Triple combination therapy trial for HR+/HER2− breast cancer halts early due to toxicity concerns

HR+/HER2− breast cancer constitutes approximately 65–75% of all breast cancer cases worldwide. Although CDK4/6 inhibitors have substantially extended progression-free survival (PFS), up to 60% of patients derive no clinical benefit from these agents, underscoring the urgent need for more effective therapeutic strategies. Preclinical evidence has suggested synergistic antitumor activity when angiogenesis inhibitors are combined with CDK4/6 inhibitors, prompting clinical investigation of this combinatorial approach. 

Dr. Min Yan from the Department of Breast Disease at Henan Cancer Hospital led an investigator-initiated, single-center, open-label phase Ib/II trial to evaluate the triple combination of famitinib, dalpiciclib, and fulvestrant. "Although preclinical evidence supports synergistic effects between antiangiogenic therapies and CDK4/6 inhibitors, clinical data on this combination remain limited," Dr. Yan noted. "We therefore initiated this trial to determine whether this regimen could address the substantial unmet clinical needs of the target patient population." The findings were published online in the Chinese Medical Journal on July 7, 2026. 

A total of 46 eligible patients were enrolled. In the phase Ib dose-finding phase (n = 18), the recommended phase II dose (RP2D) was established as famitinib 10 mg daily plus dalpiciclib 100 mg daily in combination with fulvestrant. In the phase II cohort (n = 28), the confirmed objective response rate (ORR) was 51.9% and the disease control rate (DCR) was 92.6%, thereby meeting the prespecified efficacy threshold for the first-stage analysis. 

However, the median PFS was 15.7 months, which did not demonstrate an advantage over current standard first-line regimens such as ribociclib plus fulvestrant, which has shown a median PFS of 20.5 months in similar patient populations.

The ORR observed in our trial was numerically higher, but this did not translate into a longer PFS. This may be attributable to the high rate of dose reductions necessitated by adverse events, which likely compromised dose intensity and long-term efficacy." 

Dr. Min Yan, Department of Breast Disease, Henan Cancer Hospital

Safety analyses revealed that the most common grade 3 or higher (≥3) treatment-related adverse events (TRAEs) were hematologic, primarily decreased neutrophil count (96.4%), decreased leukocyte count (75.0%), and decreased platelet count (10.7%). Nearly all patients required dose reductions due to adverse events. The addition of famitinib exacerbated hematologic toxicities beyond those seen with either agent alone, necessitating frequent dose reductions that likely undermined treatment efficacy-a phenomenon the researchers attribute to a potential CYP3A4-mediated drug–drug interaction between famitinib and dalpiciclib. 

Exploratory biomarker analyses did not show statistically significant differences in outcomes based on PIK3CA or BRCA1/2 mutation status, though patients with these mutations had numerically shorter PFS compared to wild-type groups. 

Due to the observed safety concerns and the lack of clear superiority over standard therapies, patient enrollment was terminated early following a comprehensive benefit–risk assessment. 

"Our findings suggest that angiogenesis inhibitors may not represent a preferred option in the frontline treatment of HR+/HER2− breast cancer, but they may have greater potential in more aggressive subtypes like triple-negative breast cancer or refractory disease," concluded Dr. Yan. 

The researchers hope that this study provides valuable insights for future clinical trial design and underscores the importance of rational combination strategies and patient selection in oncology drug development.