BL0175, a novel nano-mediated polypeptide conjugate of protein degrader, in patients (pts) with locally advanced/metastatic HR+/HER2− breast cancer (HR+, HER2- LA/mBC): Initial results from a phase 1 study.

Abstract

1078 Background: BL0175 is a novel nano-conjugate (~10 nm) composed of PEG-modified poly (amino acid), enzyme-responsive peptide linkers, and the protein-degrader payload fulvestrant. It accumulates in the tumor microenvironment (TME), where enzymatic cleavage releases fulvestrant continuously. The released fulvestrant penetrates tumor cells, effectively inducing cell death. Nonclinical studies demonstrated that BL0175 provides superior tumor distribution of fulvestrant, enhanced tumor growth inhibition, and greater progesterone receptor suppression compared with conventional fulvestrant injection at equivalent doses. This first-in-human Phase I study reports preliminary safety, efficacy, and pharmacokinetic (PK) data for BL0175. Methods: Postmenopausal pts with HR+, HER2- LA/mBC received intramuscular BL0175 (Cycle 1: Days 1, 15; thereafter every 4 weeks) at doses ranging from 50 mg to 500 mg. Data are summarized across all cohorts unless otherwise specified. Results: As of January 14, 2026, 22 pts were treated (50 mg: n=1; 100, 200, 300, 400, 500 mg: n=3 each; 250 mg: n=6). The median number of prior lines of therapy was 3 (range: 1–7). Safety: Adverse events (AEs) and treatment-related AEs (TRAEs) occurred in 64% of pts (14/22). All AEs were Grade 1–2, with no dose-dependent trends or unexpected safety signals. Efficacy: Eleven pts had post-baseline tumor assessments (50 mg & 300 mg: n=1 each; 100, 200, 400 mg: n=3 each). Disease control rate (DCR) was 100% in cohorts receiving ≥200 mg. Three partial responses (PR) were observed in cohorts ≥200 mg, yielding an objective response rate (ORR) of 42.9% (3/7). The pts who achieved PR comprised individuals with prior progression on standard CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (aromatase inhibitor or fulvestrant injection), as well as those presenting with brain metastases at baseline. These data suggest that 200 mg may be an effective therapeutic dose. Pharmacokinetics: PK exposure (C max and AUC 0–336h ) of both released and total fulvestrant increased dose-proportionally. BL0175 was stable in systemic circulation (release rate ≤0.03% across doses). Notably, in two pts (50 mg and 100 mg cohorts), released fulvestrant concentrations in tumor tissue were 9-fold and 18-fold higher, respectively, than in plasma, confirming tumor-specific enrichment. Conclusions: BL0175 demonstrated promising efficacy in pts with HR+, HER2- LA/mBC, including those with prior progression on fulvestrant injection and CDK4/6i-based therapy and in brain metastases. The preliminary results validate BL0175's design rationale, supporting its tumor-targeted delivery and potential for enhanced efficacy at lower doses. These findings warrant further investigation of BL0175 in this patient population. Clinical trial information: NCT06738966 .