Contributions
Abstract: S769
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 08:00 - 08:15
Location: Hall A
Background
Ibrutinib is a first-in-class, once-daily oral inhibitor of Bruton’s tyrosine kinase. Ibrutinib as a single agent is indicated by the EMEA and US FDA for the treatment of adult patients with CLL and allows for treatment without chemotherapy. The phase 3 RESONATE trial in patients with relapsed CLL showed superior efficacy of ibrutinib compared with ofatumumab (Byrd NEJM 2014).
Aims
We report updated safety and efficacy results of the RESONATE trial with up to 4 years of follow-up.
Methods
Eligibility criteria included ≥1 prior therapy, ineligibility for treatment with a purine analog, and ECOG performance status 0-1. Informed consent was obtained from all patients prior to study initiation. Patients received oral ibrutinib (420 mg once daily) until disease progression or unacceptable toxicity or intravenous ofatumumab (300 mg week 1; 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks) for up to 24 weeks. At the interim analysis (median follow-up of 9 months), the data monitoring committee declared superiority of ibrutinib vs ofatumumab for progression-free survival (PFS) and overall survival (OS), and access to ibrutinib was recommended for all patients in ofatumumab arm who had disease progression. Long-term follow-up of efficacy endpoints are per investigator assessment. Patients randomized to ofatumumab were censored at crossover for OS.
Results
A total of 391 patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). The median age was 67 years, with 40% age ≥70 years, and Rai stage III/IV in 57% of patients. At a median follow-up of 44 months (maximum 53 months) for the ibrutinib arm, PFS was significantly longer for ibrutinib vs ofatumumab (median NR vs 8 months, [HR 0.133; P<0.0001]). The 3-year PFS was 59% for ibrutinib vs 3% for ofatumumab. A significant PFS benefit was observed across baseline subgroups. In the ibrutinib arm, PFS for the del11q subgroup trended to have the most favorable outcome; however, PFS outcomes were not statistically different for patients with del17p or del11q or patients without these FISH abnormalities. At time of analysis, with the majority of patients randomized to ofatumumab (68%) crossing over to receive ibrutinib therapy, OS was longer for ibrutinib vs ofatumumab (median OS NR for either arm). The 3-year OS rate for ibrutinib was 74%. The ORR for ibrutinib was 91% with a CR/CRi rate that increased over time (currently 9%). Baseline cytopenias improved with extended ibrutinib therapy for hemoglobin (85% of patients), platelet (95% of patients), and absolute neutrophil counts (95% of patients). The adverse event (AE) profile of ibrutinib was consistent with previous reports. During a follow-up of up to 4 years, major hemorrhage occurred in 6%, grade ≥3 atrial fibrillation occurred in 6%, and grade ≥3 hypertension occurred in 8% of patients. The incidence of most grade ≥3 AEs decreased from year 1 vs year 2-3: neutropenia: 18% vs 8%; pneumonia: 11% vs 4%; atrial fibrillation: 4% vs 2%, respectively. The most frequent reasons for treatment discontinuation were progressive disease (27%) and AEs (12%). At analysis, 90 patients randomized to ibrutinib (46%) continue to receive ibrutinib.
Conclusion
In this international phase 3 RESONATE study with median follow-up of up to 4 years, long-term treatment with ibrutinib showed a favorable tolerability profile with sustained PFS and OS benefit regardless of high-risk cytogenetics. The results in relapsed del17p and del11q patients compared favorably to those previously reported in phase 2 studies.
Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical
Keyword(s): Long-term follow-up, Chronic Lymphocytic Leukemia, Tyrosine kinase inhibitor
Abstract: S769
Type: Oral Presentation
Presentation during EHA22: On Sunday, June 25, 2017 from 08:00 - 08:15
Location: Hall A
Background
Ibrutinib is a first-in-class, once-daily oral inhibitor of Bruton’s tyrosine kinase. Ibrutinib as a single agent is indicated by the EMEA and US FDA for the treatment of adult patients with CLL and allows for treatment without chemotherapy. The phase 3 RESONATE trial in patients with relapsed CLL showed superior efficacy of ibrutinib compared with ofatumumab (Byrd NEJM 2014).
Aims
We report updated safety and efficacy results of the RESONATE trial with up to 4 years of follow-up.
Methods
Eligibility criteria included ≥1 prior therapy, ineligibility for treatment with a purine analog, and ECOG performance status 0-1. Informed consent was obtained from all patients prior to study initiation. Patients received oral ibrutinib (420 mg once daily) until disease progression or unacceptable toxicity or intravenous ofatumumab (300 mg week 1; 2000 mg weekly for 7 weeks and then every 4 weeks for 16 weeks) for up to 24 weeks. At the interim analysis (median follow-up of 9 months), the data monitoring committee declared superiority of ibrutinib vs ofatumumab for progression-free survival (PFS) and overall survival (OS), and access to ibrutinib was recommended for all patients in ofatumumab arm who had disease progression. Long-term follow-up of efficacy endpoints are per investigator assessment. Patients randomized to ofatumumab were censored at crossover for OS.
Results
A total of 391 patients were randomized to receive ibrutinib (n=195) or ofatumumab (n=196). The median age was 67 years, with 40% age ≥70 years, and Rai stage III/IV in 57% of patients. At a median follow-up of 44 months (maximum 53 months) for the ibrutinib arm, PFS was significantly longer for ibrutinib vs ofatumumab (median NR vs 8 months, [HR 0.133; P<0.0001]). The 3-year PFS was 59% for ibrutinib vs 3% for ofatumumab. A significant PFS benefit was observed across baseline subgroups. In the ibrutinib arm, PFS for the del11q subgroup trended to have the most favorable outcome; however, PFS outcomes were not statistically different for patients with del17p or del11q or patients without these FISH abnormalities. At time of analysis, with the majority of patients randomized to ofatumumab (68%) crossing over to receive ibrutinib therapy, OS was longer for ibrutinib vs ofatumumab (median OS NR for either arm). The 3-year OS rate for ibrutinib was 74%. The ORR for ibrutinib was 91% with a CR/CRi rate that increased over time (currently 9%). Baseline cytopenias improved with extended ibrutinib therapy for hemoglobin (85% of patients), platelet (95% of patients), and absolute neutrophil counts (95% of patients). The adverse event (AE) profile of ibrutinib was consistent with previous reports. During a follow-up of up to 4 years, major hemorrhage occurred in 6%, grade ≥3 atrial fibrillation occurred in 6%, and grade ≥3 hypertension occurred in 8% of patients. The incidence of most grade ≥3 AEs decreased from year 1 vs year 2-3: neutropenia: 18% vs 8%; pneumonia: 11% vs 4%; atrial fibrillation: 4% vs 2%, respectively. The most frequent reasons for treatment discontinuation were progressive disease (27%) and AEs (12%). At analysis, 90 patients randomized to ibrutinib (46%) continue to receive ibrutinib.
Conclusion
In this international phase 3 RESONATE study with median follow-up of up to 4 years, long-term treatment with ibrutinib showed a favorable tolerability profile with sustained PFS and OS benefit regardless of high-risk cytogenetics. The results in relapsed del17p and del11q patients compared favorably to those previously reported in phase 2 studies.
Session topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical
Keyword(s): Long-term follow-up, Chronic Lymphocytic Leukemia, Tyrosine kinase inhibitor