Utidelone exhibits favorable responses in refractory patients with advanced breast cancer
Highlight box
Key findings
• Utidelone demonstrated favorable efficacy in heavily pretreated refractory advanced breast cancer (ABC). Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) disease achieved better outcomes. In brain metastases (BMs) patients, utidelone plus anti-angiogenic therapy achieved an intracranial disease control rate of 100%. Neurotoxicity was manageable, with no grade 4 events.
What is known and what is new?
• It is known that utidelone plus capecitabine improves survival in second-line treatment of ABC after anthracycline/taxane resistance, and that utidelone has a favorable safety profile. However, its efficacy in subsequent-line, real-world settings—especially in patients with BMs or prior cyclin-dependent kinase 4/6 inhibitor exposure—remains unknown.
• This study provides the first real-world evidence that utidelone remains effective in heavily pretreated patients (95% beyond third line), shows enhanced efficacy in HR+/HER2− patients, and suggests promising intracranial activity when combined with anti-angiogenic agents, an area not previously reported.
What is the implication, and what should change now?
• Utidelone combined with anti-angiogenic therapy should be considered a viable option for refractory ABC, including patients with BMs. Prospective trials are needed to isolate utidelone’s independent contribution and to validate its intracranial efficacy in larger cohorts.
Introduction
In recent years, the incidence of breast cancer has risen significantly, making it one of the most common malignant tumors globally (1). In China, breast cancer ranks as the leading cancer among women, and its incidence continues to rise (2). Although breast cancer at early stage has become a curable disease, 30–40% of cases progress to advanced breast cancer (ABC) (2). ABC remains essentially incurable, with 5- and 10-year survival rates of approximately 27% and 13%, respectively, and a median overall survival (OS) of only 2–3 years (3,4). For patients with ABC, the primary treatment goals are to prolong survival and improve quality of life.
Most breast cancer patients undergo perioperative therapy involving anthracyclines and/or taxanes. However, for those who experience recurrence or metastasis, there is currently no standardized treatment protocol (5,6). Epothilones, natural compounds derived from myxobacteria, exhibit a mechanism of action yet distinct from that of taxanes (7,8). This distinction suggests that patients resistant to taxanes may still respond to epothilones (9). Utidelone, a genetically engineered derivative of epothilones (10), has demonstrated significant clinical benefits. In a multicenter, randomized, controlled phase III study, the combination of utidelone and capecitabine significantly improved progression-free survival (PFS) and OS compared to capecitabine alone in metastatic breast cancer (MBC) patients with anthracycline- or taxane-resistance (11,12). Notably, utidelone is associated with lower incidences of hematological toxicity, gastrointestinal toxicity, and hepatic or renal dysfunction, positioning it as a promising therapeutic option. It provides an alternative for patients with ABC who have developed resistance to prior therapy, including anthracyclines and taxanes (11,13). Despite these promising results, there remains a scarcity of real-world clinical data. This study aims to evaluate the efficacy and safety of utidelone in the treatment of refractory ABC in real-world clinical settings. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2884/rc).
Methods
Patient inclusion
In this retrospective cohort study, we consecutively included all eligible patients who received utidelone treatment at the Cancer Hospital, Chinese Academy of Medical Sciences, Shenzhen from March 2021 to December 2023. The inclusion criteria were as follows: (I) histologically confirmed diagnosis of breast cancer; (II) unresectable breast cancer or MBC; and (III) prior exposure to anthracyclines and/or taxanes during the recurrent or metastatic stage. Patients were excluded if they met either of the following criteria: (I) completed fewer than two cycles of utidelone treatment; or (II) were lost to follow-up without efficacy evaluation. The primary endpoint of the study was PFS, while secondary endpoints included objective response rate (ORR), disease control rate (DCR), and treatment safety.
The sample size was determined by feasibility, encompassing all eligible patients who received utidelone at Cancer Hospital, Chinese Academy of Medical Sciences, Shenzhen within the specified time frame, rather than by a formal power calculation.
This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College (No. YW2023-53-1, date of approval: January 17, 2024). Due to the retrospective design of this study and patient anonymization, the Ethics Committee determined that informed consent was not required.
Patient assessments
Patients underwent spiral computed tomography (CT) or magnetic resonance imaging (MRI) scans every two treatment cycles. Additionally, physical examinations, blood tests, serum chemistry, and electrocardiograms (ECGs) were conducted at least once per cycle. Treatment efficacy was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. Tumor imaging reviews (CT/MRI) were retrieved from the hospital’s Picture Archiving and Communication System (PACS). Response assessments were performed independently by two experienced oncologists who were blinded to the clinical outcomes. Any discrepancies were resolved by consensus with a third senior investigator. The ORR was defined as the proportion of patients achieving a complete response (CR) or partial response (PR), while the DCR was defined as the proportion of patients achieving CR, PR, or stable disease (SD). PFS was calculated as the duration from the initiation of utidelone treatment to the first occurrence of disease progression or death from any cause. Adverse events were systematically monitored throughout the treatment period and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Statistical analysis
Given the exploratory and descriptive nature of this small, single-arm retrospective study, formal sample size calculation and multivariable adjustment for confounding were not performed. Baseline characteristics were summarized using descriptive statistics: medians and ranges for continuous variables, and frequencies and percentages for categorical variables. The primary efficacy endpoint, PFS, was estimated using the Kaplan-Meier method, and the median PFS with its 95% confidence interval (CI) was reported. Differences in PFS across predefined subgroups (e.g., molecular subtypes) were explored using the log-rank test. The ORR and DCR were calculated with exact binomial 95% CIs. All analyses were conducted using SPSS software (version 18.0; IBM Corp., Armonk, NY, USA). A two-sided P value of <0.05 was considered statistically significant, although all analyses were primarily descriptive.
