Data from Single-Agent Ibrutinib for Rituximab-Refractory Waldenström Macroglobulinemia: Final Analysis of the Substudy of the Phase III Innovate<sup>TM</sup> Trial

<div>AbstractPurpose:<p>The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported.</p>Patients and Methods:<p>Ibrutinib 420 mg was administered once daily to patients (<i>N</i> = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed.</p>Results:<p>After a median follow-up of 58 months (range: 9–61), median PFS was 39 months [95% confidence interval (CI): 25–not evaluable]; 60-month PFS rate was 40%. In MYD88<sup>L265P</sup>/CXCR4<sup>WHIM</sup> and MYD88<sup>L265P</sup>/CXCR4<sup>WT</sup> subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of −37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation.</p>Conclusions:<p>In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia.</p></div>