Addition of angiogenesis inhibitors to CDK4/6 inhibitors and fulvestrant in hormone receptor-positive, HER2-negative advanced breast cancer.

The role of angiogenesis inhibitors in breast cancer (BC) remains unclear. Potential synergistic activity is observed between antiangiogenic tyrosine kinase inhibitors and cyclin-dependent kinase 4/6 inhibitors. This trial evaluated the feasibility of combining the angiogenesis-targeting tyrosine kinase inhibitor famitinib with the cyclin-dependent kinase 4/6 inhibitor dalpiciclib in patients with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+/HER2-) BC. Patients with HR+/HER2- advanced BC were enrolled and treated with famitinib and dalpiciclib in combination with fulvestrant. A phase Ib dose-escalation study using a standard 3+3 design was conducted to determine the recommended phase II dose (RP2D). Phase II subsequently assessed the efficacy and safety of the RP2D. Exploratory biomarker analyses were performed to evaluate key gene mutations associated with this BC subtype, including PIK3CA and BRCA1/2. Based on dose-limiting toxicities and preliminary efficacy, daily famitinib 10 mg combined with dalpiciclib 100 mg plus fulvestrant was selected as the RP2D. An additional 28 patients were enrolled in phase II. The confirmed objective response rate (ORR) was 51.9% (95% confidence interval [CI]: 32.0%-71.3%), with a median progression-free survival (PFS) of 15.7 (95% CI: 7.3-25.4) months. The 2-year overall survival rate was 96.3% (95% CI: 76.5%-99.5%). Comparable ORRs and median PFS were observed regardless of PIK3CA or BRCA1/2 mutation status. Treatment-related adverse events of grade ≥3 were predominantly hematologic, including decreased neutrophil count (96.4%), decreased leukocyte count (75.0%), and decreased platelet count (10.7%). Patient enrollment was terminated after a comprehensive assessment of the benefit-risk profile of this regimen. Although the objective response threshold in the first stage of phase II was met, the median PFS did not demonstrate superiority over standard front-line regimens for HR+/HER2- advanced BC, and overlapping hematologic toxicities were observed. ClinicalTrials.gov (NCT05176080) and Chictr.org.cn (ChiCTR2100053950).