A phase II trial of anlotinib and fulvestrant in patients with HR-positive and HER2-negative, secondary aromatase inhibitor–resistant, metastatic breast cancer.
Authors: Wang Xiaojia , Huang Jian , Chen Wenyan , Sun Zhengkui , Liu Jian , Cui Jiuwei , Wei Songzhi , Lv Zheng , Wu Fan , Yu Tenghua 
Published: June 2024

e13065

Background: Fulvestrant is used after aromatase inhibitor (AI) failure in metastatic breast cancer but resistance develops quickly. We hypothesized that using anlotinib, a novel multi-target tyrosine kinase inhibitor, may delay fulvestrant resistance in patients (pts) and thus improve its efficacy. This single-arm, phase II trial aims to evaluate the efficacy and safety of the combined regimen in pts with HR-positive and HER2-negative, previously AI treated, locally advanced or metastatic breast cancer. Methods: The key enrolled criteria were women aged 18 years or older of any menopausal status (premenopausal or perimenopausal women received ovarian function suppression), ECOG PS 0-1, histologically confirmed HR-positive and HER2-negative breast cancer, and disease relapse within 12 months after a more than 24 months AI adjuvant setting or disease progress after a more than 6 months AI metastatic setting. Eligible pts received 500 mg fulvestrant by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days). Pts were also given 12 mg oral anlotinib once daily for 2 weeks, followed by a week off in a 21-day cycle. The primary endpoints is progression-free survival (PFS) and the secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Results: 30 pts have been enrolled from Aug 2021 to Dec 2023. After a median follow-up time of 12.9 months (95% CI, 9.0-16.8), the overall median PFS was 6.4 months (95% CI 3.4-9.5) and the mOS has not reached. In the 29 pts whose efficacy could be evaluated, the ORR was 20.7% (95% CI, 8.0-39.7) and the DCR was 79.3% (95% CI, 60.3-92.0), with partial response and stable disease recorded in 6 and 17 pts. The CBR was 41.4% (95% CI, 23.5-61.1), with 6 pts reach SD for more than 6 months. Pts who have not received CDK 4/6 inhibitors previously had longer PFS (14.8 months, 95% CI 3.7-25.9) than those who have received CDK 4/6 inhibitors (4.6 months, 95% CI 3.0-6.3) in the subgroup analysis (HR=0.33, P=0.038). At the same time, we find pts who have not received systemic chemotherapy previously also had longer PFS (9.7 months, 95% CI 6.0-13.2) than those who have received systemic chemotherapy (5.5 months, 95% CI 3.6-7.4) (HR=0.47, P=0.12). TEAEs of any grade were observed in 90.0% of pts, and the frequent AEs included hypertension (43.3%), wight loss (20.0%), proteinuria (20.0%), increased TSH (20.0%), and hand-foot syndrome (20.0%). Grade 3 TEAEs occurred in 11 (36.7%) pts, the most common of which was hypertension (26.7%). Dose reductions or discontinuation of anlotinib occurred in 12 (40.0%) pts. Conclusions: Anlotinib combined with fulvestrant showed a promising efficacy with an acceptable safety profile for patients with metastatic breast cancer previously treated with AI. Further results are expected. Clinical trial information: NCT05075512 .