@article{3076472,
    title = "Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study",
    author = "Buske, C. and Tedeschi, A. and Trotman, J. and García-Sanz, R. and MacDonald, D. and Leblond, V. and Mahe, B. and Herbaux, C. and Matous, J.V. and Tam, C.S. and Heffner, L.T. and Varettoni, M. and Palomba, M.L. and Shustik, C. and Kastritis, E. and Treon, S.P. and Ping, J. and Hauns, B. and Arango-Hisijara, I. and Dimopoulos, M.A.",
    journal = "Journal of clinical oncology: official journal of the American Society of Clinical Oncology",
    year = "2022",
    volume = "40",
    number = "1",
    pages = "52-62",
    publisher = "NLM (Medline)",
    doi = "10.1200/JCO.21.00838",
    keywords = "adenine;  antineoplastic agent;  chemokine receptor CXCR4;  CXCR4 protein, human;  ibrutinib;  MYD88 protein, human;  myeloid differentiation factor 88;  piperidine derivative;  rituximab;  tumor marker, adult;  aged;  clinical trial;  comparative study;  controlled study;  double blind procedure;  female;  genetics;  human;  male;  middle aged;  mortality;  multicenter study;  mutation;  phase 3 clinical trial;  randomized controlled trial;  time factor;  very elderly;  Waldenstroem macroglobulinemia, Adenine;  Adult;  Aged;  Aged, 80 and over;  Antineoplastic Combined Chemotherapy Protocols;  Biomarkers, Tumor;  Double-Blind Method;  Female;  Humans;  Male;  Middle Aged;  Mutation;  Myeloid Differentiation Factor 88;  Piperidines;  Progression-Free Survival;  Receptors, CXCR4;  Rituximab;  Time Factors;  Waldenstrom Macroglobulinemia",
    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."
}