Addressing potential bias
To minimize selection bias, we applied clear, pre-defined eligibility criteria and sought to include all consecutive eligible patients during the study period. Information bias was addressed by using standardized criteria (RECIST version 1.1 and CTCAE version 5.0) for outcome and adverse event assessment, and by having key outcomes reviewed independently. The retrospective nature of the study precludes the elimination of unmeasured confounding.
Results
Patient characteristics
A total of 20 female patients with ABC were enrolled. The median follow-up time was 21.8 months. The clinical characteristics of the cohort are summarized in Table 1. The median age of the patients was 54 years (range, 42–64 years). Among the participants, 50% (n=10) were hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−), 25% (n=5) were HER2-positive (HER2+), and the remaining 25% (n=5) were triple-negative. Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores were one for half of the patients and two for the other half.
Table 1
| Characteristics | Data |
|---|---|
| Age (years) | 54 [42–64] |
| <50 | 7 [35] |
| ≥50 | 13 [65] |
| Visceral metastasis | |
| Yes | 17 [85] |
| No | 3 [15] |
| Number of treatment lines of utidelone | 5 [2–12] |
| <3 | 1 [5] |
| ≥3 | 19 [95] |
| Combination medication | |
| Anti-antiogenic therapy ± others | 18 [90] |
| Others | 2 [10] |
| BMs | |
| Yes | 5 [25] |
| No | 15 [75] |
| Menopausal status | |
| Premenopausal | 9 [45] |
| Postmenopausal | 11 [55] |
| Molecular subtype | |
| HR+/HER2− | 10 [50] |
| HER2+ | 5 [25] |
| TNBC | 5 [25] |
| Number of metastatic sites | |
| <3 sites | 7 [35] |
| ≥3 sites | 13 [65] |
| Tumor metastasis | |
| Lymph node | 17 [85] |
| Lung | 11 [55] |
| Bone | 13 [65] |
| Liver | 15 [75] |
| Pleura | 9 [45] |
| Brain | 6 [30] |
| Other | 11 [55] |
Data are presented as median [range] or number [%]. BMs, brain metastases; HER2+, human epidermal growth factor receptor 2-positive; HR+/HER2−, hormone receptor-positive/human epidermal growth factor receptor 2-negative; TNBC, triple negative breast cancer.
Visceral metastases were present in 85% (n=17), with 65% (n=13) having metastases in three or more sites. Additionally, 25% (n=5) had brain metastases (BMs) prior to utidelone therapy. The median number of lines for utidelone was 5 (range, 2–12), with 95% of patients receiving utidelone as third-line therapy or later. All patients had previously received taxanes, capecitabine, gemcitabine, vinorelbine, or eribulin. HER2+ patients had also received anti-HER2 therapies, including trastuzumab, lapatinib, or pertuzumab. Among HR+/HER2− patients, 80% (n=8) had prior exposure to cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Regarding combination therapies, 90% (n=18) received anti-angiogenic agents (anlotinib, apatinib, or bevacizumab), while 20% (n=2) were treated with other medications.
Data on baseline demographic and clinical characteristics were complete for all 20 included patients. No missing data were present for the variables reported in Table 1.
Clinical response
The overall ORR and DCR were 15% and 80%, respectively (Figure 1, Table 2), and the median PFS was 4.7 months (95% CI: 2.98–6.42) (Figure 2). HR+/HER2− patients exhibited an ORR of 30% and a DCR of 90% (Table 2). Among patients with BMs, the intracranial ORR (iORR) and DCR (iDCR) were 20% and 100%, respectively (Table 3). Notably, one patient maintained a PR in intracranial lesions despite extracranial progression (Figure 3). Another triple-negative breast cancer (TNBC) patient showed stable intracranial disease despite extracranial progression.
