For the second-line treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or with small lymphocytic leukemia (SLL), ibrutinib improved progression-free survival (PFS), overall survival (OS), and overall response rate ORR compared with ofatumumab, results of the phase 3 RESONATE study demonstrated. The results were presented at ASCO 2014 and were also published in the New England Journal of Medicine (Byrd JC, et al. 2014;371:213-223).
“Ibrutinib beat a standard comparator in CLL for the first time,” said John C. Byrd, MD, Director, Division of Hematology, the Ohio State University Comprehensive Cancer Center, Columbus, OH. “If I were a patient with CLL, I would want this drug. In the relapsed and refractory setting after 1 prior therapy, there is no good reason not to give this drug outside of a few circumstances.”
Ibrutinib is a first-in-class irreversible inhibitor of Bruton’s tyrosine kinase, and the drug has been given breakthrough therapy designation and was approved for use in patients with CLL earlier in the year by the US Food and Drug Administration.
Improvement in PFS, OS, and Response Rate
In the RESONATE study, patients with CLL or SLL who received at least 1 previous therapy were randomized to oral ibrutinib or to intravenous ofatumumab.
At 6 months follow-up, PFS rates (the study’s primary end point) were 83% in the ibrutinib arm compared with 49% in the ofatumumab arm. The median PFS was not yet reached in the ibrutinib arm and was 8.1 months with ofatumumab (P <.001), representing a 78% reduction in the risk for progression. The impact on PFS was observed in all patient groups, including the elderly and those with deletions in chromosome 17p (ie, the poor-prognosis subsets).
Furthermore, the OS rates (the secondary end point of the trial) were also significantly improved with ibrutinib—90% with ibrutinib versus 81% with ofatumumab, representing a 57% reduction in the risk of death (P <.049). The improvement in survival remained significant despite the crossover of 57 patients who had progressed with ofatumumab.
The ORR was also significantly better with ibrutinib, at 42.6% for ibrutinib compared with only 4.1% for ofatumumab (P <.001). At a median follow-up of 9.4 months, 86% of patients receiving ibrutinib had durable responses and were continuing to receive treatment, with minimal side effects.
“This is remarkable, especially considering that standard CLL therapies typically produce a 35% to 40% response rate,” Dr Byrd commented.
Both regimens were fairly well tolerated, with similar rates of major hemorrhage and renal toxicities; the rates of atrial fibrillation were higher with ibrutinib, whereas neuropathy was more common with ofatumumab. The risk of diarrhea often observed with ibrutinib was modest and manageable in most patients, Dr Byrd said.
Experts Call to Embrace Ibrutinib
“The findings of phase 2 and the confirmatory phase 3 study show ibrutinib should be used for all relapsed refractory CLL,” Dr Byrd maintained.
Gregory A. Masters, MD, Director, Medical Oncology Fellowship, Helen F. Graham Cancer Center, Newark, DE, commented. “It is impressive to see an OS benefit in CLL….This drug’s efficacy can potentially transform the treatment of CLL, replacing more toxic therapy,” Dr Masters said.
Ibrutinib will soon be tested in a phase 3 trial in patients with mantle-cell lymphoma versus the combination of bendamustine plus rituximab. Ibrutinib is also currently being tested in a phase 3 study as first-line therapy for CLL.