Abstract PD10-10: A Multicenter, Open-Label, Phase 2 Study of nab-Sirolimus (HB1901) Plus Endocrine Therapy in HR+/HER2- Advanced Breast Cancer Following Standard Therapy Failure

Abstract Background: There was no standard therapy regimen for HR+/HER2- advanced breast cancer progressing after CDK4/6 inhibitors (CDK4/6i) administration. Sirolimus, also known as rapamycin, is an mTOR specific inhibitor, but its oral bioavailability is low. By binding nanoparticle albumin to sirolimus (nab-Sirolimus) and increasing its water solubility, the bioavailability of sirolimus can be improved. Herein, we reported the efficacy and safety of nab-Sirolimus (HB1901) combined with endocrine therapy (ET) in patients following progression on/after CDK4/6i based regimen. Methods: This multicenter, open-label, phase 2 trial enrolled patients with pathologically confirmed HR+/HER2- advanced BC who had previously failed aromatase inhibitor (AI)/fulvestrant ± CDK4/6i. Patients failing prior AI ± CDK4/6i received nab-Sirolimus (100 mg/m2) + fulvestrant, while those failing fulvestrant ± CDK4/6i received nab-Sirolimus (100 mg/m2) + AI. Primary endpoint was 6-month progression-free survival (PFS) rate. Secondary endpoints included objective response rates (ORR), disease control rate (DCR), PFS, safety and tolerability. Tumor tissue and/or blood samples from patients were subjected to next-generation sequencing. Results: A total of 65 patients were enrolled in this study, with a median age of 54 years (range 31-72). 34 and 31 eligible patients were allocated to receive nab-Sirolimus 100 mg/m2 Q2W + fulvestrant or exemestane, respectively. Among them, 64 patients (98.5%) had received ET + CDK4/6i, 51 patients (78.5%) had visceral metastases at baseline, and 33 patients (50.8%) had received at least one type of chemotherapy for advanced/metastatic diseases. At data cut-off (May 31, 2025), with a median follow-up time of 9.1 months, 15 patients remained on study treatment. Among 60 efficacy-evaluable patients, the ORR was 20%, with DCR of 88.3% (12 partial responses [PR] and 41 stable diseases [SD]), median PFS of 5.7 months (95%CI 5.03-9.03), and 6-month PFS rate of 49.5%. In the nab-Sirolimus + fulvestrant cohort (n=31), improved activity was observed: ORR of 29%, DCR of 93.5% (9 PR and 20 SD), median PFS 7.5 months (95%CI 5.13-9.2), and 6-month PFS rate of 58.3%. Twenty-four patients (36.9%) had PIK3CA/AKT1/PTEN alteration. In the nab-Sirolimus + fulvestrant cohort, 11 efficacy-evaluable patients with PIK3CA/AKT1/PTEN alteration showed a median PFS of 9.1 months [95%CI 3.75- not reached] and 6-month PFS rate of 70.1%, with ORR of 27.3% and DCR of 100% (3 PR and 8 SD). Notably, 20 efficacy-evaluable patients with PIK3CA/AKT1/PTEN wild-type showed promising responses (ORR of 30 % and DCR of 90% [6 PR and 12 SD]), with median PFS of 7.4 months [95%CI 4.4 - 9.2] and 6-month PFS rate of 52.6%). The treatment-related adverse events (TRAEs) associated with nab-sirolimus occurred in 98.5% (64/65) of patients, mostly grade 1-2. The most frequently reported TRAEs were hypertriglyceridemia (61.5%), hypercholesterolemia (60%) and hypokalemia (60%). A total of 26 patients (40.0%) had ≥Grade 3 treatment-related adverse events, which had an incidence rate ≥ 5% were hypokalemia (16.9%) and hypertriglyceridemia (10.8%). No drug-related events leading to death occurred. Only 1 patient experienced an event leading to permanent discontinuation. Conclusion: Nab-sirolimus exhibited manageable toxicity and promising antitumor activity, particularly when combined with fulvestrant (achieving an ORR of 29% and a median PFS of 7.5 months). Nab-sirolimus + fulvestrant showed good efficacy in both PIK3CA/AKT1/PTEN altered and wild-type HR+ breast cancer patients. This novel mTOR inhibitor-based regimen may address the unmet need in CDK4/6i-failed HR+/HER2- advanced breast cancer. Clinical trial information: NCT06957379. Citation Format: F. Ma, Q. Zhang, H. Mo, J. Cui, B. Zhao, F. Xu, L. Wang, L. Gan, Y. Liu, F. Luo, Z. Song, Y. Lv, X. Wang, T. Sun, X. Ling, H. Sun, Y. Yin, C. Wang, Z. Xia, H. Su, X. Chen, Y. Li, H. Yang, Y. Wang, Y. Xin, X. Zhang, Y. Chen, X. Luo, F. Wang, M. Luo. A Multicenter, Open-Label, Phase 2 Study of nab-Sirolimus (HB1901) Plus Endocrine Therapy in HR+/HER2- Advanced Breast Cancer Following Standard Therapy Failure [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 PD10-10.