August 2014, Vol 3, No 5
Ibrutinib Tops Ofatumumab as Second-Line Therapy for CLL
For the second-line treatment of chronic lymphocytic leukemia (CLL), ibrutinib improved not only progression-free survival (PFS) but also overall survival (OS), the phase 3 RESONATE study showed.
In conjunction with the ASCO presentation, the study was published online in the New England Journal of Medicine.
“Ibrutinib beat a standard comparator in CLL for the first time,” said John C. Byrd, MD, of the Ohio State University Comprehensive Cancer Center in Columbus. “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 by the FDA.
The RESONATE study randomized previously treated patients with CLL and small lymphocytic leukemia to oral ibrutinib or IV ofatumumab. The overall response rate was 42.6% for ibrutinib versus 4.1% for ofatumumab (P<.001). At a median follow-up of 9.4 months, 86% of patients on ibrutinib had durable responses and were continuing on treatment with minimal side effects.
“This is remarkable, especially considering that standard CLL therapies typically produce a 35% to 40% response rate,” Byrd commented.
Improvement in PFS and OS, and Well Tolerated
At 6 months, PFS rates were 83% in the ibrutinib arm versus 49% in the ofatumumab arm. Median PFS was not yet reached in the ibrutinib arm and was 8.1 months with ofatumumab (P<.0001), representing a 78% reduction in the risk of 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.
OS was significantly improved at 90% with ibrutinib versus 81% with ofatumumab, representing a 57% reduction in risk of death (P<.0049). The improvement in survival remained significant despite the crossover of 57 patients who had progressed on ofatumumab.
Both regimens were fairly well tolerated, with similar rates of major hemorrhage and renal toxicities; rates of atrial fibrillation were higher with ibrutinib, while neuropathy was more common with ofatumumab. The risk of diarrhea often observed with ibrutinib was modest and manageable in most patients, he said.
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,” Byrd maintained.
Gregory Masters, MD, of the Helen F. Graham Cancer Center, Newark, DE, who moderated an ASCO press conference, seemed to agree. “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,” he said.
Ibrutinib will soon undergo phase 3 testing in mantle cell lymphoma with bendamustine/rituximab as the comparator. Ibrutinib is also in phase 3 study as first-line therapy for CLL.
Dr Puzanov is currently an associate professor of medicine at Vanderbilt University School of Medicine and the director of melanoma clinical research at Vanderbilt-Ingram Cancer Center in Nashville, TN. He received his MD from Charles University in Prague, Czech Republic. His major interests are phase 1 drug development with emphasis [ Read More ]
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C. Daniel Mullins, PhD, is a professor and former department chair of the Pharmaceutical Health Services Research Department at the University of Maryland School of Pharmacy. Linda Bosserman, MD, is a community medical oncologist at Wilshire Oncology. Andrew Stainthorpe, PhD, is associate director of the National Institute of Health and [ Read More ]