or who have received minimal previous therapy. "In fact, these results are even better," Dr. Byrd said. In part of another trial that he headed, there was a subset of 29 patients with previously untreated CLL, the results on whom were recently published in the Lancet Oncology (2014;15:48-58).

"This showed that in elderly patients who received ibrutinib as initial therapy, the 24-month disease-free survival was 96%. To put this in perspective, the best combination therapy of chlorambucil and obinutuzumab reached 50% at that same time period," he said. "So it's really blowing the pants off what we are standardly doing in elderly CLL patients," he said.

These results with ibrutinib in untreated CLL come from a single nonrandomized trial, but "they are very, very good," he said, and patients tolerate the drug very well. He emphasized: "This is a patient-friendly drug." These results have led to large phase 3 trials, which are ongoing.

Based on these results, "I would predict that we will be using ibrutinib, either alone or in combination with a monoclonal antibody, in place of chemotherapy for most CLL patients," Dr. Byrd said.


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