Abstract 880: Anti-tubulin antibody drug conjugates potentiate venetoclax activity in non-Hodgkin lymphoma by targeting MCL-1
Authors: Amin Dhara N. , Oeh Jason , Zindal Anuradha , Musick Lisa , Hirata Jamie , Mobasher Mehrdad , Polson Andy , Sampath Deepak , Wertz Ingrid E. 
Published: August 2018

Abstract
Venetoclax, a potent, orally bioavailable inhibitor that selectively targets BCL-2 and induces intrinsic apoptosis, is currently approved for the treatment of relapsed/refractory chronic lymphocytic leukemia with 17p deletion (R/R 17p del CLL) and also has profound efficacy in broad R/R CLL as a single agent or in combination with obinutuzumab (anti-CD20 antibody). However, evidence of robust efficacy by venetoclax as a single agent in certain subtypes of non-Hodgkin lymphoma (NHL) has been limited. For example, diffuse large B-Cell lymphoma (DLBCL) is the most common sub-type of NHL, yet the overall response rate of DLBCL patients to venetoclax was 18% in contrast to 61% in other NHL sub-types. It has been proposed that expression of other pro-survival BCL-2 family members may limit single-agent venetoclax efficacy and is thus considered a potential major resistance factor. To this end, we have observed that low sensitivity to venetoclax monotherapy is correlated with MCL-1 expression in NHL cell lines. We have previously reported that anti-tubulin agents promote MCL-1 degradation. Given that polatuzumab vedotin is a novel antibody drug conjugate targeted to CD79b and delivers an auristatin anti-tubulin agent, we hypothesized that combining polatuzumab with venetoclax presents a mechanism-driven combination strategy for maximizing anti-tumor responses in NHL. In NHL patients, both polatuzumab vedotin and venetoclax have acceptable and non-overlapping toxicities and the combination of both drugs may provide an improved therapeutic index relative to conventional chemotherapy. Here, we demonstrate that polatuzumab vedotin synergizes with venetoclax both in vitro and in vivo. Mechanistically, the combination of both drugs promotes apoptosis in NHL cell lines as indicated by caspase 3/7 activation and dependence on BAX/BAK expression, and decreases MCL-1 protein levels. Furthermore, the combination of venetoclax with polatuzumab vedotin is more efficacious in vitro than the combination of venetoclax with a selective MCL-1 small molecule inhibitor (AMG 176). The combination of polatuzumab vedotin with venetoclax results in durable tumor regressions in diffuse large B-cell and mantle cell lymphoma xenograft models at tolerated doses and is more efficacious than the combination of venetoclax plus bendamustine, a standard chemotherapeutic agent. Based on our pre-clinical data and the strong mechanistic rationale, a drug combination regimen of venetoclax with polatuzumab vedotin and obinutuzumab is currently being evaluated in Phase1b clinical trials in R/R FL and DLBCL (ClinicalTrials.gov identifier NCT02611323).
Citation Format: Dhara N. Amin, Jason Oeh, Anuradha Zindal, Lisa Musick, Jamie Hirata, Mehrdad Mobasher, Andy Polson, Deepak Sampath, Ingrid E. Wertz. Anti-tubulin antibody drug conjugates potentiate venetoclax activity in non-Hodgkin lymphoma by targeting MCL-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 880.