Abstract 6150: AZD0466, a dual BCL-2/XL targeting nanomedicine, is active in small cell lung cancer models
Authors: Andersen Courtney L. , Fabbri Giulia , Jenkins David , Cader Zumla , Sharma Shringi , Tabatabai Areya , Balachander Srividya , Roebuck Jordan , Galvin Melanie , Simpson Kathryn , Dive Caroline , Ahnert Jordi Rodon , Saeh Jamal 
Published: April 2023

Abstract
Small cell lung cancer (SCLC) is an aggressive malignancy with critical need for new therapies. While currently treated as a single disease, SCLC is heterogenous, comprised of several transcriptional subtypes. Each of these subtypes has distinct drivers and may warrant unique therapeutic targets. Two potential therapeutic targets for SCLC are the pro-survival proteins BCL-2 and BCL-XL. BCL-2 is overexpressed in ASCL1 (A) and POUF3 (P) subtypes of SCLC. We therefore sought to evaluate efficacy of the dual BCL-2/XL inhibitor AZD0466 in SCLC models and to determine whether transcriptional subtype would predict response. AZD0466 is a novel drug-dendrimer conjugate. The active moiety, AZD4320, is a potent dual inhibitor of BCL-2 and BCL-XL. AZD4320 is covalently conjugated to a 5th-generation PEGylated poly-lysine dendrimer through a hydrolytically labile linker to make AZD0466. AZD0466 has been optimized to deliver efficacy while mitigating potential Cmax-driven on-target toxicities of AZD4320. AZD4320 was active (IC50 ≤0.1 µM) in 9/27 SCLC cell lines. AZD4320 in vitro sensitivity was enriched in cell lines that represented A and P subtypes of SCLC compared to NEUROD1 and YAP1 subtypes. We next profiled AZD0466 in a panel of SCLC patient-derived models: 14 patient-derived xenografts and 10 circulating tumor cell-derived xenografts. AZD0466 monotherapy dosed weekly IV was active in 12/24 SCLC xenografts, driving regressions in 8 models. AZD0466 drove efficacy and cleaved caspase-3 induction in a dose-dependent manner. Similar to in vitro, AZD0466 in vivo efficacy was enriched in subtype-A, driving responses in 10/14 ASCL1 models (7 regression, 3 stable disease). AZD0466 response also correlated strongly with BCL-2 mRNA expression (P&lt;0.0001). AZD0466 outperformed the selective BCL-2 inhibitor venetoclax in 6/10 models. Notably, AZD0466 was active in models resistant to platinum/etoposide chemotherapy, the standard-of-care for SCLC. Together, these data suggest BCL-2/XL inhibition has therapeutic potential in SCLC. AZD0466 is in clinical development. The first-in-human study treated 9 patients with advanced solid tumors (NCT04214093) at doses from 50-200mg, all of which were well-tolerated. The BOR was SD observed in 3 patients (100mg) with 1 patient receiving treatment for 5.5 months. AZD0466 is now under evaluation in patients with hematologic malignancies (NCT04865419 and NCT05205161). AZD0466 has been dosed in 33 patients up to 2400mg. No DLTs have been reported to date. Initial clinical activity has been observed through reduction of bone marrow blasts following AZD0466 treatment. AZD0466 exhibits linear PK, consistent across solid tumor and leukemia patients. The doses tested are in line with preclinical studies in SCLC.
Citation Format: Courtney L. Andersen, Giulia Fabbri, David Jenkins, Zumla Cader, Shringi Sharma, Areya Tabatabai, Srividya Balachander, Jordan Roebuck, Melanie Galvin, Kathryn Simpson, Caroline Dive, Jordi Rodon Ahnert, Jamal Saeh. AZD0466, a dual BCL-2/XL targeting nanomedicine, is active in small cell lung cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6150.