New 10-Year Data Show Ibrutinib's Lasting Efficacy in CLL/SLL

Final results from the landmark RESONATE-2 trial (NCT01722487) offer the longest follow-up to date for any targeted chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) therapy, underscoring the long-term efficacy and safety of first-line ibrutinib (Imbruvica).¹

The phase 3 compared single-agent ibrutinib with chlorambucil in previously untreated patients with CLL/SLL who were aged 65 or older and did not have a del(17p) mutation. After a median follow-up of 9.6 years for the ibrutinib arm, the final analysis revealed a median progression-free survival of 8.9 years for patients on ibrutinib compared with just 1.3 years for those who received chlorambucil. This sustained benefit was observed across various patient subgroups.

The data reinforce ibrutinib's role as a cornerstone in managing CLL/SLL, particularly in older patients with high-risk genomic features.

Enduring Benefit for Patients with High-Risk Features

A key finding of the final analysis is the durable efficacy of ibrutinib in patients with high-risk genomic features, which have historically been associated with poor outcomes with traditional chemotherapy. These features include unmutated IGHV, del(11q), TP53 mutation, or complex karyotype.

For this high-risk subgroup, the median PFS with ibrutinib was 8.4 years, a stark contrast with the 0.7 years seen with chlorambucil. The 9-year PFS rate for these patients on ibrutinib was 47%, highlighting the ability of the BTK inhibitor to overcome the poor prognosis typically associated with these genetic alterations.

Furthermore, the median overall survival (OS) for patients on ibrutinib was not reached, with a 9-year OS rate of 68% for all patients in the ibrutinib arm and 66% for those with at least 1 high-risk genomic feature.

Safety and Tolerability Profile Over a Decade

With a median treatment duration of 6.2 years, the final analysis of RESONATE-2 provides a comprehensive look at the long-term safety of ibrutinib. The most frequent adverse events (AEs) of any grade were diarrhea (52%), fatigue (41%), cough (39%), and nausea (32%). The prevalence of AEs remained stable over time, with no new safety signals emerging during the extended follow-up period.

A quarter of patients (25%) required a dose reduction due to AEs at some point during the study. Importantly, AEs improved in 88% of these patients, demonstrating that active dose management strategies are effective in mitigating AEs and allowing patients to remain on treatment. This managed tolerability enables patients to continue benefiting from long-term therapy, a crucial factor in chronic diseases like CLL/SLL.

Treatment discontinuation due to AEs occurred in 33% of patients, with the most common reasons being atrial fibrillation and pneumonia. The study noted no increasing trend in discontinuation rates over time, further supporting the long-term tolerability of the drug.

A Look Back at Early Data

The first analysis of RESONATE-2 was published in December 2015 in The New England Journal of Medicine.² Here, ibrutinib resulted in significantly longer PFS than chlorambucil (median, not reached vs 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than chlorambucil (HR, 0.16; P <.001). Ibrutinib significantly prolonged OS, with an estimated survival rate at 24 months of 98% with ibrutinib vs 85% with chlorambucil and a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (HR, 0.16; P =.001). Additionally, the overall response rate was higher with ibrutinib than with chlorambucil (86% vs 35%, P<0.001).

Sustained Responses and Future Treatment Options

These new data also showed that responses to ibrutinib deepened over time. The cumulative rate of complete response (CR) or CR with incomplete bone marrow recovery (CRi) increased during the first 7 years of the study, stabilizing at 36% in the later years.¹ At study closure, 27% of patients remained on first-line ibrutinib therapy, underscoring the drug's sustained efficacy.

For patients who discontinued first-line ibrutinib, a variety of second-line therapies were utilized, including venetoclax (Venclexta) and acalabrutinib (Calquence). The study also examined the outcomes of patients originally in the chlorambucil arm who crossed over to receive second-line ibrutinib after their disease progressed. These patients experienced a median PFS of 48.5 months and a 4-year OS rate of 68% after the crossover, demonstrating that ibrutinib remains an effective option even in the second-line setting.

“With its global approvals and use in more than 320,000 patients worldwide to date, ibrutinib has been established as a cornerstone in the disease management of these patients,” study authors conclude. “These findings highlight the durable clinical benefits of ibrutinib across various subgroups of patients, including those with high prognostic risk genomic or clinical factors.”

REFERENCES:

1. Burger JA, Barr PM, Prof TR, et al. Final analysis of the RESONATE-2 study: up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL. Blood. 2025 Jul 30:blood.2024028205. doi: 10.1182/blood.2024028205. Online ahead of print.

2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. doi: 10.1056/NEJMoa1509388. Epub 2015 Dec 6.