IBRUTINIB PLUS RITUXIMAB (IR) VS PLACEBO PLUS RITUXIMAB (R) FOR WALDENSTROM’S MACROGLOBULINEMIA (WM): FINAL ANALYSIS AFTER FIVE YEARS OF FOLLOW-UP FROM THE RANDOMIZED PHASE 3 INNOVATE STUDY
Author(s): ,
Ramón García-Sanz
Affiliations:
Department of Hematology,University Hospital of Salamanca (HUS/IBSAL), CIBERONC and Cancer Research Institute of Salamanca-IBMCC (USAL-CSIC),Salamanca,Spain
,
Christian Buske
Affiliations:
Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital of Ulm,Ulm,Germany
,
Alessandra Tedeschi
Affiliations:
ASST Grande Ospedale Metropolitano Niguarda,Milan,Italy
,
Judith Trotman
Affiliations:
Concord Hospital, University of Sydney,Sydney, NSW,Australia
,
David MacDonald
Affiliations:
The Ottawa Hospital, University of Ottawa,Ottawa, ON,Canada
,
Veronique Leblond
Affiliations:
Département d’ Hématologie Hôpital Pitié-Salpêtrière APHP,UPMC Université Paris,Paris,France
,
Beatrice Mahe
Affiliations:
Centre Hospitalier Universitaire de Nantes,Nantes,France
,
Charles Herbaux
Affiliations:
Centre Hospitalier Régional Universitaire de Lille, Institute of Hematology-Tranfusion,Lille,France
,
Jeffrey V. Matous
Affiliations:
Colorado Blood Cancer Institute,Denver, CO,United States
,
Constantine S. Tam
Affiliations:
Peter MacCallum Cancer Centre & St. Vincent’s Hospital and the University of Melbourne,Melbourne, VIC,Australia
,
Leonard T. Heffner
Affiliations:
Winship Cancer Institute of Emory University,Atlanta, GA,United States
,
Marzia Varettoni
Affiliations:
Fondazione IRCCS Policlinico San Matteo,Pavia,Italy
,
M. Lia Palomba
Affiliations:
Memorial Sloan Kettering Cancer Center,New York, NY,United States
,
Chaim Shustik
Affiliations:
Royal Victoria Hospital at McGill University Health Centre,Montreal, QC,Canada
,
Efstathios Kastritis
Affiliations:
National and Kapodistrian University of Athens School of Medicine,Athens,Greece
,
Steven P. Treon
Affiliations:
Dana-Farber Cancer Institute,Boston, MA,United States
,
Jerry Ping
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
Bernhard Hauns
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
,
Israel Arango-Hisijara
Affiliations:
Pharmacyclics LLC, an AbbVie Company,Sunnyvale, CA,United States
Meletios A. Dimopoulos
Affiliations:
National and Kapodistrian University of Athens School of Medicine,Athens,Greece
EHA Library. García-Sanz R. 06/09/21; 325540; EP782
Prof. Dr. Ramón García-Sanz
Prof. Dr. Ramón García-Sanz
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP782

Type: E-Poster Presentation

Session title: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Background
Ibrutinib is a once-daily Bruton’s tyrosine kinase inhibitor approved as either a single agent or in combination with rituximab (R) for treatment of patients (pts) with WM across all lines of therapy. In the primary analysis of the phase 3 iNNOVATETM study (NCT02165397; median follow-up 26.5 mo), IR demonstrated superior progression-free survival (PFS) vs placebo plus R in pts with WM.

Aims
We present results from the final analysis of the randomized arms of iNNOVATE.

Methods
Pts with confirmed symptomatic WM were randomized (75 pts per arm) to once-daily ibrutinib 420 mg or placebo plus R (375 mg/m2/wk IV at weeks 1–4 and 17–20). Pts could receive first-line treatment or be previously treated; pts with prior R therapy had to have achieved at least a minor response (MR) to their last R-based regimen. Endpoints included PFS and response rates per Independent Review Committee, overall survival (OS), hemoglobin (Hgb) improvement, time to next treatment (TTNT), and safety. Change in serum IgM was also assessed.

Results
Pt characteristics were well balanced between arms. After a median follow-up of 50 mo (range 0.5+ to 63), median PFS had not been reached (NR; 95% CI 57.7 mo to not estimable) with IR vs 20.3 mo (95% CI 13.0−27.6) with R (hazard ratio [HR] 0.25 [0.15−0.42]; P<0.0001) (Figure); 54-mo PFS rates were 68% vs 25%. PFS benefit with IR vs R was independent of prior treatment status (HR [95% CI]: first-line, 0.32 [0.14−0.70]; previously treated, 0.22 [0.11−0.43]) or genotype (HR [95% CI]: MYD88L265P/CXCR4WT, 0.18 [0.08−0.43]; MYD88L265P/CXCR4WHIM, 0.27 [0.12−0.62]; MYD88WT/CXCR4WT, 0.29 [0.07−1.19]). Improved PFS with IR was observed across prespecified subgroups, including age, serum IgM, Hgb, IPSSWM, and MYD88 mutation status. Major response rates (≥partial response) with IR increased and were sustained over time, reaching 76% vs 31% with R (P<0.0001); overall response rates (≥MR) were 92% vs 44% (P<0.0001). A greater proportion of pts achieved sustained Hgb improvement with IR vs R (77% vs 43%; P<0.0001). IgM decreased rapidly during the first year; maximum change was −33.5 g/L with IR (56 mo) vs −26.9 g/L with R (57 mo). Median OS was NR in either arm; 54-mo OS rates were 86% with IR vs 84% with R. Median TTNT was NR with IR and 18 mo with R; 87% of pts receiving IR and 29% receiving R had not received subsequent treatment at 54 mo. Thirty-five pts (47%) on R crossed over to single-agent ibrutinib after disease progression. The safety profile of IR was consistent with previous reports. The prevalence of grade ≥3 AEs of clinical interest with IR generally decreased over time. Of 12 pts with grade 3−4 atrial fibrillation, 9 (75%) remained on treatment; no other ibrutinib discontinuations due to common (≥10%) grade 3−4 AEs occurred. 88% of AEs that led to an ibrutinib dose reduction resolved following dose reduction. After study closure, 68 pts (45%) remained on treatment (32 in an extension study; 36 in a commercial setting).

