Efficacy, safety, and molecular response predictors of oral ixazomib and short-course rituximab in untreated iNHL

Abstract

Patients with indolent B-cell non-Hodgkin lymphoma (iNHL) generally require treatment but experience normal survival, emphasizing the need for simpler, safer therapies. Proteasome inhibitors target aberrant signaling pathways within iNHL and have manageable toxicities. We evaluated the oral proteasome inhibitor ixazomib as initial monotherapy, and combined with rituximab, for first-line treatment of iNHL. Treatment-naïve patients with iNHL needing therapy received oral ixazomib 4 mg weekly until progressive disease or unacceptable adverse events. A 4-week course of rituximab was added during month 7. The primary end point was overall response rate (ORR) during the ixazomib monotherapy window. Correlations included gene expression profiling and response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Thirty-three patients with follicular lymphoma (FL) (n = 20), marginal zone lymphoma (n = 7), and other iNHL were treated with a median follow-up of 30.3 months. During the 6-month ixazomib window, the ORR was 24%, including 35% in FL. The best ORR over the entire study period was 52% overall and 65% in FL; complete response was achieved in 33% and 45%, respectively. The median duration of response was 25.8 months (range, 0-49.7), and the 24-month progression-free and overall survival rates were 51% (95% confidence interval [CI], 32-67) and 91% (95% CI, 74-97), respectively. Ixazomib was well tolerated. Baseline downregulation of proteasome genes, PSMB9 (P = .03) and PSMB8 (P = .007), were associated with response. All evaluated patients generated anti-S antibodies to SARS-CoV-2 vaccination, with a median of 254.9 binding arbitrary unit per mL. Ixazomib demonstrated efficacy alone and with short-course rituximab in untreated iNHL while exhibiting favorable toxicity, convenience, and retention of the B-cell immune response. This trial is registered at www.clinicaltrials.gov as NCT02339922.

Conflict of interest statement

Conflict-of-interest disclosure: S.A.G. received research funding from TG Therapeutics, AstraZeneca, BeiGene, GSK, and MorphoSys. R.C.L. serves as a consultant for MorphoSys; received research funding from TG Therapeutics, SeaGen, RAPT, Juno Therapeutics, Incyte, Bayer, Cyteir, and Genentech. C.S.U. serves as a consultant for Atara, AstraZeneca, AbbVie, ACDT, Epizyme, TG Therapeutics, Pharmacyclics, and BeiGene. A.J.C. received research funding from Bristol Myers Squibb, Harpoon, and Nektar; serves as a consultant for Secura Bio, GSK, and Cellectar; and serves as a consultant and received research funding from Sanofi Aventis, AbbVie, and Janssen. S.D.S. serves as a consultant for Millenium/Takeda, Karyopharm, KITE pharm, Incyte, and ADC Therapeutics; received research funding from Portola Pharmaceuticals, Incyte Corporation, Merck Sharp & Dohme Corp, Genetech, Acerta Pharma BV, De Novo Biopharma, and Bayer; received research funding from Ignyta (spouse), Bristol Myers Squibb (spouse), Ayala (spouse); and serves as a consultant and received research funding from BeiGene and AstraZeneca. M.S. serves as a consultant for AbbVie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, BeiGene, Bristol Myers Squibb, MorphoSys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, and Atara Biotherapeutics: Consultancy; and received research funding from Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, BeiGene, AstraZeneca, Sunesis, Atara Biotherapeutics, and GenMab. E.N.L. serves as a consultant and received research funding from Janssen; and received research funding from BMS, Genentech, and GSK. A.K.G. received research funding from Agios, Takeda, IGM Biosciences, AstraZeneca, Bristol Myers Squibb, and Teva; serves as a consultant for and received Honoraria from BeiGene, Servier, ADC Therapeutics, Kite, Acrotech, Karyopharm, Epizyme, Nurix Inc, and Cellectar; received Honoraria from MorphoSys and Incyte; serves as a consultant for, received research funding and Honoraria from Merck, SeaGen, Genetech, Gilead, I-Mab Biopharma, and Janssen.

© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Objective response rates. Best objective response in evaluable patients (N = 31) during initial ixazomib window and after addition of rituximab, overall (A) and for patients only with FL (B). Note, 2 patients administered ixazomib stopped therapy on study before first scheduled restaging evaluation.

Figure 2.

Outcomes of patients evaluable for response (N = 31). Best response as measured by % change in SPD of index lesions. Color corresponds to histology of iNHL. Change in SPD after course of rituximab indicated by red bars. SPD, sum of product of diameters.

Figure 3.

Survival outcomes. Kaplan-Meier plots of PFS and OS in all patients (N = 33) treated (A) and for patients only with FL (N = 20) (B).

Figure 4.

Hierarchical cluster analysis of GEP among patients with FL with vs without objective response to ixazomib monotherapy. Heat map shows normalized RNA expression levels.