Abstract Background: While novel HER2-targeted agents (including TKIs and ADCs) have demonstrated intracranial activity in HER2 positive (HER2 +) metastatic breast cancer (MBC) with active brain metastases (BM), effective management of TKI- and/or ADC-refractory disease remains an ongoing clinical challenge. Building on preclinical evidence of utidelone's superior blood-brain barrier penetration and bevacizumab's established anti-edema effects, we conducted this phase II study (NCT05357417) evaluating the combination in TKI-progressed HER2+ BM patients. Methods: This multicenter, two-cohort, single-arm phase II trial (NCT05357417) enrolled adult patients (≥18 years) with breast cancer who had brain metastases, either radiotherapy-naïve or with documented progression following prior radiotherapy. The results from HER2-negative cohort (U-BOMB study) have been completed and published Yan M, et al. JAMA Oncol, 2025 Jun 26; e251694. Here we present the preliminary findings from HER2-positive cohort (U-BOMB-HER) of patients with HER2-positive breast cancer who developed progressive brain metastases following treatment failure with trastuzumab and TKI. Patients received utidelone (30 mg/m2 IV on days 1-5) plus bevacizumab (15 mg/kg IV on day 1) every 3 weeks until disease progression or intolerance. The primary endpoint was central nervous system (CNS) objective response rate (CNS-ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with secondary endpoints including CNS disease control rate (CNS-DCR), progression-free survival (PFS), CNS-PFS, overall survival (OS) and safety. Results: From May 2022 to April 2025, 50 evaluable patients were enrolled (median age 52.0 years; range 32-68) with a median of 3 prior lines of therapy (range 0-9). Baseline characteristics included: 1 brain metastasis (n=14), 2 metastases (n=10), and ≥3 metastases (n=26). The cohort comprised 56.0% (28/50) radiotherapy-naïve patients and 44.0% (22/50) with post-radiotherapy progression, with 52.0% (26/50) having prior anti-HER2 ADC exposure (including 4 patients treated with ≥2ADCs with different payloads).Among 50 response-evaluable patients, the CNS objective response rate (CNS-ORR) was 54.0% (95% CI 39.3-68.2%), with a disease control rate of 92.0% (46/50; 95% CI 80.8-97.8%). For all 50 patients, median progression-free survival (PFS) was 8.6 months (95% CI 7.0-10.2) at data cutoff (June 30, 2025; median follow-up 14.0 months), with median overall survival (OS) of 11.0 months (95% CI 8.4-13.6).Treatment emergent adverse events (TEAEs) of any grade included peripheral neuropathy (96.0%), leukopenia (58.0%), ALT/AST elevation (52.0%), neutropenia (50.0%), anemia (42.0%), hypertension (42.0%), and proteinuria (38.0%). Grade 3 AEs occurred in peripheral neuropathy (6.0%), neutropenia (16.0%), leukopenia (8.0%), thrombocytopenia (4.0%), hypertension (12.0%), anemia (2.0%), and GGT elevation (2.0%). No grade ≥4 treatment-related AEs were observed. Conclusions: Preliminary findings from the U-BOMB-HER study indicate that utidelone plus bevacizumab demonstrates clinically meaningful CNS activity, along with a manageable safety profile, in patients with HER2-positive breast cancer brain metastases, refractory to trastuzumab and TKI. ClinicalTrials.gov: NCT05357417. Citation Format: H. Lv, S. Wang, Y. Song, L. Niu, M. Zhang, Z. Liu, J. Wu, X. Sun, Y. Cui, J. Wang, Y. Feng, H. Sun, J. Huang, J. Zhang, L. Wang, M. Lv, H. Zeng, S. Chen, M. Yan. Utidelone plus bevacizumab for the treatment of HER2-positive breast cancer brain metastases (U-BOMB-HER): A multicenter, single-arm phase IIstudy 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 PS5-01-13.
Lv et al. (2026) studied this question.