ASH 2016 Abstract 234. Updated Efficacy and Safety from the Phase 3 Resonate-2 Study: Ibrutinib As First-Line Treatment Option in Patients 65 Years and Older with Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia
Paul Barr et al.
Results: Median age of the 269 pts was 73 y (70% ≥70 y). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline, including CIRS score >6, reduced creatinine clearance, or ECOG performance status of 2. With a median follow-up of 28.6 mo, prolongation of PFS for ibr vs clb was sustained (89% vs 34% at 24-mo; HR, 0.121; 95% CI 0.074-0.198; P<0.0001; Figure). PFS was significantly improved for ibr across high-risk subgroups, including del11q and unmutated IGHV gene (Figure). Overall, 4 of 135 pts discontinued ibr due to PD. 1 case of Richter’s transformation was observed in each arm. With 41% of pts switching from clb to ibr, the OS analysis in the ITT population resulted in 2-yr survival rate estimates of 95% and 84% in the ibr and chlorambucil arms, respectively. The investigator-assessed ORR was 92% with ibr vs 36% with clb (P<0.0001). CR/CRi within the ibr arm improved from 11% at 18.4 mo to 18% with longer follow-up of 28.6-mo. Sustained hematological improvements were higher for ibr vs clb for those with anemia (90% vs 45%; P<0.0001) or thrombocytopenia (80% vs 46%; P=0.0055) at baseline. The most frequent adverse events in ibrutinib treated pts (AEs; ≥20%) are presented in the Table. Grade [Gr] ≥3 AEs in ≥5% of pts included neutropenia (12%), pneumonia (7%), anemia (7%), and hypertension (5%); AEs (any Gr) leading to dose reductions occurred in 13%. The most common reason for discontinuation was AEs (12%), with most occurring during the first yr of ibr therapy. The incidence of the common Gr ≥3 AEs in these ibr-treated pts typically decreased over time. Major hemorrhage occurred in 7% (1 Gr 2, 7 Gr 3, 1 Gr 4; 5 in first 12 mo and 4 between 1-2 y) and atrial fibrillation occurred in 10% (1 Gr 1, 7 Gr 2, 6 Gr 3) of ibr-treated pts. With a median treatment duration of 28.5 mo (range, 1-36), 79% of pts remain on first-line ibr.
Conclusions: With a median time on study of 28.6 mo, ibr continued to have substantial efficacy, with 88% reduction in risk of progression or death. Furthermore, the quality of responses has improved over time, with 18% of CLL/SLL pts achieving a CR/CRi with single agent ibr. Treatment limiting AEs decreased in frequency with longer follow-up, with 79% of this elderly pt population continues daily ibr. Lastly, even with a high rate of cross-over in the clb arm, OS remains significantly improved for pts randomized to ibr.
CARE Faculty Perspective: Results from the RESONATE-2 trial were first published in 2015 (Byrd et al.) and showed a significant improvement in survival and safety with the use of ibrutinib in the front-line CLL setting. Longer follow-up for this study was presented during this year’s ASH conference and further confirmed ibrutinib’s efficacy and safety across risk groups. Interestingly, results also showed that quality of response actually improved over time with durable PFS and OS
While these results validate and build on previous findings, there are still limitations to knowing the full impact that this will have in Canadian practice given the use of chlorambucil as the comparator (not the current standard of care chlorambucil with obinutuzumab). Clinical trials with more relevant comparators are awaited, however it is clear that novel oral agents like ibrutinib are challenging the current R-Chemo standard.