Abstract 245: Preclinical development of HDM2020, a novel ADC targeting FGFR2b, in gastric cancer (GC) and squamous non-small cell lung cancer (sq-NSCLC) xenograft models

Abstract Introduction: FGFR2b is a novel protein biomarker detected by IHC with the overexpression rate of ∼30% (any 2+/3+) in gastric or gastroesophageal junction cancer(GC/GEJC) patients, and among those patients ∼40% are not eligible for currently approved targeted therapies (HER2, PD-L1, MMR and CLDN18.2)1. HDM2020 is a topoisomerase Inhibitor based DAR8 ADC developed using a novel Ab targeted against FGFR2b, which has the potential to treat FGFR2b overexpressing tumor with reasonable safety window2. Methods: In vivo cell line (CDX) and patient derived xenograft (PDX) models were conducted to validate the therapeutic potential of HDM2020 against GC and sq-NSCLC. FGFR2b expression were detected by IHC using various tumor paraffin sections. Results: Combination of HDM2020 and avastin or paclitaxel demonstrated a synergistic effect in GC CDX model. Single-agent therapeutic activity of HDM2020 was demonstrated in two FGFR2b-positive GC PDX models with TP53 or BCOR gene mutation and at least 1st line chemotherapy. At a dose of 10mg/kg, the maximum tumor growth inhibition rate were 98% and 99%. In FGFR2b middle expressed sq-NSCLC PDX model, complete response was observed at single dose of 10mg/kg. The minimum effective doses were between 2.5-3mg/kg in above three models. FGFR2b is overexpressed in GC, sq-NSCLC, TNBC and may other tumor types. Conclusion: Based on the clinical validation of FGFR2b in GC and signs of early preclinical activity in sq-NSCLC with significant unmet need, HDM2020 might has promising efficacy in these indications. HDM2020 is expected to enter clinical development in 2025. References:1: Seiya Sato, Shannon L Rhodes, et al. Fibroblast Growth Factor Receptor 2 Isoform IIIb (FGFR2b) Protein Overexpression and Biomarker Overlap in Patients With Advanced Gastric or Gastroesophageal Junction Cancer(GC/GEJC). ESMO, 2024.2: Tingyang Wang, Liubin Guo, et al. Development of a novel FGFR2b-targeting ADC with robust anti-tumor efficacy in preclinical evaluation. World ADC SAN DIEGO 2024. Citation Format: Tingyang Wang, Liubin Guo, Kuan Lu, Hao Pan, Yang Chen, Zhaoxing Yu, Yayun Zhao, Shengxing Zhao, Qingli We, Ruizhe Wang, Yan Xia, Hongwen Li, Dongzhou Jeffrey Liu. Preclinical development of HDM2020, a novel ADC targeting FGFR2b, in gastric cancer (GC) and squamous non-small cell lung cancer (sq-NSCLC) xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 245.