A phase II trial, SUT_EXE-08, investigated the efficacy and safety of neoadjuvant sunitinib in combination with exemestane for postmenopausal women with ER+/HER2- localized breast cancer. The study successfully identified a tolerable dose of sunitinib that can be combined with exemestane as preoperative endocrine therapy (ET) in this patient population.
The recommended dosage from the study is 25 mg exemestane plus 25 mg sunitinib in a 3-weeks ON/1 OFF regimen. This regimen was chosen due to tolerability issues observed with continuous regimens of sunitinib at higher doses (37.5 mg or 25 mg daily). The standard sunitinib dose for gastrointestinal stromal tumors and advanced renal cell carcinoma is 50 mg daily on a 4-weeks on/2-weeks off schedule, while neuroendocrine tumors are treated with 37.5 mg daily without interruption.
Safety and Tolerability
Hypertension was a significant toxicity, with Grade 3 hypertension observed in 22% of patients. This aligns with previous studies of antiangiogenic agents in breast cancer, such as the LEA trial, which evaluated bevacizumab plus endocrine therapy. While some research suggests a correlation between hypertension during antiangiogenic treatment and improved outcomes, this relationship was not assessed in the current study due to the small sample size.
Efficacy Outcomes
The combination therapy demonstrated promising efficacy, with 66.6% of patients achieving a clinical objective response and 50% showing a partial radiological response as measured by MRI. Historical data shows that single-agent neoadjuvant exemestane yields overall response rates between 51% and 63%. In this trial, 40% of patients were able to undergo breast-conserving surgery (BCS), a rate similar to that seen with neoadjuvant exemestane alone. No patients achieved a pathological complete response (pCR).
Biomarker Analysis
An extensive translational research component of the study aimed to identify biomarkers predictive of response to the combination therapy. A statistically significant reduction in VEGFR-2 plasma levels was observed after four weeks of treatment. There was also a trend suggesting a correlation between baseline ANG-2 levels and radiological response (p = 0.08). The study also found that the combination of exemestane and sunitinib was able to significantly downregulate ER (p = 0.037) as well as PgR (p = 0.01).
Impact on Tumor Biology
Assessment of paired tumor biopsies revealed changes in tumor biology, with some tumors potentially transforming to a luminal A subtype or shifting to a basal subtype. These observations suggest that the combination of exemestane and sunitinib can significantly alter tumor biology. However, some upregulated genes are also associated with tumor growth, as EGFR, MYC, SFRP1 and FOXC1.
Limitations and Future Directions
The study has several limitations, including its non-randomized design, small sample size, and the fact that it was conducted several years ago. Additionally, the list of genes analyzed was limited, potentially overlooking other relevant genetic factors. The development of sunitinib for breast cancer was discontinued by Pfizer in favor of other tumor settings. Despite these limitations, the findings provide valuable insights into the safety, benefits, and biological effects of combining an antiangiogenic drug with hormone therapy in early-stage breast cancer. This trial represents the first one combining sunitinib with an aromatase inhibitor in the neoadjuvant setting, marking a novel approach in ER+/HER2-negative breast cancer.
