July 2014 Edition Vol.8, Issue 7

Novel Therapies for Leukemia Attract Attention at ASCO 2014

Novel Therapies for Leukemia Attract Attention at ASCO 2014

By Lynne Lederman, PhD

During this year’s ASCO Annual Meeting, progress in the development of novel therapies for hematologic malignancies was presented. Promising results of 4 leukemia trials presented are highlighted below.

Ibrutinib in CLL: Results from the RESONATE Trial

John C. Byrd, MD, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, presented late-breaking results of the RESONATE trial comparing ibrutinib with ofatumumab in relapsed or refractory chronic lymphocytic leukemia(CLL)/small lymphocytic lymphoma (SLL, the same disease as CLL).1 Results of this trial (NCT01578707), which was funded by Pharmacyclics and Janssen, were published in conjunction with the meeting.2 Patients with CLL or SLL who have a short duration of response to initial therapy, older than age 65 years, or have deletion 17p13.1 have poor outcomes and limited treatment options.

Ibrutinib is a first-in-class, oral, covalent (irreversible) inhibitor of Bruton’s tyrosine kinase, an enzyme that is required for B-cell function. Ibrutinib had previously been designated a breakthrough therapy by the FDA and given accelerated approval on the basis of overall response (OR) in a phase 2 trial for patients with mantle-cell lymphoma in November 2013,3 and for CLL in February 2014, for patients who had received at least one prior therapy.4

RESONATE, a phase 3 open-label trial initiated on the basis of early phase 2 trial results, randomly assigned patients with previously treated, relapsed or refractory CLL or SLL to once daily oral ibrutinib (n=195) or to the anti-CD20 antibody ofatumumab (n=196), an approved, active control agent. The primary endpoint was duration of progression-free survival (PFS); secondary endpoints were duration of overall survival (OS) and OR. During this trial, patients in the ofatumumab group who had disease progression were allowed to cross over to ibrutinib treatment (n=57).

At a median follow-up of 9.4 months, ibrutinib significantly prolonged PFS (median not reached) compared with ofatumumab (median 8.1 months; P<.0001). Ibrutinib reduced the risk of disease progression or death by 78% compared with ofatumumab. OS was not reached in either arm, but was significantly prolonged with ibrutinib compared with ofatumumab (P<.0049), with a 57% reduction in the risk of death in the ibrutinib group, despite the crossover of patients on ofatumumab with progressive disease. The benefits of ibrutinib were not affected by patient age, presence of del 17p, presence of purine analog-refractory disease, or other patient or disease characteristics. As assessed by the independent review committee (IRC) 43% of patients receiving ibrutinib had a partial response compared with 4% receiving ofatumumab; OR was 63% for ibrutinib if partial response with lymphocytosis was not considered to be disease progression. Lymphocytosis was resolved in most patients.

Adverse events (AE) were similar to those previously reported for both agents, e.g., infusion-related reactions for ofatumumab but not ibrutinib. The most frequent AEs for ibrutinib compared with ofatumumab were diarrhea (47.7% vs. 17.8%), fatigue (27.7% vs. 29.8%), and nausea (26.2% vs. 18.3%); the rates of atrial fibrillation were 5.1% vs. 0.5%, and major hemorrhages were 1.0% vs. 1.6%, respectively, although Grade 1 bleeding events were higher with ibrutinib. Patients requiring warfarin but not other types of anticoagulant therapy were excluded from the trial. Neuropathy was higher with ofatumumab (13% vs. 4% for ibrutinib). Rates of renal toxicities and discontinuation were similar for both agents. At the time of the analysis, 86% of patients were still receiving ibrutinib. Richter’s transformation occurred in only 2 patients in each arm.

Dr. Byrd commented that this is the first time that ibrutinib was shown to be superior to a standard comparator agent, and this trial validates ibrutinib as an effective, orally-administered single-agent treatment for patients with relapsed CLL/SLL. Gregory A. Masters, MD, Helen F. Graham Cancer Center, Newark, Delaware and a member of ASCO’s Cancer Communications Committee, commented that it was “impressive to see an OS benefit in CLL. Ibrutinib represents an encouraging option as a drug with a low toxicity profile, and may replace other agents for treatment of this disease.” Phase 3 trials of ibrutinib as first-line therapy for CLL and SLL are ongoing, and in combination with other agents for mantle cell lymphoma and CLL/SLL.

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