Ibrutinib versus Chlorambucil in Patients ?65 Years with Treatment-Naïve CLL/SLL: Results from the Phase 3 RESONATE-2 Study
Standard chemoimmunotherapy regimens are often not tolerated by the majority of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who are typically older patients with considerable comorbidities and disease-related immunosuppression. Treatment options for this patient population are limited; they are commonly treated with alkylating agents such as chlorambucil, underscoring the need for novel and effective therapies. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase that is approved for treatment of patients with CLL who had received ?1 prior therapies and for those with deletion 17p cytogenetic abnormality.1 In treatment-naïve patients aged ?65 years, ibrutinib treatment resulted in an overall response rate (ORR) of 84%, including complete responses in 23% of patients and a 30-month progression-free survival (PFS) of 96%.2 Based on these encouraging results, a head-to-head comparison of the efficacy and safety of ibrutinib versus chlorambucil was conducted by the randomized, open-label phase 3 RESONATE-2TM trial in treatment-naïve older patients with CLL/SLL; Tedeschi and colleagues reported on these results at the meeting.3
A total of 269 patients were enrolled (median age, 73 years) and treated with ibrutinib (420 mg daily) or chlorambucil (0.5 mg/kg) until progression. At a median follow-up of 18.4 months, ibrutinib significantly prolonged Independent Review Committee (IRC)-assessed PFS compared with chlorambucil (median not reached [NR] vs 18.9 months; hazard ratio [HR], 0.16; P <.0001); ibrutinib decreased the risk of progression or death by 84%. This impressive PFS benefit also extended to patient subgroups, including those aged ?70 years, as well as those with high-risk features such as del11q and unmutated IgHV. Importantly, ibrutinib therapy resulted in significant prolongation of overall survival (OS; median OS: NR in both arms; HR, 0.16; P = .0010), and a 24-month OS of 97.8% (vs 85.3%) compared with control. Patients treated with ibrutinib achieved a higher IRC-assessed ORR of 86.0% versus 35.3% with chlorambucil. Moreover, a significantly greater proportion of ibrutinib-treated patients achieved a ?50% reduction in lymph node burden (91.2% vs 36.8%; P <.0001); reduction in spleen enlargement (75.7% vs 39.1%; P <.0001); and sustained hematologic improvements, including in patients with baseline anemia (84% vs 45%; P <.0001) or thrombocytopenia (77% vs 43%; P = .0054). Common adverse events (AEs) associated with ibrutinib therapy were diarrhea, fatigue, cough, and nausea. AEs that occurred at higher rates in the ibrutinib cohort included atrial fibrillation (6% vs 1%), hypertension, and hemorrhage (4% vs 2%). However, AEs leading to treatment discontinuation were less frequent with ibrutinib therapy (9% vs 23%). Based on these results, the authors concluded that single-agent ibrutinib therapy was superior to standard chlorambucil in terms of efficacy outcomes, including PFS, OS, and ORR in treatment-naïve older CLL/SLL patients, and was associated with an acceptable safety profile.
- Imbruvica (ibrutinib) [Prescribing information]. 2015.
- Byrd JC, et al. Blood. 2015;125:2497-2506.
- Tedeschi A, et al. ASH 2015. Abstract 495.