Abstract A044: Characterization of DS8201 (Enhertu) in a Clinically Pretreated NSCLC Patient-Derived Xenograft (PDX) Model

Abstract Background: HER2 (Human Epidermal Growth Factor Receptor 2) amplification is a key molecular alteration defining multiple cancer types. The recent HER2-targeted antibody-drug conjugate (ADC), DS8201 (Enhertu), representing a groundbreaking advancement, demonstrated remarkable and practice-changing efficacy across diverse clinical settings. Despite DS8201 achieving significant clinical benefit in multiple HER2-positive tumor types, the existence of non-responders and acquired resistance remains a recognized challenge requiring further investigation. In this study, we established an Enhertu-pretreated patient-derived xenograft (PDX) model, LU9681, derived from a patient's progressive lesion biopsy after multiple treatments, including Enhertu. Method: The NSCLC PDX model LU9681, was established by subcutaneously engrafted in immunodeficient mice. HER2 expression level in the tumor tissue was detected by IHC and FISH. Treatment of DS8201 (2mg/kg, 5mpk and 10mpk, i.v. Q3W) in LU9681 was started when the average tumor volume reached around 150-180mm3. The progressive disease of the treatment group was defined according the RECIST guideline (version 1.1) as follow: At least a 20% increase in the TV, taking as reference the smallest TV on study, calculated as ΔVm-f %=100% × ((Vfinal – Vminimum) / Vminimum). Result: In this study, we established a NSCLC PDX model, LU9681, derived from metastatic pleural effusion of a patient who had undergone multiple treatments including 5 cycles Enhertu, (400mg once every 3 weeks via infusion). During this treatment, patient’s pleural effusion resolved temporarily and had stable disease before relapse. In preclinical studies, amplification and expression of HER2 was detected in the tumor tissue of LU9681. The in vivo efficacy studies demonstrated tumor progression in the 2 mpk and 5 mpk DS8201 treatment groups. In the 10 mpk DS8201 treatment groups, initial tumor regression was observed at the beginning of each treatment cycle, followed by tumor progression at later stages, which is similar to patient response in clinical settings. With long-term continuous treatment of 10 mpk DS8201, some tumors showed persistent progression without regression. HER2 IHC analysis of the relapsed tumors revealed decreased HER2 protein expression on the cytomembrane, and translocation of HER2 to cytoplasm and nucleus compared to untreated LU9681 tumors. Conclusion: The Enhertu-pretreated PDX model, LU9681, validated in this study, provides robust and clinically relevant platform for the investigating mechanisms of resistantce to DS8201 and assists in the exploration and development of novel therapeutic strategies. Citation Format: Jinxi Wang, Ling Chen, Leilei Chen, Likun Zhang, Wubin Qian, Mingxuan Du, Ludovic Bourre, Jessie Jingjing. Wang. Characterization of DS8201 (Enhertu) in a Clinically Pretreated NSCLC Patient-Derived Xenograft (PDX) Model [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A044.