Conclusion
With up to 5 years of follow-up, IR showed ongoing superiority across clinical outcomes in pts with WM regardless of genotype, prior treatment, and key pt characteristics. Similar patterns of response with IR were observed in pts receiving first-line treatment and in previously treated pts. No new safety signals were observed; IR maintained a manageable safety profile after an additional 24 months of follow-up.

Keyword(s): Ibrutinib, Phase III, Rituximab, Waldenstrom's macroglobulinemia

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP782

Type: E-Poster Presentation

Session title: Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Background
Ibrutinib is a once-daily Bruton’s tyrosine kinase inhibitor approved as either a single agent or in combination with rituximab (R) for treatment of patients (pts) with WM across all lines of therapy. In the primary analysis of the phase 3 iNNOVATETM study (NCT02165397; median follow-up 26.5 mo), IR demonstrated superior progression-free survival (PFS) vs placebo plus R in pts with WM.

Aims
We present results from the final analysis of the randomized arms of iNNOVATE.

Methods
Pts with confirmed symptomatic WM were randomized (75 pts per arm) to once-daily ibrutinib 420 mg or placebo plus R (375 mg/m2/wk IV at weeks 1–4 and 17–20). Pts could receive first-line treatment or be previously treated; pts with prior R therapy had to have achieved at least a minor response (MR) to their last R-based regimen. Endpoints included PFS and response rates per Independent Review Committee, overall survival (OS), hemoglobin (Hgb) improvement, time to next treatment (TTNT), and safety. Change in serum IgM was also assessed.

Results
Pt characteristics were well balanced between arms. After a median follow-up of 50 mo (range 0.5+ to 63), median PFS had not been reached (NR; 95% CI 57.7 mo to not estimable) with IR vs 20.3 mo (95% CI 13.0−27.6) with R (hazard ratio [HR] 0.25 [0.15−0.42]; P<0.0001) (Figure); 54-mo PFS rates were 68% vs 25%. PFS benefit with IR vs R was independent of prior treatment status (HR [95% CI]: first-line, 0.32 [0.14−0.70]; previously treated, 0.22 [0.11−0.43]) or genotype (HR [95% CI]: MYD88L265P/CXCR4WT, 0.18 [0.08−0.43]; MYD88L265P/CXCR4WHIM, 0.27 [0.12−0.62]; MYD88WT/CXCR4WT, 0.29 [0.07−1.19]). Improved PFS with IR was observed across prespecified subgroups, including age, serum IgM, Hgb, IPSSWM, and MYD88 mutation status. Major response rates (≥partial response) with IR increased and were sustained over time, reaching 76% vs 31% with R (P<0.0001); overall response rates (≥MR) were 92% vs 44% (P<0.0001). A greater proportion of pts achieved sustained Hgb improvement with IR vs R (77% vs 43%; P<0.0001). IgM decreased rapidly during the first year; maximum change was −33.5 g/L with IR (56 mo) vs −26.9 g/L with R (57 mo). Median OS was NR in either arm; 54-mo OS rates were 86% with IR vs 84% with R. Median TTNT was NR with IR and 18 mo with R; 87% of pts receiving IR and 29% receiving R had not received subsequent treatment at 54 mo. Thirty-five pts (47%) on R crossed over to single-agent ibrutinib after disease progression. The safety profile of IR was consistent with previous reports. The prevalence of grade ≥3 AEs of clinical interest with IR generally decreased over time. Of 12 pts with grade 3−4 atrial fibrillation, 9 (75%) remained on treatment; no other ibrutinib discontinuations due to common (≥10%) grade 3−4 AEs occurred. 88% of AEs that led to an ibrutinib dose reduction resolved following dose reduction. After study closure, 68 pts (45%) remained on treatment (32 in an extension study; 36 in a commercial setting).

Conclusion
With up to 5 years of follow-up, IR showed ongoing superiority across clinical outcomes in pts with WM regardless of genotype, prior treatment, and key pt characteristics. Similar patterns of response with IR were observed in pts receiving first-line treatment and in previously treated pts. No new safety signals were observed; IR maintained a manageable safety profile after an additional 24 months of follow-up.

Keyword(s): Ibrutinib, Phase III, Rituximab, Waldenstrom's macroglobulinemia

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