FDA Expands Approval of Ibrutinib for CLL

Dr. Richard Pazdur from the FDA’s Center for Drug Evaluation and Research

Richard Pazdur, MD

The FDA has expanded the approval of ibrutinib (Imbruvica) to include the treatment of patients with chronic lymphocytic leukemia (CLL) who harbor a 17p deletion, based on findings from the phase III RESONATE trial.

In the phase III RESONATE study, treatment with ibrutinib lowered the risk of progression by 75% in patients with CLL who harbored a 17p deletion and by 78% in the full population of the study when compared with ofatumumab. As a result of this benefit, in addition to the expanded approval, the FDA has also granted a full approval to ibrutinib as a treatment for patients with CLL who have received at least one previous therapy.

“We continue to see advances in the availability of therapies to treat chronic lymphocytic leukemia, especially for difficult-to-treat patient populations,” 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 press release. “Imbruvica is the fourth drug approved to treat CLL that received a breakthrough therapy designation, reflecting the promise of the breakthrough therapy designation program and demonstrating the FDA’s commitment to working cooperatively with companies to expedite the development, review and approval of these important new drugs.”

Ibrutinib is an irreversible small-molecule inhibitor of BTK and works by blocking B-cell activation and signaling, preventing the growth of malignant B cells that overexpress BTK.

In the RESONATE study, 391 patients with CLL were randomized in a 1:1 ratio to either ibrutinib at 420 mg once daily (n = 195) or ofatumumab for up to 24 weeks at an initial dose of 300 mg at week 1, followed by a dose of 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks (n = 196). The median age of patients in each arm was 67 years. Patients in the ibrutinib arm received a median of 3 prior therapies, whereas those in the ofatumumab arm had received a median of 2 prior therapies.

According to findings presented at the 2014 ASCO Annual Meeting, the median PFS in the ibrutinib arm was not reached compared with an 8.1-month median with ofatumumab (hazard ratio [HR] = 0.22, 95% CI, 0.15—0.32, P < .0001). At 6 months, 88% of patients treated with ibrutinib were progression-free compared with 65% in the ofatumumab group. Additionally, a similar benefit was observed in patients with high-risk characteristics and those treated with a purine analog. In patients with the 17p13.1 deletion, the HR was 0.25 (95% CI, 0.14-0.45).

For the secondary endpoint of OS, ibrutinib also demonstrated superior efficacy. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% in the ofatumumab group. The median OS was not reached for patients treated with ibrutinib (HR = 0.43; 95% CI, 0.24-0.79; P = .005).

By traditional response criteria, the ORR with ibrutinib was 43% (all partial responses [PR]) compared with 4% for ofatumumab (odds ratio = 17.4; 95% CI, 8.1-37.3; P < .001). Lymphocytosis, which was observed in 69% of patients in the ibrutinib arm, does not generally indicate progression in patients treated with BTK inhibitors. Once including patients with a lymphocytosis who had a PR, the ORR was 63% with ibrutinib.

"The RESONATE data expands our understanding of the efficacy and safety of IMBRUVICA to an even greater degree," lead investigator John C. Byrd, MD, director, Division of Hematology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital & Richard J. Solove Research Institute, said in a statement. "This approval is particularly exciting for people with del 17p CLL, considering Imbruvica is the first treatment to be approved specifically for this difficult-to-treat patient population."

Richter's transformation was found to be equivalent in both groups, with 2 patients developing the complication in each arm. The most frequently observed adverse events of any grade for ibrutinib and ofatumumab, respectively, were diarrhea (47.7% vs 17.8%), fatigue (27.7% vs 29.8%), and nausea (26.2% vs 18.3%). The most common grade 3/4 adverse events with ibrutinib and ofatumumab were neutropenia (16% vs 14%), pneumonia (7% vs 5%), and thrombocytopenia (6% vs 4%).

Atrial fibrillation was more frequent with ibrutinib (5.1% vs 0.5%) and major hemorrhages were reported in 1.0% versus 1.6%, for ibrutinib and ofatumumab. Treatment discontinuation due to adverse events was similar between both arms, with 86% of patients remaining on ibrutinib treatment at the time of the analysis.

"We're very pleased this approval came swiftly," said Peter F. Lebowitz, MD, PhD, Global Oncology Head, Janssen Research & Development, LLC, the company developing the drug, said in a release. "These phase III results reinforce the data on which the original approval was granted; they also offer greater clinical understanding of the impact of efficacy related to progression-free and overall survival and, more importantly, the safety of IMBRUVICA in this patient population."

Ibrutinib was first approved as a treatment for patients with mantle cell lymphoma (MCL) in November 2013. This initial approval followed multiple breakthrough therapy designations from the FDA in early 2013 as a treatment for CLL/SLL, MCL, and Waldenstr&ouml;m's macroglobulinemia. The drug continues to be explored extensively as a monotherapy and in combination across a variety of B cell malignancies.