Up to seven years of follow-up in the RESONATE-2 study of first-line ibrutinib treatment for patients with chronic lymphocytic leukemia.

Abstract

7523 Background: Ibrutinib, a once-daily Bruton’s tyrosine kinase inhibitor, is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized phase 3 studies versus established therapies in patients (pts) with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Extended long-term follow-up data for the RESONATE-2 study of first-line ibrutinib vs chlorambucil in older pts with CLL/SLL are reported. Methods: In the phase 3 RESONATE-2 study, older pts (≥65 years [y]) with previously untreated CLL/SLL and without del(17p) (N=269) were randomly assigned 1:1 to once-daily single-agent ibrutinib 420 mg until disease progression (PD) or unacceptable toxicity (n=136) or chlorambucil 0.5–0.8 mg/kg up to 12 cycles (n=133). Outcomes included PFS, OS, overall response rate (ORR), and safety. Long-term responses were investigator-assessed per 2008 iwCLL criteria. Results: With up to 7y of follow-up (median, 74.9 months; range, 0.1–86.8), significant PFS benefit was sustained for pts treated with ibrutinib vs chlorambucil (hazard ratio [HR] 0.160 [95% confidence interval (CI): 0.111–0.230]). At 6.5y, PFS was 61% in pts treated with ibrutinib vs 9% in pts treated with chlorambucil. This PFS benefit was observed across all subgroups, including in ibrutinib-treated pts with high-risk genomic features of unmutated IGHV (HR 0.109 [95% CI: 0.063–0.189]) or del(11q) (HR 0.033 [95% CI: 0.010–0.107]). OS at 6.5y was 78% with ibrutinib treatment. ORR was 92% for ibrutinib-treated pts with complete response (CR/CRi) rate increasing to 34% with this follow-up. Ongoing rates of grade ≥3 adverse events (AEs) of interest remained low for hypertension (5–6y interval: 5%, n=4; 6–7y: 4%, n=3) and atrial fibrillation (5–6y: 1%, n=1; 6–7y: 1%, n=1); no grade ≥3 major hemorrhage occurred in 5–7y. Dose reductions due to grade ≥3 AEs occurred in 1% (n=1) of pts during the 5–6y and 6–7y intervals. Across full follow-up, 31 pts had dose reductions due to any-grade AEs of whom 22/31 (71%) had resolution or improvement the AE. Primary reason for discontinuations in 5–7y was PD (5–6y: 5%, n=4; 6–7y: 6%, n=4). Any-grade AEs leading to discontinuations were seen in 3% (n=2) of pts from 5–6y and none in 6–7y. With over 7y of follow-up, 47% of pts remain on single-agent ibrutinib. Conclusions: Extended long-term data from RESONATE-2 demonstrate the sustained PFS and OS benefit of first-line ibrutinib treatment for pts with CLL, including for pts with high-risk genomic features. Responses continue to deepen over time. Rates of grade ≥3 AEs of interest continued to be low at up to 7y follow-up and further discontinuations and dose reductions due to AEs were rare; most AEs leading to dose reduction resolved or improved. Ibrutinib remains well tolerated with no new safety signals observed. Clinical trial information: NCT01722487, NCT01724346.

Real-world management of targeted therapies in chronic lymphocytic leukemia

“…A seven-year follow-up of RESONATE-2 encouragingly reported a sustained PFS benefit of ibrutinib at 6.5 years (61% vs. 9%). 20 The iLLUMINATE trial, a phase III, open-label, randomized controlled trial (RCT) compared ibrutinib-obinutuzumab to chlorambucil-obinutuzumab in patients either 65 years of age or older or with coexisting conditions. 21 Median PFS was significantly longer with ibrutinib-obinutuzumab (not reached vs. 19 months, p < 0.0001).…”

“…BTKis maintain durable remissions with continuous therapy, as response generally deepens over time. 20 Disadvantages of zanubrutinib include twice daily dosing, higher rates of neutropenia compared to other BTKis, and a lack of mature data in the CLL population. 40,100…”

“…BTKis maintain durable remissions with continuous therapy, as response generally deepens over time. 20 Disadvantages of zanubrutinib include twice daily dosing, higher rates of neutropenia compared to other BTKis, and a lack of mature data in the CLL population. 40,100 Of the available agents, ibrutinib has the most mature data with seven-year follow-up of the RESONATE-2 trial demonstrating a sustained PFS benefit over chlorambucil.…”

“…40,100 Of the available agents, ibrutinib has the most mature data with seven-year follow-up of the RESONATE-2 trial demonstrating a sustained PFS benefit over chlorambucil. 20 Zanubrutinib and acalabrutinib have not yet been compared head-to-head in any setting, although tolerability of these second-generation BTKis appears superior to ibrutinib. Given overall similar efficacy between these agents, treatment selection is largely based on patient-specific factors including preference, comorbidities, and concomitant medications.…”

Evolving Treatment Paradigm in Frontline CLL

“…3 This trial was recently updated with a 7-year follow-up and continues to show the superiority of ibrutinib or chlorambucil. 4 Notably, the progression-free survival (PFS) at 6.5 years was 61% with ibrutinib monotherapy.…”