Krigsfeld, Gabriel

Introduction: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), changed the treatment landscape by demonstrating improved overall survival (OS) compared with chemotherapy/chemoimmunotherapy across multiple phase 3 trials in patients (pts) with CLL, including those with high-risk genomic features. Recently, data were reported for pts treated with ibrutinib in the phase 3 RESONATE-2 trial with up to 10 years of follow-up, representing the longest follow-up of any BTKi used in first-line treatment of CLL. With the most robust long-term follow-up data among BTKis, ibrutinib therapy trials are uniquely positioned to assess the long-term OS benefit of first-line BTKi treatment in pts with CLL across pt subgroups. We previously demonstrated that first-line ibrutinib is associated with OS rates that are similar to those in the age-matched general population, with a median follow-up of 5.9 years since initial diagnosis (Ghia P et al. HemaSphere 2024), but it remains unclear whether this holds true for pts with high-risk genomic features. This updated analysis evaluated long-term OS outcomes with a median follow-up of 8 years since randomization and 10 years since initial diagnosis in a pooled population of pts with previously untreated CLL, including those with high-risk features, who received first-line ibrutinib treatment in 2 phase 3 trials with comparison of survival estimates to the US age-matched general population. Methods: Data were pooled for pts who received first-line treatment with single-agent ibrutinib or ibrutinib + rituximab in the RESONATE-2 (NCT01722487) and ECOG-ACRIN E1912 (NCT02048813) trials, respectively. OS probabilities from the time of randomization and from the time of initial diagnosis for ibrutinib-treated pts were compared with an age-matched general population using 2021 life tables for the total US population published by the Centers for Disease Control and Prevention using the Kaplan-Meier method. Subgroup analyses were performed for high-risk pts, defined as those with del(11q), del(17p), mutated TP53, and/or unmutated IGHV (uIGHV). Results: A total of490 pts were pooled across the 2 studies: 352 pts (71.8%) were treated with ibrutinib + rituximab, and 135 pts (27.6%) were treated with single-agent ibrutinib; 3 pts did not receive study treatment. The median age at time of randomization was 61 years; 36.5% (179/490) were aged ≥65 years, 21.8% had del(11q), 7.8% had del(17p) and/or mutated TP53, and 54.7% had uIGHV. The median time from initial CLL diagnosis to randomization was 20.9 months (range, 0.0-341.8); the median follow-up was 123.5 months (10.3 years) from initial diagnosis and 99.2 months (8.3 years) from the time of randomization. From the time of randomization, estimated 9-year OS rates were 81.2% (95% CI, 76.8-84.9) in all ibrutinib-treated pts versus 82.0% (95% CI, 78.3-85.2) in the age-matched population (hazard ratio [HR] 1.17; 95% CI, 0.86-1.58). In high-risk pts, estimated 9-year OS rates were 79.5% (95% CI, 73.5-84.3) for ibrutinib-treated pts versus 83.2% (95% CI, 78.5-86.9) in the age-matched general population (HR 1.24; 95% CI, 0.84-1.84). In pts aged ≥65 years, estimated 9-year OS rates were 68.7% (95% CI, 60.5-75.6) for ibrutinib-treated pts and 68.7% (95% CI, 61.4-75.0) in the age-matched general population (HR 1.12; 95% CI, 0.77-1.63). In pts aged <65 years, estimated 9-year OS rates were 89.3% (95% CI, 84.6-92.7) for ibrutinib-treated pts and 90.0% (95% CI, 86.1-92.9) in the age-matched general population (HR 1.15; 95% CI, 0.68-1.94). From the time of initial diagnosis, estimated 15-year OS rates were 78.4% (95% CI, 72.8-83.0) in all ibrutinib-treated pts versus 72.0% (95% CI, 67.8-75.7) in the age-matched general population (HR 0.83; 95% CI, 0.62-1.11). Study treatment had been discontinued in 59.8% (293/490) of pooled ibrutinib-treated pts; the most frequent reasons for discontinuation were adverse events (43.0%; 126/293) and progressive disease (20.5%; 60/293). Study treatment was ongoing in 31.8% of pooled pts (156/490). Conclusions: With the longest follow-up time for any commercially available targeted therapy, this pooled analysis demonstrates that, regardless of evaluation from randomization or initial diagnosis, and irrespective of age or high-risk features, first-line treatment with ibrutinib provides long-term OS benefit with survival estimates that appear similar to those of a US age-matched cohort.