S115 EXABS-225-PLENIII Emerging BCL2 Inhibitors Mary Ann Anderson, MBBS, FRACP, FRCPA, PhD1,2,3,* 1Department of Clinical Haematology Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Victoria, Australia, 3000 2Division of Blood Cells and Blood Cancer, The Walter and Eliza Hall Institute, Victoria, Australia, 3000 3Department of Medicine, The University of Melbourne, Victoria, Australia, 3000 *Corresponding author: manderson@wehi.edu.au Keywords Venetoclax, small molecule inhibitors, apoptosis, BCL2, chronic lymphocytic leukemia Therapeutic Targeting of BCL2 Hematological malignancies including chronic lymphocytic leukemia (CLL) and many types of non-Hodgkin lymphoma (NHL) demonstrate resistance to chemoimmunotherapy (CIT) at least in part by overexpression of the pro-survival protein BCL2.1 BH3 mimetics are rationally designed small molecules that mimic the natural action of the pro-death BH3-only family of proteins, binding to and inhibiting pro-survival BCL2 proteins including BCL2, BCLxL and MCL1.2 Crucially a true BH3 mimetic is defined by four key characteristics: 1) its biological activity is mediated via induction of BAX and BAK mediated apoptosis; 2) it must bind with high affinity to at least one BCL2 family member; 3) the agent’s activity must corelate with the expression of the relevant BCL2 family member; and 4) detectable apoptotic biomarkers should accompany activity of the agent.2,3 Therapeutic targeting of MCL1 and BCLxL has been delayed by on target adverse events including cardiac toxicity with MCL1 inhibitors4 and thrombocytopenia with BCLxL inhibitors.5 Venetoclax is the first in class selective BCL2 inhibitor (BCL2i) to have progressed to routine clinical use. Venetoclax works by potently and selectively targeting BCL2 overexpressing cancer cells, restoring their ability to undergo programmed or apoptotic cell death.6,7 The most significant toxicity observed with venetoclax therapy is tumor lysis syndrome (TLS)8. Venetoclax was the firstapproved drug in this new class of anti-cancer agents with Federal Drug Administration (FDA), European Medicines Agency (EMA) and Therapeutic Goods Administration (TGA) approvals.8,9 It is also approved for use in acute myeloid leukemia (AML) and has the potential to revolutionize treatment in other subtypes of hematological malignancy. Venetoclax has allowed many patients to enjoy prolonged remissions without the traditional toxicities of CIT.10–13 Despite these advances, there is a proportion of patients who do not respond (primary resistance) or show an initial favorable response followed by disease progression (secondary resistance) when treated with venetoclax. Furthermore, despite widespread BCL2 expression in many subtypes of NHL14 response rates to venetoclax are highly variable (18 to 75%),15 indicating that expression of the target alone is insufficient to predict cancer response.16,17 Work is ongoing to optimize treatment outcomes with this therapeutic strategy by engaging rational therapeutic partners and importantly by development of new BCL2 inhibitory approaches. Emerging BCL2i There are two classes of BCL2 inhibitors in development: those that selectively target BCL2 and those that dual target both BCL2 and BCLxL with the potential for additive anti-tumor effects but also greater toxicity.18 Selective BCL2 Inhibitors in Development Lisaftoclax or APG-2575, developed by Ascentage, is a highly potent BAX/BAK dependent orally available inhibitor of BCL2 currently undergoing phase I testing18,19 in relapsed/refractory (RR) multiple myeloma (MM) (NCT04942067, NCT04674514), RR CLL (NCT05147467, NCT04494503, NCT04215809), AML (NCT04964518, NCT04501120), pediatric RR acute lymphoblastic leukemia (ALL) (NCT05495035), T prolymphocytic leukemia (TPLL) (NCT05495035), and Waldenstrom macroglobulinemia (WM) (NCT04260217). Among 52 patients with hematological malignancies the maximum tolerated dose (MTD) was not reached and no clinical TLS was observed.20 In this study of 22 evaluable patients with RR CLL there was an overall response rate (ORR) of 63.6% (14/22).20 A larger study of 114 patients with RR CLL evaluated lisaftoclax in combination with either the Bruton’s tyrosine kinase inhibitor (BTKi) acalabrutinib or the anti CD20 monoclonal antibody rituximab (NCT04215809). In this study no dose limiting toxicity was identified, however TLS was observed in three patients (2%) with two cases of clinical TLS and one case of laboratory TLS, notably all patients had bulky disease.21 In another study of 45 patients with RR CLL there was one case of clinical TLS again without a defined MTD.22 In this study there was an ORR of 68.3% (27 of 41 evaluable patients) all partial remissions.22 Among 40 patients with RR NHL there was no MTD and no TLS observed and the ORR was 63.6% with a median duration of treatment of 4 months.22 BGB-11417 developed by Beigene,23 this highly selective, potent, oral BCL2i24 is currently in phase I clinical trials in mature B cell malignancies (NCT04883957; NCT04277637), MCL (NCT05471843), CLL (NCT05479994), myeloid malignancies (NCT04771130) and MM (NCT04973605). While these trials are
RkJQdWJsaXNoZXIy MTk3NTQxMg==