Editor’s Note: The 48th San Antonio Breast Cancer Symposium (SABCS 2025) recently concluded successfully in San Antonio, USA. At the meeting, Professor Ma Fei and his team from the Cancer Hospital, Chinese Academy of Medical Sciences reported results of a study evaluating nab-sirolimus (HB1901) combined with endocrine therapy in patients with HR+/HER2− advanced breast cancer who had progressed after CDK4/6 inhibitor (CDK4/6i) treatment (Abstract No. PD10-10).
As a novel mTOR inhibitor, nab-sirolimus employs albumin-bound nanoparticle technology to enhance drug bioavailability. The regimen demonstrated encouraging efficacy in patients with aberrant activation of the PI3K/AKT/mTOR pathway, with a manageable safety profile. Notably, potential clinical benefit was observed regardless of PI3K pathway mutation status, offering a new therapeutic direction for decision-making in the post-CDK4/6i era. Oncology Frontier invited Professor Ma Fei to provide an in-depth interpretation of the study.
Study Overview
Study Background
Aberrant activation of the PI3K/AKT/mTOR signaling pathway is recognized as a key mechanism of resistance to both endocrine therapy and CDK4/6 inhibitors in HR+/HER2− advanced breast cancer.
nab-sirolimus (HB1901) is an mTOR inhibitor formulated using albumin-bound nanoparticle technology, which improves the solubility of this poorly water-soluble drug and enhances bioavailability compared with conventional sirolimus.
This study aimed to evaluate the antitumor efficacy and safety of nab-sirolimus combined with endocrine therapy in patients who experienced disease progression after CDK4/6i treatment. The updated results presented at SABCS 2025 focused particularly on the impact of PI3K/AKT/mTOR pathway mutations on the efficacy of nab-sirolimus plus fulvestrant.
Methods
This study enrolled patients with HR+/HER2− advanced breast cancer who had failed prior treatment with aromatase inhibitors (AI) or fulvestrant, with or without CDK4/6 inhibitors.
- Patients who progressed after AI ± CDK4/6i received nab-sirolimus plus fulvestrant
- Patients who progressed after fulvestrant ± CDK4/6i received nab-sirolimus plus exemestane
Results
As of the data cutoff date (May 31, 2025), 65 patients had been enrolled, with 60 patients evaluable for efficacy. The median follow-up time was 9.1 months.
Among the 60 evaluable patients, the objective response rate (ORR) was 20%.
In the nab-sirolimus plus fulvestrant cohort:
- 11 evaluable patients with PIK3CA / AKT1 / PTEN alterations demonstrated improved activity, with a median progression-free survival (PFS) of 9.1 months
- 20 patients with wild-type PI3K/AKT/mTOR pathway had a median PFS of 7.4 months, with an ORR of 30.0%
Safety
Treatment-related adverse events (TRAEs) were manageable, and no treatment-related deaths were reported.
The most common grade ≥3 TRAEs were metabolism-related disorders, including:
- Hypokalemia
- Hypertriglyceridemia
- Hyperglycemia
Overall, the safety profile was considered acceptable and clinically manageable.
Conclusions
For patients with disease progression after CDK4/6 inhibitor therapy, nab-sirolimus combined with fulvestrant appears to be a promising treatment option, regardless of PI3K pathway mutation status.
Investigator’s Perspective
1. Background and Clinical Significance
Aberrant activation of the PI3K/AKT/mTOR pathway is one of the major mechanisms underlying resistance to endocrine therapy and CDK4/6 inhibitors. While agents targeting this pathway—such as PI3Kα inhibitors (e.g., alpelisib)—are already available in clinical practice, their use is often limited by tolerability concerns.
By optimizing the drug-delivery system and improving bioavailability, nab-sirolimus may offer a more favorable balance between efficacy and safety.
This study specifically addresses patients who have failed CDK4/6 inhibitor therapy, a population that represents one of the most challenging and clinically relevant treatment scenarios in current practice.
2. Key Efficacy Highlights
- Encouraging overall activity: Among evaluable patients, the ORR was 20%. In the fulvestrant combination cohort, ORR reached 29%, with a median PFS of 7.5 months, indicating meaningful antitumor activity.
- Enhanced benefit in mutation-enriched populations: Patients harboring PI3K/AKT/mTOR pathway alterations achieved a median PFS of 9.1 months, with a 6-month PFS rate (PFS6) of 70.1%, suggesting greater benefit in biomarker-selected subgroups.
- Manageable safety profile: Grade ≥3 TRAEs occurred in 40% of patients, predominantly metabolic abnormalities such as hypokalemia, hypertriglyceridemia, and hyperglycemia, which were generally controllable with appropriate supportive care.
Professor Ma Fei
