Single-agent ibrutinib for rituximab-refractory waldenström macroglobulinemia: Final analysis of the substudy of the phase III innovateTM trial

Judith Trotman; Christian Buske; Alessandra Tedeschi; Jeffrey V. Matous; David MacDonald; Constantine S. Tam; Olivier Tournilhac; Shuo Ma; Steven P. Treon; Albert Oriol; Jerry Ping; Eva M. Briso; Israel Arango-Hisijara; Meletios A. Dimopoulos

doi:10.1158/1078-0432.CCR-21-1497

Single-agent ibrutinib for rituximab-refractory waldenström macroglobulinemia: Final analysis of the substudy of the phase III innovate^TM trial

Judith Trotman, Christian Buske, Alessandra Tedeschi, Jeffrey V. Matous, David MacDonald, Constantine S. Tam, Olivier Tournilhac, Shuo Ma, Steven P. Treon, Albert Oriol, Jerry Ping, Eva M. Briso, Israel Arango-Hisijara, Meletios A. Dimopoulos

Research output: Contribution to journal › Article › peer-review

28 Citations (Scopus)

Abstract

Purpose: The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported. Patients and Methods: Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed. Results: After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88^L265P/CXCR4^WHIM and MYD88^L265P/CXCR4^WT subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of -37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation. Conclusions: In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia.

Original language	English
Pages (from-to)	5793-5800
Number of pages	8
Journal	Clinical Cancer Research
Volume	27
Issue number	21
DOIs	https://doi.org/10.1158/1078-0432.CCR-21-1497
Publication status	Published - Nov 15 2021
Externally published	Yes

Bibliographical note

Funding Information:
This study was funded by Pharmacyclics LLC, an AbbVie Company.

Funding Information:
J. Trotman reports grants from Roche, Beigene, Janssen, Pharmacyclics LLC, an AbbVie Company, Celgene, and Takeda outside the submitted work. C. Buske reports personal fees from Beigene, Pfizer, Novartis, Gilead, Regeneron, and X4; grants and personal fees from Roche, Janssen, Celltrion, and Bayer; grants from Amgen and MSD; and personal fees from Morphosys outside the submitted work. A. Tedeschi reports other support from Janssen, AstraZeneca, AbbVie, and Beigene outside the submitted work. J.V. Matous reports other support from Pharmacyclics outside the submitted work. D. MacDonald reports personal fees from Roche, AbbVie, Janssen, AstraZeneca, Gilead, and Servier outside the submitted work. C.S. Tam reports personal fees and other support from Janssen during the conduct of the study, as well as personal fees and other support from AbbVie outside the submitted work. O. Tournilhac reports personal fees from Janssen outside the submitted work. S. Ma reports grants and personal fees from AbbVie, AstraZeneca, Beigene, Janssen, and Pharmacyclics LLC, an AbbVie Company; grants from Loxo, Juno, and TG Therapeutics; and personal fees from Genentech during the conduct of the study. S. Ma also reports personal fees from Verastem outside the submitted work. S.P. Treon reports grants, personal fees, and other support from Pharmacyclics LLC, an AbbVie Company; personal fees from Janssen; grants and personal fees from Beigene and BMS; and grants from Eli Lilly during the conduct of the study. A. Oriol reports personal fees from BMS/Celgene, Sanofi, Amgen, GSK, and Oncopeptides outside the

Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research

ASJC Scopus Subject Areas

Oncology
Cancer Research

PubMed: MeSH publication types

Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/1078-0432.CCR-21-1497

Cite this

Trotman, J., Buske, C., Tedeschi, A., Matous, J. V., MacDonald, D., Tam, C. S., Tournilhac, O., Ma, S., Treon, S. P., Oriol, A., Ping, J., Briso, E. M., Arango-Hisijara, I., & Dimopoulos, M. A. (2021). Single-agent ibrutinib for rituximab-refractory waldenström macroglobulinemia: Final analysis of the substudy of the phase III innovate^TM trial. Clinical Cancer Research, 27(21), 5793-5800. https://doi.org/10.1158/1078-0432.CCR-21-1497

