Utidelone in combination with etoposide and bevacizumab in HER2-negative breast cancer patients with brain metastasis: A prospective, single-arm, phase II trial.

2012 Background: For advanced HER2 negative breast cancer patients with brain metastasis, systematic therapy has failed to yield satisfied efficacy, although bevacizumab and etoposide have shown some effectiveness as mono- or combination therapy. Novel microtubule inhibitor utidelone demonstrated good efficacy in advanced breast cancer patients in several clinical trials, and was also suggested a capability of blood-brain barrier penetration. Therefore, utidelone in combination with bevacizumab and etoposide would be a promising regimen for HER2 negative breast cancer patients with brain metastasis. Methods: Breast cancer patients with brain metastasis were enrolled and Simon’s two-stage optimal trial design was used for this trial. If more than 3 out of 13 patients showed central nervous system (CNS) response, 30 more patients would be further enrolled. The acceptable ORR was set to be 40% for the trial. Utidelone (30mg/m 2 /day, iv, d1-5), and etoposide (100mg/m 2 , iv, d1-3) were concurrently administered with bevacizumab (10mg/kg iv, d1) every 21 days for 6 cycles, followed by maintenance treatment with utidelone and bevacizumab until disease progression or unacceptable toxicity. The primary endpoint is CNS-ORR. Secondary endpoints include CNS-clinical benefit rate (CNS-CBR), CNS-PFS, PFS, and safety. Results: 34 female HER2 negative patients were enrolled, including 11 triple negative breast cancer patients and 23 patients of luminal subtype, with a median age of 52 years (range 34-74) and a median treatment lines of three. Five patients had prior brain radiotherapy and 2 patients were previously treated with brain surgery. As of December 2, 2024, the median follow up duration was 11.5 months. The CNS-ORR was 67.6% (23/34), and the CNS-CBR was 88.2% (30/34). The median PFS was 6 months (95% confidence interval [CI], 4.265-7.735). The median CNS-PFS was 15 months (95% CI, 6.760-23.240), with supportive treatment for some of the patients after extracranial progression which included etoposide re-administration, or abraxane, endocrine therapy, radiotherapy and immunotherapy. The major AE was peripheral neuropathy with 8.8% (3/34) of Grade 3, primarily classified as sensory. Most of the treatment-related AEs were grade 1 or 2 and were considered manageable and reversible. Conclusions: Utidelone in combination with etoposide and bevacizumab has shown promising anti-tumor activity and manageable toxicity in HER2 negative breast cancer patients with brain metastasis, and a randomized control trial is warrantied. Clinical trial information: NCT05781633 .