Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13).

Background

The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL.

Methods

In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3 + 3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min-max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458.

Findings

Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67 > 30%, blastoid or pleomorphic variant, p53 overexpression,

Interpretation

The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features.

Funding

SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen.

Informations de copyright

© 2023 The Authors.

Déclaration de conflit d'intérêts

U.N. reports consulting fees and advisory board participation to/through the institution from and with Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, Beigene, Kyowa Kirin, Gilead, Pierre Fabre and Miltenyi, payment of honoraria to the institution form Celgene (BMS), Novartis, Takeda, and Gilead, and meeting and/or travel support to the institution from Janssen, Roche, Gilead and Takeda. M.D. reports grants or contracts for research from Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, and Roche to the institution, payment of honoraria from AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis and Roche, meeting and/or travel support from Janssen and Roche, and Data Safety Monitoring Board or Advisory Boards with Abbvie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, and Roche. C.S. reports consulting fees from BMS and Janssen, payments of honoraria from BMS and AstraZeneca, and meeting and/or travel support from Kite Gilead. E.D. reports and research funding from ADC Therapeutics and Takeda, consulting fees from Roche, Beigene, Abbvie, AstraZeneca, and Takeda, payments or honoraria from Abbvie, Roche, Incyte and Beigene, support for meetings and/or travel from Abbvie and Beigene, a Data Safety Monitoring Board or Advisory Board role with Abbvie, Beigene, Takeda, and Roche, and the receipt of equipment, materials, drugs, medical writing, gifts or other services from ADC Therapeutics. T.Z. reports consulting fees from Beigene Switzerland GmbH. G.H. reports grants or contracts for research from Gilead/Kite, Incyte, Janssen, Morphosys, Pfizer, Roche, and Abbvie, consulting fees from Abbvie, ADC Therapeutics, AstraZeneca, BMS, Genmab, Gilead/Kite, Incyte, Janssen, Miltenyi, Novartis, Roche, and Lilly, payments or honoraria from Abbvie, AstraZeneca, Beigene, BMS, Genmab, Gilead, Incyte, Janssen, Lilly, and Roche, meeting and/or travel support from Janssen and Gilead/Kite, and Data Safety Monitoring Board or Advisory Boards with Miltenyi. U.M. reports meeting and/or travel support from Janssen-Cilag, an advisory board role with Janssen-Cilag, and participation in the committee of the German-Swiss-Austrian guidelines for mantle cell lymphoma. S.F. reports grants or contracts for research, consulting fees, honoraria, meeting and/or travel support, and advisory board activities from and with Janssen. S.B. reports grants or contracts for research from Janssen-Cilag Neuss and Miltenyi Bergisch Gladbach to the institution, honoraria from Roche, Abbvie, Janssen, AstraZeneca, and Sanofi, and a travel support from Janssen. E.Z. reports grants or contracts for research from AstraZeneca, Beigene, Celgene, Incyte, Janssen, and Roche, for research to the institution from Incyte, AstraZeneca, Beigene, Celgene/BMS, Merck/MSD, and Roche, honoraria for an educational event from Abbvie, an advisory board role with Abbvie, AstraZeneca, Beigene, Celgene/BMS, Celltrion Healthcare, Curis, Eli Lilly, Gilead/Kite, Incyte, Ipsen, Janssen, MeiPharma, Miltenyi Biomedicine, Merck/MSD, and Roche, Data Safety Monitoring Board activities with Merck/MSD, and meeting and/or travel support from Abbvie, Gilead/Kite, Janssen, and Roche, and an expert statement for Bristol Myers Squib. C.R. reports consulting fees to the institution from Abbvie, Celgene/BMS, and Roche, honoraria to the institution from Amgen, Janssen, Abbvie, Celgene/BMS, and Takeda, payment for expert testimonies to the institution from Gilead and Janssen, and meeting and/or travel support from Sanofi and Amgen. All other authors declare no competing interests.