Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenstrom&#39;s Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

Buske, C; Tedeschi, A; Trotman, J; Garcia-Sanz, R; MacDonald, D; Leblond, V; Mahe, B; Herbaux, C; Matous, JV; Tam, CS; Heffner, LT; Varettoni, M; Palomba, ML; Shustik, C; Kastritis, E; Treon, SP; Ping, J; Hauns, B; Arango-Hisijara, I; Dimopoulos, MA

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

Author(s): Buske, C; Tedeschi, A; Trotman, J; Garcia-Sanz, R; MacDonald, D; Leblond, V; Mahe, B; Herbaux, C; Matous, JV; Tam, CS; Heffner, LT; Varettoni, M; Palomba, ML; Shustik, C; Kastritis, E; Treon, SP; Ping, J; Hauns, B; Arango-Hisijara, I; Dimopoulos, MA;
Details: Publication Year 2022-01-01,Volume 40,Issue #1,Page 52-62
Journal Title: Journal of Clinical Oncology
Publication Type: Research article
Abstract: PURPOSE: The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenstrom'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.
Keywords: Adenine/adverse effects/*analogs & derivatives/therapeutic use; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use; Biomarkers, Tumor/genetics; Double-Blind Method; Female; Humans; Male; Middle Aged; Mutation; Myeloid Differentiation Factor 88/genetics; Piperidines/adverse effects/*therapeutic use; Progression-Free Survival; Receptors, CXCR4/genetics; Rituximab/adverse effects/*therapeutic use; Time Factors; Waldenstrom Macroglobulinemia/diagnosis/*drug therapy/genetics/mortality
Department(s): Clinical Haematology
PubMed ID: 34606378
Publisher's Version: https://doi.org/10.1200/JCO.21.00838
Open Access at Publisher's Site: https://doi.org/10.1200/jco.21.00838
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-11 04:24:49

Last Modified: 2024-10-11 04:26:13