Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for Trial Registration: clinicaltrials.gov identifier: NCT01578707.

clinicaltrials.gov Identifier: NCT02055781.

CTI BioPharma Corp.

Long-term data are critical for physicians and patients to inform treatment decisions. Here we report extended long-term follow-up from the RESONATE-2 phase 3 study of the once-daily Bruton's tyrosine kinase inhibitor ibrutinib, which is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized phase 3 CLL studies. Patients (≥65 years) with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n=136) or chlorambucil 0.5-0.8 mg/kg up to 12 cycles (n=133). With up to 8 years of follow-up (range 0.1-96.6; median, 82.7 months), significant PFS benefit was sustained for ibrutinib versus chlorambucil (HR 0.154 [95% CI: 0.108-0.220]). At 7 years, PFS was 59% for ibrutinib versus 9% for chlorambucil. PFS benefit was also observed for ibrutinib- versus chlorambucil-randomized patients with high-risk genomic features: del(11q) (HR 0.033 [95% CI: 0.010-0.107]) or unmutated IGHV (HR 0.112 [95% CI: 0.065-0.192]). OS at 7 years was 78% with ibrutinib. Prevalence of adverse events (AEs) of clinical interest was consistent with previous 5-year follow-up. Ibrutinib dosing was held (≥7 days) for 79 patients and reduced for 30 patients due to AEs. These AEs resolved or improved with dose modifications in 85% (67/79) and 90% (27/30) of patients, respectively. With up to 8 years of follow-up, 42% of patients remain on single-agent ibrutinib. Long-term RESONATE-2 data demonstrate sustained benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. These trials are registered at www.clinicaltrials.gov as NCT01722487 and NCT01724346.