Abstract 2652: In vitro and in vivo antitumor activity of SYD985, a novel HER2-targeting ADC: a comparison with T-DM1

SYD985 is a HER2-targeting ADC based on trastuzumab and Synthon's proprietary cleavable linker-duocarmycin payload. The preclinical profile, including mechanism of action studies, PK, efficacy, and safety studies are described in the accompanying abstract. We have further compared SYD985 to T-DM1 (Kadcyla) and have focused on the in vitro and in vivo efficacies of both of these HER2-targeting ADCs. SYD985 and T-DM1 were compared head-to-head in a panel of 10 cell lines expressing different levels of HER2, including levels characterized as HER2 0, 1+, 2+, or 3+. SYD985 was 3 to 5 times more potent in one HER2 2+ and two HER2 3+ cell lines, while similar potencies were obtained on two other HER2 3+ cell lines. In cell lines with lower HER2 membrane expression (HER2 1+), SYD985 was a factor 7 to 300-fold more potent. These data show that the difference in potencies between SYD985 and T-DM1 becomes more pronounced at lower HER2 expression levels. Subsequently, we next studied how the in vitro data correlate with in vivo anti-tumor activities. In a xenograft with a breast BT-474 cell line (IHC HER2 3+) both SYD985 and T-DM1 dose-dependently reduced tumor growth after single dose (SD) i.v. administration. SYD985 was approximately 5-fold more potent than T-DM1 (tumor stasis at 1 mg/kg vs 5 mg/kg respectively). Subsequently, both ADCs were evaluated (SD i.v.) in a series of patient-derived xenografts (PDX) using HER2 FISH negative tumors from breast cancer patients. We have tested both ADCs in two models classified as Triple Negative Breast Cancer (TNBC; ER negative/PR negative/HER2 negative) with IHC HER2 1+ staining, two TNBC models with IHC HER2 2+ staining, and two Hormone Positive tumor models with IHC HER2 2+ staining. One model (TNBC IHC HER2 2+) did not respond to either SYD985 or T-DM1. In the other five models, SYD985 was more active than T-DM1. Corroborating with the in vitro data, the improved anti-tumor activity of SYD985 versus T-DM1 is most prominent in the PDX models with lowest HER2 expression. In the two TNBC IHC HER2 1+ models, SYD985 induced CR at 1-3 mg/kg, whereas T-DM1 was inactive at all dosages tested, up to 30 mg/kg. We conclude that i) SYD985 is more potent than T-DM1, both in vitro and in vivo in all responsive models; ii) In these studies, the potency advantage of SYD985 over T-DM1 is enhanced even further in the tumor cell lines and PDX models with low HER2 expression (i.e. IHC HER2 1+); iii) The preclinical profile of SYD985 enables