Despite significant advancements in the treatment of hormone receptor (HR)-positive/HER2-negative metastatic breast cancer, there remains an unmet need to identify optimal therapeutic options for patients who experience disease progression following endocrine therapy or cyclin-dependent kinase (CDK)4/6 inhibitor−based regimens. Anlotinib, a novel multitarget tyrosine kinase inhibitor, combined with fulvestrant, was hypothesized to be a potential treatment option for this patient population. This article summarizes data from the single-arm, phase 2 trial (NCT05075512) that was conducted to evaluate the efficacy and safety of anlotinib plus fulvestrant in patients with HR-positive/HER2-negative metastatic or unresectable breast cancer who had previously been treated with aromatase inhibitor (AI)- or CDK4/6 inhibitor−based therapy.
Eligible patients were women aged 18 to 75 years with histologically confirmed HR-positive/HER2-negative breast cancer, an ECOG performance status of 0 to 1, and disease relapse within 12 months of completing >24 months of adjuvant AI therapy, or progression after >6 months of AI therapy in the metastatic setting. Patients received 500 mg of fulvestrant administered intramuscularly on days 1 and 15 of the first cycle, followed by day 1 of each subsequent 28-day cycle. Additionally, patients were treated with 12 mg of oral anlotinib once daily for 2 weeks followed by a 1-week treatment break in a 21-day cycle. Premenopausal or perimenopausal women also received ovarian function suppression. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety.
The data cutoff date of the study was August 20, 2025. A total of 40 patients were enrolled between August 2021 and April 2025, with a median age of 56.5 years (range, 48.0-62.8). Of the enrolled patients, 21 had previously been treated with CDK4/6 inhibitor therapy. After a median follow-up time of 27.1 months (95% confidence interval [CI], 17.2-36.9), the median PFS was 5.9 months (95% CI, 1.3-10.6), while the median OS was not yet reached at the time of data cutoff. The ORR was 20.0%, with a partial response (PR) observed in 8 patients, and the disease control rate was 75.0%, with stable disease (SD) noted in 22 patients. The CBR was 37.5%, as 15 patients experienced a PR or SD >6 months. Analysis revealed a median PFS of 9.6 months (95% CI, 2.3-22.8) for patients who had not previously received CDK4/6 inhibitor therapy, and 5.6 months (95% CI, 1.9-9.1) for patients who had. Treatment-emergent adverse events (TEAEs) of any grade were reported in 92.5% of patients, with the most common TEAEs being hypertension (40.0%), increased gamma-gutamyl transferase levels (22.5%), proteinuria (22.5%), decreased thyroid-stimulating hormone (20.0%), hypertriglyceridemia (20.0%), and hand-foot syndrome (20.0%). Grade 3 TEAEs occurred in 12 (30.0%) patients, with the most common being hypertension (20.0%).
The combination of anlotinib and fulvestrant demonstrated promising efficacy and an acceptable safety profile in patients with HR-positive/HER2-negative metastatic breast cancer who had progressed after AI- or CDK4/6 inhibitor−based therapy. Further investigation is warranted to confirm these findings and evaluate long-term outcomes.
Source: Wang X, Shao X, Chen W, et al. A phase II trial of anlotinib and fulvestrant in patients with HR-positive and HER2-negative, secondary hormone resistant, metastatic breast cancer. Presented at: ESMO Congress 2025. October 20, 2025; Berlin, Germany. Abstract 509P.