Nab-Sirolimus Regimens Show Promise in HR+/HER2-Negative Breast Cancer

Combining the targeted mTOR inhibitor nab-sirolimus (HB1901) with endocrine therapy exhibited promising antitumor activity and a manageable safety profile among patients with hormone receptor (HR)–positive, HER2-negative advanced breast cancer, according to data from a phase 2 trial (NCT06957379) presented in a poster session at the 2025 San Antonio Breast Cancer Symposium (SABCS).¹

Among patients who received nab-sirolimus in combination with fulvestrant (Faslodex; n = 31) and exemestane (Aromasin; n = 29), the overall response rate (ORR) was 29% and 10.3%, respectively, yielding an ORR of 20% across the overall population (n = 60). In the fulvestrant and exemestane cohorts, the disease control rate (DCR) was 93.5% and 82.8%, and the clinical benefit rate (CBR) was 45.2% and 20.7%.

Among patients with PIK3CA-, AKT-, or PTEN-mutant disease (n = 11) or wild-type disease (n = 20) in the fulvestrant cohort, data showed an ORR of 27.3% and 30.0%, respectively. Partial responses (PRs) occurred in 27.3% and 30.0% of each group. Additionally, the DCRs were 100.0% and 90.0%, and the CBRs were 72.7% and 65.0%.

The 6-month progression-free survival (PFS) rates were 58.3% with nab-sirolimus plus fulvestrant compared with 39.9% with nab-sirolimus plus exemestane. In the PI3K/AKT/mTOR mutant and wild-type subgroups of patients who received nab-sirolimus plus fulvestrant, the 6-month PFS rates were 70.1% vs 52.6%, respectively; the median PFS in each group was 9.1 months (95% CI, 3.75-not evaluable [NE]) and 7.4 months (95% CI, 4.40-9.20).

“Nab-sirolimus exhibited manageable toxicity and promising antitumor activity, particularly when combined with fulvestrant (achieving an ORR of 29% and a median PFS of [7.4] months),” lead study author Fei Ma, from the Medical Oncology Department of China Cancer Institute and Hospital in Beijing, China, wrote with coauthors in the poster.¹ “The novel mTOR inhibitor-based regimen may address the unmet need in CDK4/6 [inhibitor]-failed [HR-positive, HER2-negative] advanced breast cancer.”

In the phase 2 trial, 34 patients who progressed on prior aromatase inhibitors with or without CDK4/6 inhibitors were assigned to receive nab-sirolimus plus fulvestrant, while 31 patients who progressed on previous fulvestrant with or without CDK4/6 inhibitors received nab-sirolimus plus exemestane. All patients received nab-sirolimus at 100 mg/m².

The trial’s primary end points were the 6-month PFS rate and safety. Secondary end points included PFS, ORR, CBR, and overall survival.

Patients 18 years and older with pathologically confirmed HR-positive, HER2-negative breast cancer, no more than 3 prior lines of chemotherapy for inoperable locally advanced or metastatic disease, and at least 1 measurable lesion per RECIST v1.1 criteria were eligible for enrollment on the trial.² Other eligibility criteria included having an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and adequate organ and bone marrow function.

Across the overall population, 64.6% of patients were postmenopausal, and 46.2% received 2 prior lines of systemic therapy. Additionally, most patients had an ECOG performance status of 1 or higher (60.0%), prior CDK4/6 inhibitor therapy (98.5%), and visceral metastases (78.5%). Overall, 36.9% of patients had PIK3CA, AKT, or PTEN mutations.

Any-grade treatment-related adverse effects (TRAEs) occurred in 98.5% of the population, with 40% experiencing grade 3 or higher events. One patient in the fulvestrant cohort discontinued study therapy due to an AE; there were no drug-related toxicities that resulted in death.

At least 1 grade 3 or higher AE occurred in 38.2% of patients in the fulvestrant cohort and 41.9% of those in the exemestane cohort. In each respective cohort, the most common grade 3 or higher toxicities included hypokalemia (23.5% vs 9.7%), hypertriglyceridemia (14.7% vs 6.5%), decreased neutrophil counts (2.9% vs 6.5%), and hyperglycemia (0% vs 6.5%).

References

1. Ma F, Zhang Q, Mo H, et al. A multicenter, open-label, phase 2 study of nab-sirolimus (HB1901) plus endocrine therapy in HR+/HER2- advanced breast cancer following standard therapy failure. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract 911.
2. Sirolimus for injection (Albumin-bound) in combination with endocrine therapy for HR+/​HER2- advanced/​metastatic breast cancer patients who have failed standard therapy. ClinicalTrials.gov. Updated May 4, 2025. Accessed December 23, 2025. https://tinyurl.com/2rrz7zfp