Christian Buske1, Alessandra Tedeschi2, Judith Trotman3, Ramón García-Sanz4, David MacDonald5, Veronique Leblond6, Beatrice Mahe7, Charles Herbaux8, Jeffrey V Matous9, Constantine S Tam10, Leonard T Heffner11, Marzia Varettoni12, M Lia Palomba13, Chaim Shustik14, Efstathios Kastritis15, Steven P Treon16, Jerry Ping17, Bernhard Hauns17, Israel Arango-Hisijara17, Meletios A Dimopoulos15. 1. Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm, University Hospital of Ulm, Ulm, Germany. 2. ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy. 3. Concord Hospital, University of Sydney, Sydney, Australia. 4. Department of Hematology, University Hospital of Salamanca (HUS/IBSAL), CIBERONC and Cancer Research Institute of Salamanca-IBMCC (USAL-CSIC), Salamanca, Spain. 5. The Ottawa Hospital, University of Ottawa, Ottawa, Canada. 6. Département d'Hématologie Hôpital Pitié-Salpêtrière AP-HP, Sorbonne Université, Paris, France. 7. Centre Hospitalier Universitaire de Nantes, Nantes, France. 8. Centre Hospitalier Régional Universitaire de Lille, Institute of Hematology-Transfusion, Lille, France. 9. Colorado Blood Cancer Institute, Denver, CO. 10. Peter MacCallum Cancer Centre & St Vincent's Hospital and the University of Melbourne, Melbourne, Australia. 11. Winship Cancer Institute of Emory University, Atlanta, GA. 12. Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 13. Memorial Sloan Kettering Cancer Center, New York, NY. 14. Royal Victoria Hospital at McGill University Health Centre, Montreal, Canada. 15. National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 16. Dana-Farber Cancer Institute, Boston, MA. 17. Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA.
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.
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.
Authors: Zachary R Hunter; Lian Xu; Guang Yang; Yangsheng Zhou; Xia Liu; Yang Cao; Robert J Manning; Christina Tripsas; Christopher J Patterson; Patricia Sheehy; Steven P Treon Journal: Blood Date: 2013-12-23 Impact factor: 22.113
Authors: Steven P Treon; Joshua Gustine; Lian Xu; Robert J Manning; Nicholas Tsakmaklis; Maria Demos; Kirsten Meid; Maria L Guerrera; Manit Munshi; Gloria Chan; Jiaji Chen; Amanda Kofides; Christopher J Patterson; Guang Yang; Xia Liu; Patricia Severns; Toni Dubeau; Zachary R Hunter; Jorge J Castillo Journal: Br J Haematol Date: 2017-11-27 Impact factor: 6.998
Authors: Steven E Coutre; John C Byrd; Peter Hillmen; Jacqueline C Barrientos; Paul M Barr; Stephen Devereux; Tadeusz Robak; Thomas J Kipps; Anna Schuh; Carol Moreno; Richard R Furman; Jan A Burger; Michael O'Dwyer; Paolo Ghia; Rudolph Valentino; Stephen Chang; James P Dean; Danelle F James; Susan M O'Brien Journal: Blood Adv Date: 2019-06-25
Authors: Guang Yang; Yangsheng Zhou; Xia Liu; Lian Xu; Yang Cao; Robert J Manning; Christopher J Patterson; Sara J Buhrlage; Nathanael Gray; Yu-Tzu Tai; Kenneth C Anderson; Zachary R Hunter; Steven P Treon Journal: Blood Date: 2013-07-08 Impact factor: 22.113
Authors: Constantine S Tam; Stephen Opat; Shirley D'Sa; Wojciech Jurczak; Hui-Peng Lee; Gavin Cull; Roger G Owen; Paula Marlton; Björn E Wahlin; Ramón Garcia Sanz; Helen McCarthy; Stephen Mulligan; Alessandra Tedeschi; Jorge J Castillo; Jaroslaw Czyz; Carlos Fernández de Larrea; David Belada; Edward Libby; Jeffrey V Matous; Marina Motta; Tanya Siddiqi; Monica Tani; Marek Trneny; Monique C Minnema; Christian Buske; Veronique Leblond; Judith Trotman; Wai Y Chan; Jingjing Schneider; Sunhee Ro; Aileen Cohen; Jane Huang; Meletios Dimopoulos Journal: Blood Date: 2020-10-29 Impact factor: 22.113
Authors: Steven P Treon; Joshua Gustine; Kirsten Meid; Guang Yang; Lian Xu; Xia Liu; Maria Demos; Amanda Kofides; Nicholas Tsakmaklis; Jiaji G Chen; Manit Munshi; Gloria Chan; Toni Dubeau; Noopur Raje; Andrew Yee; Elizabeth O'Donnell; Zachary R Hunter; Jorge J Castillo Journal: J Clin Oncol Date: 2018-07-25 Impact factor: 44.544
Authors: Steven P Treon; Lian Xu; Maria Luisa Guerrera; Cristina Jimenez; Zachary R Hunter; Xia Liu; Maria Demos; Joshua Gustine; Gloria Chan; Manit Munshi; Nicholas Tsakmaklis; Jiaji G Chen; Amanda Kofides; Romanos Sklavenitis-Pistofidis; Mark Bustoros; Andrew Keezer; Kirsten Meid; Christopher J Patterson; Antonio Sacco; Aldo Roccaro; Andrew R Branagan; Guang Yang; Irene M Ghobrial; Jorge J Castillo Journal: J Clin Oncol Date: 2020-02-21 Impact factor: 44.544
Authors: Susan O'Brien; Richard R Furman; Steven Coutre; Ian W Flinn; Jan A Burger; Kristie Blum; Jeff Sharman; William Wierda; Jeffrey Jones; Weiqiang Zhao; Nyla A Heerema; Amy J Johnson; Ying Luan; Danelle F James; Alvina D Chu; John C Byrd Journal: Blood Date: 2018-02-02 Impact factor: 25.476
Authors: Jan A Burger; Paul M Barr; Tadeusz Robak; Carolyn Owen; Paolo Ghia; Alessandra Tedeschi; Osnat Bairey; Peter Hillmen; Steven E Coutre; Stephen Devereux; Sebastian Grosicki; Helen McCarthy; David Simpson; Fritz Offner; Carol Moreno; Sandra Dai; Indu Lal; James P Dean; Thomas J Kipps Journal: Leukemia Date: 2019-10-18 Impact factor: 11.528
Authors: Francesco Piazza; Veronica Di Paolo; Greta Scapinello; Sabrina Manni; Livio Trentin; Luigi Quintieri Journal: Front Oncol Date: 2022-01-11 Impact factor: 6.244