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Clinical Trial
. 2022 Jan 1;40(1):52-62.
doi: 10.1200/JCO.21.00838. Epub 2021 Oct 4.

Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

Christian Buske  1 , Alessandra Tedeschi  2 , Judith Trotman  3 , Ramón García-Sanz  4 , David MacDonald  5 , Veronique Leblond  6 , Beatrice Mahe  7 , Charles Herbaux  8 , Jeffrey V Matous  9 , Constantine S Tam  10 , Leonard T Heffner  11 , Marzia Varettoni  12 , M Lia Palomba  13 , Chaim Shustik  14 , Efstathios Kastritis  15 , Steven P Treon  16 , Jerry Ping  17 , Bernhard Hauns  17 , Israel Arango-Hisijara  17 , Meletios A Dimopoulos  15
Affiliations
Clinical Trial

Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

Christian Buske et al. J Clin Oncol. .

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.

Trial registration: ClinicalTrials.gov NCT02165397.

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Conflict of interest statement

Christian BuskeHonoraria: Roche/Genentech, Janssen, BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead Sciences, Celltrion, MorphoSys, RegeneronConsulting or Advisory Role: Gilead Sciences, Janssen, Roche, Pfizer, BeiGene, Celltrion, AbbVie, Incyte, Regeneron, MorphoSys, NovartisSpeakers' Bureau: Roche, Janssen, BeiGene, Celltrion, AbbVie, Pfizer, Gilead SciencesResearch Funding: Roche/Genentech, Janssen, Celltrion, MSD, Pfizer, Amgen, Alessandra TedeschiConsulting or Advisory Role: Janssen, BeiGene, AstraZeneca, AbbVieSpeakers' Bureau: AbbVie, AstraZeneca, Janssen, BeiGene Judith TrotmanResearch Funding: BeiGene, Roche/Genentech, Pharmacyclics, Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Roche/Genentech Ramón García-SanzHonoraria: Janssen, Takeda, Amgen, BeiGene, NovartisConsulting or Advisory Role: JanssenResearch Funding: Gilead Sciences, IncytePatents, Royalties, Other Intellectual Property: BIOMED-2 primersTravel, Accommodations, Expenses: Janssen, Takeda (I)Other Relationship: Spanish Society of Hematology (SEHH) David MacDonaldResearch Funding: Celgene, Servier Veronique LeblondHonoraria: AstraZeneca, Roche Pharma AG, BeiGene, Amgen, Janssen Oncology, AbbVie, MSD Oncology, LillyConsulting or Advisory Role: BeiGene, Janssen, AstraZeneca, Lilly, AbbVieSpeakers' Bureau: BeiGene, AstraZeneca, AbbVieTravel, Accommodations, Expenses: AbbVie Charles HerbauxHonoraria: Roche, Janssen-Cilag, AbbVieResearch Funding: TakedaTravel, Accommodations, Expenses: Janssen-Cilag, AbbVie, Roche Jeffrey V. MatousConsulting or Advisory Role: Pharmacyclics, BeiGene Constantine S. TamHonoraria: Janssen-Cilag, AbbVie, Novartis, BeiGene, PharmacyclicsConsulting or Advisory Role: Janssen, Loxo, Roche, AbbVieResearch Funding: Janssen-Cilag, AbbVie Leonard T. HeffnerSpeakers' Bureau: Kite, a Gilead companyResearch Funding: Pharmacyclics, Genentech, Kite, a Gilead Company, ADC Therapeutics, Astex Pharmaceuticals, Loxo, Cellectar Marzia VarettoniConsulting or Advisory Role: Janssen-Cilag, Roche, Janssen, AstraZenecaTravel, Accommodations, Expenses: Gilead Sciences, Janssen-Cilag, AbbVie, Janssen Lia PalombaStock and Other Ownership Interests: Seres Therapeutics (I)Honoraria: Flagship Biosciences (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), Merck (I), Seres Therapeutics (I)Consulting or Advisory Role: Flagship Biosciences (I), Novartis (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), Merck (I), Seres Therapeutics (I), Kite, a Gilead Company, BeiGeneResearch Funding: Seres Therapeutics (I)Patents, Royalties, Other Intellectual Property: Intellectual Property Rights (I), Juno Intellectual Property Rights Chaim ShustikExpert Testimony: Janssen Oncology Efstathios KastritisHonoraria: Amgen, Genesis Pharma, Janssen Oncology, Takeda, Prothena, PfizerConsulting or Advisory Role: Amgen, Janssen Oncology, Takeda, Genesis Pharma, Prothena, PfizerResearch Funding: Janssen Oncology, AmgenTravel, Accommodations, Expenses: Janssen Oncology, Genesis Pharma, Takeda, Pfizer Steven P. TreonConsulting or Advisory Role: Janssen, Pharmacyclics, BeiGene, X4 Pharmaceuticals, Bristol Myers SquibbResearch Funding: Pharmacyclics, Bristol Myers Squibb, X4 Pharmaceuticals, Lilly, BeiGene, AbbViePatents, Royalties, Other Intellectual Property: My institution holds patents related to the use of MYD88 and CXCR4 testing for which a predetermined financial distribution to the laboratory and individuals is provided. I have not received any income to this date related to these patents.Travel, Accommodations, Expenses: Janssen OncologyOther Relationship: Janssen, Pharmacyclics, BeiGene Jerry PingEmployment: AbbVieStock and Other Ownership Interests: AbbVieTravel, Accommodations, Expenses: AbbVie Bernhard HaunsEmployment: AbbVie/PharmacyclicsStock and Other Ownership Interests: AbbVieTravel, Accommodations, Expenses: AbbVie Israel Arango-HisijaraEmployment: Janssen Oncology, Abbvie/PharmacyclicsStock and Other Ownership Interests: Bristol Myers Squibb/Celgene, AbbvieHonoraria: Janssen Oncology, Abbvie/Pharmacyclics Meletios A. DimopoulosHonoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeiGeneConsulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, BeiGeneNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
PFS (A) in the intention-to-treat population, (B) by genotype, and (C) by prior treatment status. For PFS by genotype and prior treatment status, Kaplan-Meier curves are shown for time points with ≥ 10 patients. HR, hazard ratio; NR, not reported; PFS, progression-free survival.
FIG 2.
FIG 2.
Overall response rates and major response rates in (A) the intention-to-treat population over time (n = 75 for each treatment arm at each timepoint) and (B) by genotypea and prior treatment status. aResponse rates exclude six patients in the ibrutinib-rituximab arm and eight patients in the placebo-rituximab arm who had unknown genotype. NOTE. Values over 100% are due to rounding. CR, complete response; MR, minor response; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
FIG 3.
FIG 3.
TTNT. HR, hazard ratio; NR, not reported; TTNT, time to next treatment.
See this image and copyright information in PMC

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References

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