TY - JOUR
TI - Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study
AU - Buske, C.
AU - Tedeschi, A.
AU - Trotman, J.
AU - García-Sanz, R.
AU - MacDonald, D.
AU - Leblond, V.
AU - Mahe, B.
AU - Herbaux, C.
AU - Matous, J.V.
AU - Tam, C.S.
AU - Heffner, L.T.
AU - Varettoni, M.
AU - Palomba, M.L.
AU - Shustik, C.
AU - Kastritis, E.
AU - Treon, S.P.
AU - Ping, J.
AU - Hauns, B.
AU - Arango-Hisijara, I.
AU - Dimopoulos, M.A.
JO - Journal of clinical oncology: official journal of the American Society of Clinical Oncology
PY - 2022
VL - 40
TODO - 1
SP - 52-62
PB - NLM (Medline)
SN - null
TODO - 10.1200/JCO.21.00838
TODO - 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
TODO - 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.
ER -