LONG‐TERM EFFICACY AND SAFETY IN THE RESONATE STUDY: IBRUTINIB IN PATIENTS WITH PREVIOUSLY TREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WITH UP TO FOUR YEARS FOLLOW‐UP

Abstract

Introduction: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA and EMEA for patients with CLL and allows for treatment without chemotherapy. RESONATE™ is a phase 3 trial of ibrutinib vs ofatumumab in relapsed CLL/SLL. This report includes updated safety and efficacy results with up to 4-year follow-up. Methods: Eligible patients had ≥1 prior therapy. Patients received 420-mg ibrutinib PO until disease progression or ofatumumab up to 24 weeks. At interim analysis (median 9 months follow-up), superiority of ibrutinib vs ofatumumab for PFS and OS was declared by the data monitoring committee, and ibrutinib access was recommended for all ofatumumab patients. For this long-term follow-up analysis, efficacy was investigator assessed. OS was censored at crossover for patients who received ibrutinib after ofatumumab. Results: of 391 patients enrolled, 195 were randomized to the ibrutinib arm and 196 to the ofatumumab arm. The median age was 67 years (age ≥70 years in 40%) and 57% had advanced disease (Rai stage III/IV). Median follow-up for the ibrutinib arm was 44 months (53 months max). Ibrutinib significantly prolonged PFS vs ofatumumab (median NR vs 8 months, [HR 0.133; P < 0.0001]; 3-year PFS 59% vs 3%). Significant PFS benefits were observed across patient subgroups. PFS on ibrutinib for the del11q subgroup trended to have the most favorable outcome, although PFS was not statistically different between ibrutinib patients with del17p vs del11q vs those without these FISH abnormalities. At analysis, with the majority of ofatumumab patients (68%) crossing over to ibrutinib, OS was longer for ibrutinib vs ofatumumab (median OS not reached for either arm). The 3-year OS for ibrutinib was 74%. ORR with ibrutinib was 91% with CR/CRi rates that increased over time (9% at current followup). With extended ibrutinib therapy, improvements in baseline cytopenias were observed for hemoglobin (85%), platelet (95%), and absolute neutrophil counts (95%). The AE profile of ibrutinib was consistent with previous reports. Major hemorrhage occurred in 6%, grade ≥ 3 atrial fibrillation in 6%, and grade ≥3 hypertension in 8% of patients over a 4-year follow-up period. Rates of most grade ≥3 AEs decreased from year 1 to years 2-3 including neutropenia (18% vs 8%), pneumonia (11% vs 4%), and atrial fibrillation (4% vs 2%). Most frequent reasons for ibrutinib discontinuations were disease progression (27%) and AE (12%). At analysis, 90 patients randomized to ibrutinib (46%) continue ibrutinib therapy. Conclusions: Long-term results of the international phase 3 RESONATE trial support the tolerability of extended ibrutinib treatment and continue to demonstrate sustained PFS and OS including in patients with high-risk cytogenetics. The results in patients with relapsed CLL with del17p or del11q abnormalities compare favorably to prior reports from phase 2 trials. Funding source: Pharmacyclics LLC, an AbbVie Company.