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Extended Phase 3 Results From RESONATE-2
months follow up after ibrutinib discontinuation and 3 have died (Online Supplementary Table S4). Ten of the patients had PR as best response, 4 patients discontinued after not responding to ibrutinib and 2 patients discontin- ued prior to response evaluation. Non-responders/non- evaluable had a PFS that ranged from 1.8 to 20.2 months, while responders tended to have a variable but longer PFS (4.2–34.0 months). As the vast majority of patients (79%) remain on single-agent ibrutinib, this analysis is limited in size and also to the patients who came off treatment fairly early (9 of the 16 patients who discontinued due to AEs did so in the first year). In total, 7 patients received subse- quent therapy after ibrutinib at a median of 7.6 months following ibrutinib discontinuation (range, 1.2 to 20.8 months), including fludarabine-cyclophosphamide- rituximab (n=3), bendamustine-rituximab (n=2), chloram- bucil (n=1), and radiation (n=1). Six of these 7 patients (86%) remain alive with median follow up of 21 months (range, 9 to 25 months).
Discussion
This extended analysis of RESONATE-2 with detailed clinical follow up demonstrates that ibrutinib continues to provide significant and sustained clinical benefits, improv- ing the quality of responses, for the first-line treatment of older patients with CLL or SLL with a manageable safety profile over extended durations of treatment. Consistent with the initial report, ibrutinib demonstrates a significant 88% reduction in the risk of PFS events (progression or death) compared with chlorambucil (P<0.0001) with extended follow up. In addition, the OS benefit for ibruti- nib compared with chlorambucil was maintained, despite crossover to treatment with ibrutinib for many patients in the chlorambucil arm (n=55). These data support the use
of ibrutinib in the first-line treatment of CLL as a chemotherapy-free option that can be taken continuously, achieving long-term disease control for the majority of patients including those with high risk features.10,13 Ibrutinib has a category 1 National Comprehensive Cancer Network® (NCCN®) recommendation as a single- agent first-line treatment for CLL without del(17p) in patients ≥65 years and for relapsed/refractory CLL with- out del(17p).18
The efficacy of ibrutinib in the first-line setting appears superior to that observed in relapsed or refractory patients.19 Nearly all patients randomly assigned to ibruti- nib achieved rapid disease reduction, with an ORR of 92% translating to high rates of 24-month PFS and OS of 89% and 95%, respectively, with similar PFS and OS rates seen regardless of age. This observation suggests that ibru- tinib may be most effective when used upfront before the acquisition of poor-risk molecular aberrations, which are selected for with chemotherapy.20,21 Additionally, sensitiv- ity analyses to adjust for the effects of patients in RES- ONATE-2 who crossed over to ibrutinib found that treat- ment with ibrutinib was still associated with statically sig- nificant OS compared with chlorambucil.16 These results also demonstrate that depth of response substantially increases over time, with higher rates of CR during the extended follow up, indicating a persistent action of the drug rather than a simple maintenance effect. Similar find- ings were observed with long-term follow up of patients enrolled in the phase 2 trial of first-line ibrutinib.11 Within this previous study, 29% of patients achieved a CR, and 92% remained alive and progression free at 5 years.22 Given these data, the CR rate will likely continue to increase in the present study as long-term disease control and high tolerability with first-line use can be expected based on the earlier phase 2 results.12
In addition to the efficacy benefits overall, sustained
Figure 3. Response rates over time in ibrutinib-treated patients. CR: complete response; CRi: complete response with incomplete blood-count recovery; nPR: nodular partial response (defined according to the International Workshop on Chronic Lymphocytic Leukemia criteria for response16 as a complete response with lymphoid nodules in the bone marrow); PR: partial response; PR-L: partial response with lymphocytosis.
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