Abstract 484: VIP236: A small molecule drug conjugate with an optimized camptothecin payload has significant activity in patient-derived and metastatic cancer models

Abstract

Abstract Introduction: We previously presented the design and preliminary characterization of VIP236—an SMDC consisting of an αvβ3 integrin binder linked to an optimized camptothecin topoisomerase I (TOP1) inhibitor payload released by neutrophil elastase in the tumor microenvironment (Lerchen et al, Cancers 2022). Herein we evaluate VIP236 in patient-derived and metastatic models of cancer. Methods: Subcutaneous patient-derived xenograft mouse models in non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), colorectal cancer (CRC), and triple negative breast cancer (TNBC) were treated with VIP236. Metastasis formation was measured by human DNA PCR in an orthotopic TNBC mouse model. Gastric cancer models included patient-derived and cell line xenograft mouse models. Tumor/control (T/C) ratios were calculated, and body weight was measured. Pharmacodynamic (PD) effect of VIP236 in a gastric cancer SNU16 xenograft mouse model was investigated. Tumor samples from vehicle- and VIP236-treated groups collected up to 144 hours postdose were analyzed for % positive γH2AX cells by a fit-for-purpose qualified immunohistochemistry assay. Results: VIP236 is efficacious in vivo patient-derived models of NSCLC, RCC, CRC and TNBC with T/C ratios of 0.0, 8.9,14.5 and 5.6 compared with vehicle control (p<0.0001, CRC p<0.01). VIP236 showed statistically improved in vivo efficacy in gastric cancer models versus trastuzumab deruxtecan (a commercial antibody-drug conjugate [ADC] with a camptothecin payload) in NCIH87 (HER2high, p<0.05), SNU16 (HER2neg, p<0.001), and GXA3040 (patient-derived, HER2low, p<0.001) xenografts. VIP236 induced statistically significant tumor growth inhibition in a patient-derived CRC liver metastasis model (p<0.01) and statistically significant reduction in lung (p<0.001) and brain (p<0.01) metastasis from an orthotopic TNBC model was observed. Across all in vivo models no clinically significant weight loss or treatment-related mortality were observed. Furthermore, a time-dependent increase of γH2AX % positive cells in SNU16 in vivo VIP236-treated tumors confirms that VIP236 drives robust TOP1 inhibition and subsequent DNA damage. Conclusions: In summary, VIP236 monotherapy efficacy in NSCLC, gastric, TNBC, RCC, CRC, and metastatic TNBC in vivo cancer models provides a rationale for clinical investigation in advanced metastatic solid tumors. In gastric cancer, VIP236 showed improved efficacy compared with the approved ADC, trastuzumab deruxtecan, regardless of HER2 expression. These results warrant further evaluation in clinical trials. Citation Format: Beatrix Stelte-Ludwig, Melanie M. Frigault, Hans-Georg Lerchen, Tibor Schomber, Raquel Izumi, Amy J. Johnson, Ahmed Hamdy. VIP236: A small molecule drug conjugate with an optimized camptothecin payload has significant activity in patient-derived and metastatic 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 484.