Trotman, J, Buske, C, Tedeschi, A, Matous, JV, MacDonald, D, Tam, CS, Tournilhac, O, Ma, S, Treon, SP, Oriol, A, Ping, J, Briso, EM, Arango-Hisijara, I & Dimopoulos, MA 2021, 'Single-agent ibrutinib for rituximab-refractory waldenström macroglobulinemia: Final analysis of the substudy of the phase III innovate^TM trial', Clinical Cancer Research, vol. 27, no. 21, pp. 5793-5800. https://doi.org/10.1158/1078-0432.CCR-21-1497

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title = "Single-agent ibrutinib for rituximab-refractory waldenstr{\"o}m macroglobulinemia: Final analysis of the substudy of the phase III innovateTM trial",

abstract = "Purpose: The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenstr{\"o}m macroglobulinemia. Results from the final analysis are now reported. Patients and Methods: Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed. Results: After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88L265P/CXCR4WHIM and MYD88L265P/CXCR4WT subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of -37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation. Conclusions: In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenstr{\"o}m macroglobulinemia.",

author = "Judith Trotman and Christian Buske and Alessandra Tedeschi and Matous, {Jeffrey V.} and David MacDonald and Tam, {Constantine S.} and Olivier Tournilhac and Shuo Ma and Treon, {Steven P.} and Albert Oriol and Jerry Ping and Briso, {Eva M.} and Israel Arango-Hisijara and Dimopoulos, {Meletios A.}",

note = "Funding Information: This study was funded by Pharmacyclics LLC, an AbbVie Company. Funding Information: J. Trotman reports grants from Roche, Beigene, Janssen, Pharmacyclics LLC, an AbbVie Company, Celgene, and Takeda outside the submitted work. C. Buske reports personal fees from Beigene, Pfizer, Novartis, Gilead, Regeneron, and X4; grants and personal fees from Roche, Janssen, Celltrion, and Bayer; grants from Amgen and MSD; and personal fees from Morphosys outside the submitted work. A. Tedeschi reports other support from Janssen, AstraZeneca, AbbVie, and Beigene outside the submitted work. J.V. Matous reports other support from Pharmacyclics outside the submitted work. D. MacDonald reports personal fees from Roche, AbbVie, Janssen, AstraZeneca, Gilead, and Servier outside the submitted work. C.S. Tam reports personal fees and other support from Janssen during the conduct of the study, as well as personal fees and other support from AbbVie outside the submitted work. O. Tournilhac reports personal fees from Janssen outside the submitted work. S. Ma reports grants and personal fees from AbbVie, AstraZeneca, Beigene, Janssen, and Pharmacyclics LLC, an AbbVie Company; grants from Loxo, Juno, and TG Therapeutics; and personal fees from Genentech during the conduct of the study. S. Ma also reports personal fees from Verastem outside the submitted work. S.P. Treon reports grants, personal fees, and other support from Pharmacyclics LLC, an AbbVie Company; personal fees from Janssen; grants and personal fees from Beigene and BMS; and grants from Eli Lilly during the conduct of the study. A. Oriol reports personal fees from BMS/Celgene, Sanofi, Amgen, GSK, and Oncopeptides outside the Publisher Copyright: {\textcopyright} 2021 The Authors; Published by the American Association for Cancer Research",

year = "2021",

month = nov,

day = "15",

doi = "10.1158/1078-0432.CCR-21-1497",

language = "English",

volume = "27",

pages = "5793--5800",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "21",

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TY - JOUR

T1 - Single-agent ibrutinib for rituximab-refractory waldenström macroglobulinemia

T2 - Final analysis of the substudy of the phase III innovateTM trial

AU - Trotman, Judith

AU - Buske, Christian

AU - Tedeschi, Alessandra

AU - Matous, Jeffrey V.

