Abstract PS4-08-03: An Exploratory Clinical Study for Neoadjuvant Treatment of HER2-low Expressing, Stage II-III Breast Cancer with Vedolizumab in Combination with Pembrolizumab

Abstract Background: HER2-low expressing breast cancer is a heterogenous subtype with limited targeted therapeutic options. Disitamab Vedotin, a novel HER2-targeted antibody-drug conjugate (ADC), and Penpulimab, an anti-PD-1 monoclonal antibody, have both shown promise in different contexts of cancer treatment. This study aims to evaluate the clinical efficacy and safety of Disitamab Vedotin in combination with Penpulimab as neoadjuvant therapy in patients with HER2-low expressing, stage II-III breast cancer. Methods: This single-center, prospective, non-randomized clinical trial included patients with newly diagnosed HER2-low expressing (IHC 1+ or 2+ without amplification by FISH), stage II-III breast cancer in West China Hospital. All patients will receive neoadjuvant treatment with Disitamab Vedotin (2.0 mg/kg IV) and Penpulimab (200 mg IV) every 3 weeks for a total of 6 cycles, followed by surgery. The primary endpoint was pathological complete response (pCR), and secondary endpoints included overall response rate (ORR) and treatment-related adverse events (AEs). As an exploratory biomarker analysis, tumor-infiltrating lymphocytes (TILs) were quantitatively assessed in pretreatment tumor biopsies. Results: A total of 20 patients were enrolled in the study from August 2023 to August 2024, with two patients withdrawn due to intolerance to adverse reactions and two others discontinued due to disease progression. At the end of the treatment, total pCR (ypT0/is ypN0) rate was 25.0% (4/16). ORR reached 56.3% (9/16) by the clinical response assessment at the end of neoadjuvant treatment. The PD-L1 positive subgroup demonstrated a higher tpCR rate compared to the PD-L1 negative subgroup (33.3% vs. 14.3%). Additionally, the IHC 1+ subgroup exhibited a lower tpCR rate than the IHC 2+ subgroup without amplification by FISH (12.5% vs. 37.5%). The most common AEs were alopecia (18/20, 90.0%) and pruritus (14/20, 70.0%), and no significant toxicities or treatment-related deaths observed. Pretreatment tumor immune analysis revealed significantly higher CD4+ TIL infiltration in patients achieving pCR (p= 0.0181). While CD8+ TILs showed a non-significant trend toward increased infiltration in the pCR group (p = 0.0676), overall immune infiltration was associated with pCR (p = 0.0451). Conclusion: Although the clinical benefit may be limited, the combination of Disitamab Vedotin and Penpulimab as neoadjuvant treatment for HER2-low expressing, stage II-III breast cancer shows manageable safety and potential for further refinement, warranting additional investigation to optimize treatment strategies. Pretreatment CD4+ TIL density and total immune infiltration may serve as predictive markers for neoadjuvant response. Citation Format: T. Luo, X. Liu, Y. Song, C. Zhuang, P. He, X. Zeng, D. Zheng, X. Yan, X. Zhong, T. Tian, B. Wei, Y. Xie, J. Chen, Q. Lv. An Exploratory Clinical Study for Neoadjuvant Treatment of HER2-low Expressing, Stage II-III Breast Cancer with Vedolizumab in Combination with Pembrolizumab abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-08-03.