Abstract 5928: Baseline serum protein analysis of patients with interstitial lung disease/pneumonitis (ILD) in 3 trastuzumab deruxtecan (T-DXd) trials: DESTINY-Breast01, DESTINY-Breast04, and DESTINY-Lung01

Abstract Background: The mechanism of T-DXd-related ILD remains unknown. Understanding the pathophysiology of drug-induced ILD and identifying biomarkers for patients (pts) at higher risk of T-DXd-related ILD is crucial. Krebs von den Lungen-6 (KL-6) has been analyzed as a biomarker for ILD, but its relevance to T-DXd-related ILD is undetermined. This exploratory analysis aimed to identify candidate ILD risk biomarkers via proteomic analysis and evaluate KL-6 levels in serum samples from pts in 3 T-DXd studies. Methods: Baseline serum samples were collected from 189 pts in 3 T-DXd clinical trials: DESTINY-Breast01 (DB-01; n = 56; NCT03248492), DESTINY-Breast04 (DB-04; n = 78; NCT03734029), and DESTINY-Lung01 (DL-01; n = 55; NCT03505710). Pts were divided into 3 groups: 94 non-ILD controls, matched 1:1 based on patient characteristics, and 95 pts who later developed ILD, further categorized by worst adjudicated grade (G): G1/2 ILD (n = 74) and G3-5 ILD (n = 21). Available baseline serum samples were analyzed using the SomaScan™ proteomics platform. Baseline and longitudinal serum KL-6 levels were measured by ELISA. Results: From ∼6000 analytes tested, elevated baseline serum interleukin 1 receptor-like 1 (ST2) levels were observed in pts with incident G3-5 ILD in all 3 studies. In DL-01, median levels of baseline ST2 relative fluorescence units (RFU; IQR [Q1-Q3]) in non-ILD pts were comparable to G1/2 ILD cases (n = 27, 3838 RFU [2873-4910] vs n = 20, 4374 RFU [3417-5122]), in contrast, the median baseline ST2 level in G3-5 ILD cases was elevated (n = 8, 8512 RFU [6824-23494]). Elevation of median baseline ST2 levels in G3-5 ILD cases was also observed in DB-01 (n = 6, 7707 RFU [6503-19035]) and DB-04 (n = 7, 5973 RFU [3972-14682]). In DB-01, the median baseline ST2 levels were 3816 RFU (n = 28, [2757-4712]) in non-ILD patients and 3529 RFU (n = 22, [2742-4695]) in G1/2 ILD cases. In DB-04, the median baseline ST2 levels were 4420 RFU (n = 39, [3051-6002]) in non-ILD patients and 4140 RFU (n = 32, [2714-5758]) in G1/2 ILD cases. Baseline KL-6 levels were elevated in G3-5 ILD cases in DB-01. This elevation was not observed in DB-04 or DL-01. Longitudinal sample analysis showed that KL-6 levels decreased with T-DXd treatment, mirroring the reduction in tumor burden observed after treatment. Conclusions: Proteomics analysis revealed elevated baseline serum ST2 levels as a potential baseline marker for T-DXd-related G3-5 ILD in lung and breast cancer. Luminex™ analysis is ongoing to quantify ST2 levels. The utility of KL-6 as a biomarker for T-DXd-related ILD appears to be limited. KL-6 levels decreased after T-DXd treatment, likely due to tumor shrinkage and reduction of tumor-derived KL-6. Given the limited number of clinical studies included and few G3-5 ILD events, the suitability of these candidate biomarkers needs further investigation. Citation Format: Zenta Tsuchihashi, Kevin Contrepois, Kazuishi Kubota, Jing Zhao, Xuya Wang, Vinit Kumar, Nuria Folguera Blasco, Brad Jakubison, Sonia Terrillon, Yingkai Cheng, Tomohiro Kaji, Miho Nakamura, Charles A. Powell, Egbert F. Smit, Shanu Modi, Peter Newham. Baseline serum protein analysis of patients with interstitial lung disease/pneumonitis (ILD) in 3 trastuzumab deruxtecan (T-DXd) trials: DESTINY-Breast01, DESTINY-Breast04, and DESTINY-Lung01 [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 5928.