AU - MacDonald, David

AU - Tam, Constantine S.

AU - Tournilhac, Olivier

AU - Ma, Shuo

AU - Treon, Steven P.

AU - Oriol, Albert

AU - Ping, Jerry

AU - Briso, Eva M.

AU - Arango-Hisijara, Israel

AU - Dimopoulos, Meletios A.

N1 - Funding Information: This study was funded by Pharmacyclics LLC, an AbbVie Company. Funding Information: J. Trotman reports grants from Roche, Beigene, Janssen, Pharmacyclics LLC, an AbbVie Company, Celgene, and Takeda outside the submitted work. C. Buske reports personal fees from Beigene, Pfizer, Novartis, Gilead, Regeneron, and X4; grants and personal fees from Roche, Janssen, Celltrion, and Bayer; grants from Amgen and MSD; and personal fees from Morphosys outside the submitted work. A. Tedeschi reports other support from Janssen, AstraZeneca, AbbVie, and Beigene outside the submitted work. J.V. Matous reports other support from Pharmacyclics outside the submitted work. D. MacDonald reports personal fees from Roche, AbbVie, Janssen, AstraZeneca, Gilead, and Servier outside the submitted work. C.S. Tam reports personal fees and other support from Janssen during the conduct of the study, as well as personal fees and other support from AbbVie outside the submitted work. O. Tournilhac reports personal fees from Janssen outside the submitted work. S. Ma reports grants and personal fees from AbbVie, AstraZeneca, Beigene, Janssen, and Pharmacyclics LLC, an AbbVie Company; grants from Loxo, Juno, and TG Therapeutics; and personal fees from Genentech during the conduct of the study. S. Ma also reports personal fees from Verastem outside the submitted work. S.P. Treon reports grants, personal fees, and other support from Pharmacyclics LLC, an AbbVie Company; personal fees from Janssen; grants and personal fees from Beigene and BMS; and grants from Eli Lilly during the conduct of the study. A. Oriol reports personal fees from BMS/Celgene, Sanofi, Amgen, GSK, and Oncopeptides outside the Publisher Copyright: © 2021 The Authors; Published by the American Association for Cancer Research

PY - 2021/11/15

Y1 - 2021/11/15

N2 - Purpose: The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported. Patients and Methods: Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed. Results: After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88L265P/CXCR4WHIM and MYD88L265P/CXCR4WT subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of -37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation. Conclusions: In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia.

AB - Purpose: The first report from the open-label substudy of the phase III iNNOVATE study (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was efficacious and well tolerated in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia. Results from the final analysis are now reported. Patients and Methods: Ibrutinib 420 mg was administered once daily to patients (N = 31) who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy. Endpoints included progression-free survival (PFS) and overall response rate (ORR; MR or better) per independent review committee, hemoglobin improvement, overall survival (OS), and safety; serum IgM was also assessed. Results: After a median follow-up of 58 months (range: 9-61), median PFS was 39 months [95% confidence interval (CI): 25-not evaluable]; 60-month PFS rate was 40%. In MYD88L265P/CXCR4WHIM and MYD88L265P/CXCR4WT subtypes, median PFS was 18 months and not reached, respectively. In all patients, ORR was 87%; responses deepened over time with major response (≥ partial response) rates increasing from 61% at 6 months to 77% at 60 months. Median OS was not reached. Seventeen of 21 patients (81%) with baseline hemoglobin ≤11.0 g/dL had sustained hemoglobin improvement. Improvements in serum IgM levels were sustained, reaching a maximum median change of -37 g/L at 54 months. Ibrutinib maintained a manageable safety profile, with no new safety signals identified. There were no events of major hemorrhage or atrial fibrillation. Conclusions: In the final analysis from iNNOVATE, single-agent ibrutinib continued to show sustained efficacy in patients with heavily pretreated, rituximab-refractory Waldenström macroglobulinemia.

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