Editor’s Note: Brain metastasis from breast cancer has a high incidence, second only to lung cancer . Previous studies have shown that patients with brain metastases have poorer survival compared to those without brain metastases, with HER2-negative breast cancer brain metastasis patients having an even worse prognosis . Due to the blood-brain barrier (BBB), many drug treatments have limited intracranial objective response rates (ORR). Utidelone, a novel microtubule inhibitor developed in China, has shown potential for treating brain metastases due to its unique physicochemical properties that allow it to penetrate the BBB. At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, a multicenter phase II study led by Professor Min Yan from Henan Cancer Hospital was selected for presentation. This study explored the efficacy and safety of utidelone combined with bevacizumab in treating HER2-negative breast cancer brain metastases. "Oncology Frontier" invited Professor Min Yan to discuss the progress in treating breast cancer brain metastases, the study design and findings, and future perspectives.Oncology Frontier: First, could you talk about the current progress in treating HER2-negative breast cancer brain metastasis (BCBM)?
Professor Min Yan: Brain metastasis is common in breast cancer, with higher rates in triple-negative and HER2-positive cases. A retrospective analysis of 16,703 patients with metastatic breast cancer (MBC) showed brain metastasis rates of 38% for TNBC, 30-50% for HER2-positive, and relatively lower rates of 19% for HR+/HER2-negative cases. Patients with brain metastasis have poor survival outcomes, and those with HER2-negative breast cancer brain metastasis have an even worse prognosis. HER2-positive breast cancer brain metastasis patients have a median progression-free survival (mPFS) of 4-15 months and a median overall survival (mOS) of over 18 months. HR+/HER2-negative breast cancer brain metastasis patients have an mPFS of about 4-6 months and an mOS of up to 16 months . TNBC brain metastasis patients have an mPFS of only 2.8 months and an mOS of 6.8 months . The treatment of brain metastasis is still primarily local, such as radiotherapy or surgery, supplemented by drug treatment. Due to the BBB and blood-tumor barrier (BTB), many drugs that are effective for extracranial metastasis have poor penetration into the brain, making it difficult to achieve effective drug concentrations intracranially . Recently, small molecule TKIs and novel ADC drugs have brought survival benefits to HER2-positive breast cancer brain metastasis patients, and drug treatment strategies have been included in guidelines. However, for HER2-negative breast cancer brain metastasis, there is no approved systemic drug treatment, and these patients are often excluded from large clinical trials. Therefore, there is a significant unmet clinical need for this patient group, and finding new drugs and treatment methods to improve survival is a key direction.
Oncology Frontier: Can you tell us about the design and main findings of the study on utidelone combined with bevacizumab for brain metastasis?
Professor Min Yan: The study (NCT05357417) was designed based on the following data: First, previous small-sample studies have shown potential efficacy of bevacizumab in treating breast cancer brain metastasis, and bevacizumab has been recommended in the CSCO clinical diagnosis and treatment expert consensus for breast cancer brain metastasis. Second, utidelone is a novel epothilone-class microtubule inhibitor, which is not a substrate of P-glycoprotein and does not bind to P-glycoprotein on cancer cell membranes, avoiding resistance due to pump-out mechanisms. Preclinical studies have shown that utidelone maintains high drug concentrations in brain tissue, suggesting potential for treating breast cancer brain metastasis. Third, in our clinical practice, we found that the combination of these two drugs was effective for asymptomatic active brain metastasis. Based on these data, our team designed a prospective, double-cohort clinical study to explore the efficacy and safety of utidelone combined with bevacizumab in patients with breast cancer brain metastasis.
The inclusion criteria for patients were: Cohort A: HER2-negative breast cancer patients; Cohort B: HER2-positive breast cancer patients who had progressed after trastuzumab and TKI treatment. Patients were ≥18 years old, had untreated brain metastases or brain metastases that progressed after radiotherapy, and had at least one measurable intracranial lesion. Patients received intravenous utidelone (30 mg/m2, days 1-5) and bevacizumab (15 mg/kg every 3 weeks) until disease progression or intolerable adverse reactions. The primary endpoint was central nervous system objective response rate (CNS-ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.
At this ASCO conference, we first reported the CNS-ORR and PFS results for Cohort A. From May 5, 2022, to October 25, 2023, a total of 47 patients were enrolled, with a median age of 53 years (range, 45-59 years). Among them, 35 patients had new active brain metastases without prior local treatment, and 12 patients had brain metastases that progressed after radiotherapy. The overall CNS-ORR was 42.6%. As of January 8, 2024, the median follow-up time was 14.6 months, and the median PFS was 7.7 months (95% CI: 5.5-10.8). For HR+/HER2-negative patients, the CNS-ORR was 33.3%, and the median PFS was 5.9 months. For HR-/HER2-negative patients, the CNS-ORR was 55%, and the median PFS was 8.4 months (Table 1). Adverse events (AEs) were mainly grade 1-2, with the most common being peripheral neuropathy (89.4%), elevated ALT/AST (59.6%), decreased white blood cell count (51.1%), decreased neutrophil count (68.1%), anemia (51.1%), diarrhea (38.3%), constipation (29.8%), decreased platelet count (21.3%), and elevated creatinine (21.3%). The study confirmed that utidelone has good anti-tumor activity in brain metastases and controllable safety, providing a new treatment option for HER2-negative breast cancer brain metastasis patients.
Oncology Frontier: What are your expectations and prospects for future research on BCBM treatment?
Professor Min Yan: From last year’s ESMO to this year’s ASCO conference, data on utidelone in the field of breast cancer treatment have been gradually released. At the 2023 ESMO conference, the preliminary data from the UTOBIA-BM [20] study on 11 patients showed a CNS-ORR of 73% and a CNS-CBR of 91% for the utidelone + etoposide + bevacizumab regimen, indicating the antitumor activity of utidelone in breast cancer brain metastasis patients. This study is ongoing. The data from Cohort A of the utidelone combined with bevacizumab study presented at this ASCO conference confirmed the efficacy and safety of this regimen for HER2-negative patients. The study on the HER2-positive cohort is ongoing. Future directions may include expanding the sample size for this regimen in real-world studies, researching brain metastasis in different molecular subtypes of breast cancer, studying brain metastasis in different cancers (such as lung cancer), and exploring different combination regimens with utidelone for brain metastasis. These efforts aim to bring survival benefits to more brain metastasis patients.
For the clinical application of utidelone-based regimens in brain metastasis, the future looks promising. Based on the above data, the US FDA approved utidelone as an orphan drug for “breast cancer brain metastasis” in March 2024. In the future, it is worth exploring its application not only in breast cancer but also in brain metastasis from lung cancer, melanoma, and other cancers. Additionally, we hope to see more innovative drugs with BBB permeability developed and applied clinically to provide more effective treatment options for brain metastasis patients. We encourage everyone to continue to follow and participate in this field of research, providing more evidence-based medicine to collectively advance brain metastasis treatment.
