Ibrutinib, an oral, once-daily Bruton’s tyrosine kinase inhibitor, has revolutionized treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study compared single-agent ibrutinib with ofatumumab in patients with relapsed/refractory CLL/SLL. Researchers evaluated the long-term efficacy and safety of ibrutinib over a 6-year period of follow-up. This is the final analysis from the RESONATE clinical trial program.
In this multicenter, open-label, crossover phase 3 study, previously treated patients with CLL/SLL were randomized to receive either oral ibrutinib 420 mg daily until disease progression or intravenous ofatumumab for up to 24 weeks. Long-term efficacy end points were assessed in the intent-to-treat population.
Patient characteristics were similar for the 2 groups. Among 391 patients randomized to receive ibrutinib (N = 195) or ofatumumab (N = 196), 86% and 79%, respectively, had high-risk genomic features, including del(17p), del(11q), TP53 mutation, and/or unmutated IGHV. At the final analysis, median follow-up for patients receiving ibrutinib was 65.3 months; for patients initially assigned to ofatumumab, it was 65.6 months. Of the patients randomized to ofatumumab, 68% crossed over to receive ibrutinib.
With an overall follow-up of 74 months, patients experienced a significant sustained, investigator-assessed progression-free survival (PFS) benefit with ibrutinib (44.1 months) versus ofatumumab (8.1 months). Median PFS in the genomic high-risk population was very similar (44.1 months vs 8.0 months receiving ibrutinib vs ofatumumab). The objective response rate with ibrutinib was 91%. Initial ibrutinib treatment conferred better overall survival than ofatumumab when censored for crossover.
The adverse event profile with ibrutinib was consistent with prior experience. The prevalence of grade 3 or higher adverse events decreased after the first year and remained stable thereafter. Among patients in the ibrutinib arm, dose reductions and dose interruptions were used to manage adverse events in 17% and 65% of patients, respectively. The most common reasons for ibrutinib discontinuation prior to study closure were disease progression (37%) and adverse events (16%). Discontinuation rates due to adverse events were similar for the duration of the study, reaching a maximum of 6% in years 0 to 1 and 4 to 5.
With up to 6 years of follow-up, extended ibrutinib treatment showed sustained efficacy in patients with relapsed/refractory CLL/SLL, including in patients with high-risk genomic features. Safety remained acceptable, with low rates of discontinuation and no new safety signals emerging during long-term therapy. This final analysis continues to support long-term disease control and tolerability with ibrutinib in the treatment of patients with CLL/SLL.
Abstract 7510; Barr PM, et al.