Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

Abstract

PURPOSE The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. METHODS Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. RESULTS With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade ≥ 3 adverse events of clinical interest generally decreased over time. CONCLUSION In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.

First‐ versus second‐generation Bruton tyrosine kinase inhibitors in Waldenström's Macroglobulinemia: A systematic review and meta‐analysis

“…21 Upon a relatively longer follow-up of 60 months, similar patterns of response for ibrutinib and rituximab in both TN and R/R patients were reported. 16 When considering the mutational status, we found superior MRR and VGPR rates with MYD88 mutated + CXCR4 wild-type patients in 1st-generation BTKi, this effect was also observed in the total cohort of both 1st-and 2nd-generation BTKi. This may be explained by the resulting disturbances of multiple prosurvival cascades including the NF-KB, AKT, ERK, and STAT3 activation when mutated MYD88 is targeted.…”

“…First-generation BTKi had a 60-month OS ranging from 73% to 87% in included studies with a median of 50 months (95% CI, 11-not reached) reported in one study. [16][17][18]21 For 60 months PFS, rates ranged from 40% to 54% with a median of 39 months (95% CI, 25-not reached). 17 As for 2ndgeneration BTKi, the longest OS was reported on the 36-month mark in two studies, 84.8% and 76.2%.…”

Determinants of Drug Resistance in B-Cell Non-Hodgkin Lymphomas: The Case of Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

“…However, this study does not answer the question whether rituximab adds value to ibrutinib alone since it lacks an ibrutinib monotherapy arm. The updated long-term data of these pivotal studies of ibrutinib in the relapse and front-line setting and of the iNNOVATE trial have been recently published, further confirming the efficacy and safety profiles (56)(57)(58).…”

Diagnosis and management of Waldenström macroglobulinaemia—A British Society for Haematology guideline

“…29 The 4-year PFS rate in the treatment-naïve cohort was 70% and 32% respectively and in those previously treated, 71% and 20%. 80 A subsidiary study of this trial investigated the role of ibrutinib alone in 31 patients with rituximab-refractory disease. After a median follow-up of 58 months, the median PFS was 39 months (95% CI 25-not evaluable).…”