Ninlaro (ixazomib) and Brentuximab Vedotin (ADCETRIS) Combination Results in Synergistic Antitumor Activity in Mouse Models of CD30 Positive Anaplastic Large Cell Lymphoma
Authors: Chattopadhyay Nibedita , Syed Sakeena , Zhang Yuhong , Yu Jie , He McDougall Dan , Yu Lunyin Yu , Tirrell Stephen , Berger Allison , van de Velde Helgi , Tremblay Christopher , Huebner Dirk 
Published: October 2019

Abstract
The ubiquitin-proteasome system (UPS) represents the primary mechanism by which cells degrade proteins. Proteasome inhibition results in accumulation of proteasome substrates, leading to cell cycle disruption, endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and, ultimately, the activation of apoptotic pathways and cell death. Ixazomib (NINLARO) is the first FDA-approved oral proteasome inhibitor, indicated in combination with lenalidomide and dexamethasone for treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib has been evaluated as a single agent in relapsed/refractory lymphoma, but additional data is needed to identify combination agents for lymphoma trials. Brentuximab vedotin (ADCETRIS) is an anti-CD30 antibody drug conjugate (ADC) that is protease cleavable linker with monomethyl auristatin E (MMAE), a highly potent antimicrotubule agent. Brentuximab vedotin binds specifically to CD30, a cell surface marker expressed at high levels on Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) tumor cells and induces cell death by direct cytotoxicity and also antibody-dependent cellular phagocytosis (ADCP). Brentuximab vedotin is approved in patients with relapsed/refractory HL, relapsed/refractory ALCL, and for consolidation in in the post autologous stem cell transplant (ASCT) setting of HL. Preclinical evidence suggests that resistance to anti-CD30 therapy can be mediated via activation of the NFkB pathway, which can be reversed by proteasome inhibitor treatment, suggesting a rationale for the combination of ixazomib and brentuximab vedotin. In the current study we evaluated this combination in three CD30+ ALCL xenograft models, SR-786, Karpas-299 and SUDHL-2 grown in immunocompromised mice. In SR-786 and Karpas-299, the combination treatment using dose levels of ixazomib and brentuximab vedotin with minimal single-agent activity resulted in synergistic effect with complete tumor regression. In most animals, the tumor did not regrow as long as 60 days after the last dose of combination drug treatment. Unlike in SR-786 and Karpas-299, no combination benefit was observed in the SUDHL-2 xenograft model. Pharmacodynamic studies are ongoing to understand the mechanism of synergy. Our data suggest that combination of ixazomib and brentuximab vedotin warrants clinical evaluation in CD30+ lymphoma patients.

Disclosures
Chattopadhyay: Takeda Pharmaceuticals: Employment. Syed:Takeda Pharmaceuticals: Employment. Zhang:Takeda Pharmaceuticals: Employment. Yu:Takeda Pharmaceuticals International Co, Cambridge, MA: Employment. He McDougall:Takeda Pharmaceuticals: Employment. Yu:Takeda Pharmaceuticals: Employment. Tirrell:Takeda Pharmaceuticals: Employment. Berger:Takeda Pharmaceuticals: Employment. van de Velde:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Tremblay:Takeda Pharmaceuticals: Employment. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership.