Abstract PS3-11-12: Efficacy and safety of disitamab vedotin combined with pyrotinib as neoadjuvant therapy for HER2-positive breast cancer: a phase II trial

Abstract Background: Dual HER2 blockade plus chemotherapy achieves significant responses in HER2+ breast cancer but carries toxicities. Disitamab vedotin (RC48), a HER2-targeting ADC, and pyrotinib, a pan-HER TKI, show synergistic antitumor activity. This trial evaluates the first chemo-free neoadjuvant combination. Methods: This multicenter, single-arm phase II trial enrolled patients with operable or locally advanced HER2+ breast cancer (T2-4/N0-3; IHC 3+ or ISH+). Patients received RC48 at a dosage of 2.0 mg/kg intravenously every 2 weeks, combined with pyrotinib at a dosage of 400 mg orally once daily (cycles 1-4). Post-surgery, adjuvant therapy (epirubicin 90 mg/m2 + cyclophosphamide 600 mg/m2 Q3W, cycles 5-8) was administered, followed by maintenance therapy (cycles 9-22): trastuzumab + pertuzumab for pCR patients, T-DM1 or trastuzumab + pertuzumab for non-pCR patients. The primary endpoint was pathological complete response (pCR, defined as ypT0/Tis ypN0); the secondary endpoints included overall response (OR), assessed per RECIST 1.1 every two cycles, event-free survival (EFS), invasive disease-free survival (IDFS), and treatment-related adverse events (TRAEs). For binary endpoints, 95% confidence intervals (CIs) were calculated using the Clopper-Pearson exact method. Furthermore, a biomarker analysis was conducted to explore HER2 dynamics and alterations within the tumor microenvironment. Results: At data cutoff for this analysis on June 25, 2025, 17 patients were evaluable with a median follow-up of 5.2 months, ranging from 1.9 to 8.5 months. All patients were female, with a mean age of 51.9 years (range 29.0- 67.0), and a mean BMI of 21.8 kg/m2 (range 17.5-30.5). All had HR-/HER2+ disease (17/17, 100%). Of the 15 patients who underwent surgery, the neoadjuvant regimen achieved a pCR in 53.3% (8/15), with a 95% CI of 26.6-78.7%. The ORR among the 17 evaluable patients assessed before surgery was 88.2% (15/17) with a 95% CI of 63.6-98.5%. No events related to EFS, including progressive disease per RECIST 1.1, failure to undergo surgery due to progression, toxicity, or death, or local or distant recurrence post-surgery, occurred. No death events occurred. As indicated in the table below, hepatic dysfunction was the most frequent TRAEs with a grade ≥ 3, and its median duration was 13 days. No treatment discontinuations occurred due to TRAEs. Conclusion: This first neoadjuvant study combining HER2-ADC and TKI demonstrated a chemo-free neoadjuvant regimen with high efficacy. The safety profile was manageable, with hepatic toxicity requiring longer follow-up. These results support randomized evaluation against standard chemotherapy-containing regimens. As the first disclosure of this regimen, the follow-up period remains limited for EFS/IDFS assessment, and exploratory biomarker data are pending. Another limitation was the single-arm design. Citation Format: T. Zeng, X. Sun, J. Wang, Y. Yin. Efficacy and safety of disitamab vedotin combined with pyrotinib as neoadjuvant therapy for HER2-positive breast cancer: a phase II trial [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 PS3-11-12.