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Clinical Trial
. 2021 Apr 20;39(12):1317-1328.
doi: 10.1200/JCO.20.01366. Epub 2021 Feb 23.

ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma

Grzegorz S Nowakowski  1 , Annalisa Chiappella  2 , Randy D Gascoyne  3 , David W Scott  3 , Qingyuan Zhang  4 , Wojciech Jurczak  5 , Muhit Özcan  6 , Xiaonan Hong  7 , Jun Zhu  8 , Jie Jin  9 , David Belada  10 , Juan Miguel Bergua  11 , Francesco Piazza  12 , Heidi Mócikova  13 , Anna Lia Molinari  14 , Dok Hyun Yoon  15 , Federica Cavallo  16 , Monica Tani  17 , Kazuhito Yamamoto  18 , Koji Izutsu  19 , Koji Kato  20 , Myron Czuczman  21 , Sarah Hersey  22 , Adrian Kilcoyne  21 , Jacqueline Russo  21 , Krista Hudak  21 , Jingshan Zhang  21 , Steve Wade  23 , Thomas E Witzig  1 , Umberto Vitolo  2
Affiliations
Clinical Trial

ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma

Grzegorz S Nowakowski et al. J Clin Oncol. .

Abstract

Purpose: Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL.

Methods: Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review.

Results: A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% v 48%), anemia (22% v 14%), thrombocytopenia (17% v 11%), and leukopenia (14% v 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and P = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease.

Conclusion: ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.

Trial registration: ClinicalTrials.gov NCT02285062.

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Conflict of interest statement

Grzegorz S. NowakowskiConsulting or Advisory Role: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/GileadResearch Funding: Celgene, NanoString Technologies, MorphoSys Annalisa ChiappellaHonoraria: Celgene, Gilead-Kite, Janssen Oncology, Roche, ServierConsulting or Advisory Role: Celgene, Gilead-Kite, Janssen-Cilag, Takeda, iQone David W. ScottConsulting or Advisory Role: Celgene, Janssen, Abbvie, AstraZenecaResearch Funding: Janssen, Roche/Genentech, NanoString TechnologiesPatents, Royalties, Other Intellectual Property: Named inventor on a pending patent describing gene expression profiling in prognostication in classical Hodgkin lymphoma. As a member of the LLMPP I am potentially a named inventor on a pending patent on the use of gene expression profiling to assign cell-of-origin in diffuse large B-cell lymphoma. I am a named inventor on a pending patent on the use of gene expression profiling to determine the proliferation signature in mantle cell lymphoma. Named inventor on a pending patent describing using gene expression profiling to identify molecular subtypes of GCB-DLBCL. Wojciech JurczakResearch Funding: Janssen-Cilag, Acerta Pharma/AstraZeneca, Merck, Loxo, TG Therapeutics, BeiGene Muhit ÖzcanHonoraria: TakedaResearch Funding: Janssen, Celgene, Takeda, Bayer, Merck, Archigen Biotech, Roche, Pharmacyclics, AbbvieTravel, Accommodations, Expenses: Takeda, Sanofi, Roche, Bristol-Myers Squibb, Abdi Ibrahim, Amgen, Janssen David BeladaConsulting or Advisory Role: Roche, Gilead Sciences, Janssen-Cilag, Takeda, MorphoSys, Debiopharm GroupResearch Funding: Roche, Gilead Sciences, Janssen-Cilag, Takeda, MorphoSys, Pharmacyclics, Archigen BiotechTravel, Accommodations, Expenses: Gilead Sciences, Takeda, Roche Juan Miguel BerguaConsulting or Advisory Role: Daiichi SankyoTravel, Accommodations, Expenses: Roche/Genentech Dok Hyun YoonHonoraria: Celltrion, Roche, Janssen, Amgen, Celgene, Samyang, Kirin PharmaceuticalsConsulting or Advisory Role: Roche, Janssen, Amgen¸Celgene, Green CrossResearch Funding: Samyang, Abclone, Roche/Genentech, Janssen Oncology, Amgen, Genmab, Boryung Federica CavalloHonoraria: Takeda, Janssen-Cilag, Gilead SciencesConsulting or Advisory Role: Janssen-Cilag, Gilead SciencesTravel, Accommodations, Expenses: Celgene Kazuhito YamamotoHonoraria: Kyowa Hakko Kirin, Takeda, Janssen, Bristol-Myers Squibb, Celgene, Sumitomo Dainippon, Ono Pharmacuetical, Chugai Pharma, Novartis, Otsuka, Mundipharma, Eisai, MSD, Meiji Seika Kaisha, Sanofi, Nippon Shinyaku, Abbvie, GlaxoSmithKlineConsulting or Advisory Role: Ono Pharmaceutical, Meiji Seika Kaisha, Chugai Pharma, Bristol-Myers Squibb, Kyowa Hakko Kirin, Takeda, Celgene, HUYA Bioscience International, Stemline Therapeutics, Eisai, Janssen, AstraZeneca, Daiichi Sankyo, AbbvieResearch Funding: Chugai Pharma, Novartis, ARIAD, Takeda, Gilead Sciences, Abbvie, Ono Pharmaceutical, Celgene, Solasia Pharma, MSD, Eisai, Zenyaku Kogyo, Bayer, SymBio Pharmaceuticals, AstraZeneca, Incyte, Mundipharma, Yakult Pharmaceutical Koji IzutsuHonoraria: Takeda, Chugai Pharma, Eisai, Janssen, Abbvie, Novartis, MSD, Dainippon Sumitomo Pharma, Ono Pharmaceutical, Mundipharma, HUYA Bioscience International, AstraZeneca, Bayer, Bristol-Myers Squibb, Kyowa Hakko Kirin, Fujifilm, CelgeneConsulting or Advisory Role: Bayer, Celgene, AstraZenecaResearch Funding: Eisai, Chugai Pharma Koji KatoHonoraria: Takeda, MSD, Kyowa-Kirin, Janssen, Celgene, Ono, Mundi, Dainippon-Sumitomo, Bristol-Myers SquibbConsulting or Advisory Role: AbbVie, AstraZeneca, Celgene, Chugai, Eisai, Janssen, Novartis, Daiichi SankyoResearch Funding: Chugai, Takeda, Kyowa Kirin, AbbVie, Novartis, Eisai, Janssen, Celgene, Ono, Novartis, Daiichi Sankyo Myron CzuczmanEmployment: CelgeneStock and Other Ownership Interests: Celgene Sarah HerseyStock and Other Ownership Interests: Novartis, Johnson & Johnson, Bristol-Myers SquibbOther Relationship: Bristol-Myers Squibb Adrian KilcoyneEmployment: CelgeneStock and Other Ownership Interests: Celgene Jacqueline RussoEmployment: Celgene/Bristol-Myers Squibb, Kite PharmaStock and Other Ownership Interests: Celgene/Bristol-Myers Squibb, Kite Pharma Krista HudakEmployment: Bristol-Myers Squibb, NovartisStock and Other Ownership Interests: Bristol-Myers Squibb, Novartis Jingshan ZhangEmployment: Celgene, Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers SquibbTravel, Accommodations, Expenses: Celgene Steve WadeEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Thomas E. WitzigConsulting or Advisory Role: Karyopharm Therapeutics, Abbvie/Genentech, Seattle Genetics, Celgene, Incyte, Epizyme, Cellectar, Tessa Therapeutics, Portola Pharmaceuticals, MorphoSys, ADC TherapeuticsResearch Funding: Celgene, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm TherapeuticsPatents, Royalties, Other Intellectual Property: I am co-inventor on a patent application filed by Mayo Clinic and pending on the combination of CRM1 inhibitors with salicylates. Please note—simply filed—not even close to being granted. Umberto VitoloConsulting or Advisory Role: Gilead Sciences, Janssen, Celgene, RegeneronSpeakers' Bureau: Gilead Sciences, Celgene, Abbvie, Roche, Janssen OncologyTravel, Accommodations, Expenses: Celgene, Gilead Sciences, RocheNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
R2-CHOP and placebo/R-CHOP CONSORT diagram (flow of patients from screening to analysis). aMain reasons for failing eligibility criteria: 8% inadequate lymph node or biopsy specimen available, 5% not Ann Arbor stage II-IV, 4% not International Prognostic Index ≥ 2, and 3% unable to adhere to protocol requirements. bTwo R2-CHOP and one placebo/R-CHOP patients were randomly assigned, but never received lenalidomide/placebo or R-CHOP. ABC, activated B-cell-like; ITT, intention to treat; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-CHOP, lenalidomide plus R-CHOP.
FIG 2.
FIG 2.
PFS, EFS, and OS in the intent-to-treat population: (A) progression-free survival by Independent Radiology Adjudication Committee (IRAC) assessment; (B) event-free survival by IRAC assessment; (C) OS. EFS, event-free survival; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-CHOP, lenalidomide plus R-CHOP.
FIG 3.
FIG 3.
PFS based on IPI status (A) IPI = 2 and (B) IPI ≥ 3 (intent-to-treat population). HR, hazard ratio; IPI, International Prognostic Index; PFS, progression-free survival; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-CHOP, lenalidomide plus R-CHOP.
FIG 4.
FIG 4.
Subgroup analyses of progression-free survival by Independent Radiology Adjudication Committee in the intent-to-treat population treated with R2-CHOP versus placebo/R-CHOP. aPrespecified stratification factor. CrCl, creatinine clearance; DLBCL, diffuse large B-cell lymphoma; HR, hazard ratio; IPI, International Prognostic Index; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-CHOP, lenalidomide plus R-CHOP.
FIG A1.
FIG A1.
ROBUST study design (ClinicalTrials.gov identifier: NCT02285062; EudraCT 2013-004054-21). Following confirmation of CD20 positivity and identification of ABC-type by gene expression profiling, patients were stratified by IPI score, bulky disease, and age, and randomly assigned 1:1 to R2-CHOP or placebo/R-CHOP. Patients with non–ABC-type DLBCL were ineligible for the study. Treatment included the following: lenalidomide (or placebo) 15 mg oral (PO) on days 1-14 of every 21-day dosing cycle plus R-CHOP21 (rituximab 375 mg/m2 intravenous [IV] day −1 or 1, cyclophosphamide 750 mg/m2 IV day 1, doxorubicin 50 mg/m2 IV day 1, vincristine 1.4 mg/m2 [maximum 2.0 mg total] IV day 1, and prednisone [or prednisolone] 100 mg PO days 1-5 [IV day 1 was acceptable]). Treatment was continued until six cycles were complete, or until intolerability, inadequate response, disease progression, or withdrawal of consent, whichever occurred first. Two additional doses of single-agent rituximab (one dose per 21-day cycle) were permitted if prespecified and considered standard of care per local practice. ABC, activated B-cell-like; DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; IV, intravenous; PO, oral; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-CHOP, lenalidomide plus R-CHOP.
FIG A2.
FIG A2.
Overall survival based on treatment group and age < 60 years (A) and ≥ 60 years (B) (ITT population). R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R2-CHOP, lenalidomide plus R-CHOP.
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