Table 2
| Patients | CR | PR | SD | Non-CR/non-PD | ORR | DCR |
|---|---|---|---|---|---|---|
| All (n=20) | 0 | 3 | 12 | 1 | 15% | 80% |
| HR+/HER2− (n=10) | 0 | 3 | 6 | 0 | 30% | 90% |
Data are presented as number, unless otherwise specified. CR, complete response; DCR, disease control rate; HR+/HER2−, hormone receptor-positive/human epidermal growth factor receptor 2-negative; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Table 3
| Patient | Molecular subtype | Lines of utidelone | Age (years) | Brain radiotherapy | Combination medication | Response | iResponse |
|---|---|---|---|---|---|---|---|
| 1 | HR+/HER2− | 12 | 58 | WBRT | Anlotinib | SD | SD |
| 2 | HR+/HER2− | 4 | 45 | – | Anlotinib | PR | PR |
| 3 | HR+/HER2− | 8 | 55 | SBRT | Apatinib | PR | SD |
| 4 | TNBC | 5 | 52 | SBRT | Apatinib | PD | SD |
| 5 | HR+/HER2− | 5 | 49 | – | Anlotinib | SD | SD |
BMs, brain metastases; HR+/HER2−, hormone receptor-positive/human epidermal growth factor receptor 2-negative; iResponse, intracranial response; PD, progressive disease; PR, partial response; SBRT, stereotactic body radiation therapy; SD, stable disease; TNBC, triple-negative breast cancer; WBRT, whole brain radiation therapy.
Toxicity assessments
The most common adverse events were neurotoxicity, elevated aspartate aminotransferase (AST), anemia, leukopenia, and neutropenia (Table 4). Grade 3 or higher chemotherapy-induced peripheral neuropathy (CIPN) occurred in 15% of patients, with no grade 4 events. Four patients (20%) underwent dose reduction due to CIPN, and three discontinued treatments.
Table 4
| Adverse events | Grade 1/2 | Grade 3 | Grade 4 | All grades | Grades 3–4 |
|---|---|---|---|---|---|
| Peripheral sensory neuropathy | 14 | 3 | 0 | 17 [85] | 3 [15] |
| AST increased | 9 | 0 | 0 | 9 [45] | 0 [0] |
| ALT increased | 4 | 0 | 0 | 4 [20] | 0 [0] |
| Nausea | 1 | 0 | 0 | 1 [5] | 0 [0] |
| Diarrhea | 1 | 0 | 0 | 1 [5] | 0 [0] |
| Asthenia | 1 | 3 | 0 | 4 [20] | 3 [15] |
| White blood cell count decreased | 5 | 2 | 0 | 7 [35] | 2 [10] |
| Neutrophil count decreased | 3 | 2 | 1 | 6 [30] | 3 [15] |
| Thrombocytopenia | 1 | 1 | 0 | 2 [10] | 1 [5] |
| Anemia | 6 | 2 | 0 | 8 [40] | 2 [10] |
Data are presented as number or number [%]. ALT, alanine transaminase; AST, aspartate transaminase.
Discussion
Utidelone, a next-generation epothilone derivative, has demonstrated significant antitumor activity in both taxane-sensitive and taxane-resistant models, including multidrug-resistant cancers (unpublished data). Its unique structural modifications may contribute to improved safety while maintaining efficacy.
Our study, a single-center retrospective analysis, included heavily pretreated patients (median of five prior lines). The observed ORR of 15% and DCR of 80% align with real-world data (14), while the median PFS of 4.7 months underscores utidelone’s efficacy in refractory ABC. Notably, HR+/HER2− patients achieved a higher ORR of 30%, consistent with findings from the BG01-1312L study. Importantly, 80% of HR+/HER2− patients in our study had prior CDK4/6 inhibitor exposure, reflecting real-world clinical practice and suggesting utidelone’s utility in this population. Utidelone’s ability to cross the blood-brain barrier (BBB) is supported by preclinical data showing higher drug concentrations in brain tissue (unpublished data). In a phase II trial, utidelone combined with bevacizumab and etoposide achieved a central nervous system’s ORR (CNS-ORR) of 73% and a CNS-clinical benefit rate (CBR) of 91% in HER2− patients with BMs (15). A multicenter phase II study reported by Yan et al. demonstrated that the combination of utidelone and bevacizumab achieved an iORR of 42.6% and a median CNS-PFS of 10.6 months in breast cancer patients with BMs (16). Previous studies showed that anlotinib/apatinib could effectively cross the BBB and demonstrated intracranial antitumor activities in patients with breast cancer and lung cancer (17-22). Research by Chen et al. also indicated that apatinib combination therapy demonstrated certain efficacy in HER2− breast cancer patients with BMs, with a median OS of 10.7 months (23). Though there have been several real-world studies on utidelone, none have specifically addressed its efficacy in breast cancer patients with BMs. Our study included five BM patients, all of whom received anti-angiogenic agents (apatinib or anlotinib), achieving an iORR of 20% and an iDCR of 100%. These results suggest that utidelone, particularly in combination with anti-angiogenic therapy, may offer a viable option for BM patients. However, the subgroup analyses are based on small numbers and should be considered hypothesis-generating only. Adverse events were manageable, with neurotoxicity being the most common. The incidence of grade three or higher CIPN was 15%, consistent with prior studies (11,12).
This study has several limitations. Firstly, the small sample size (n=20) limits the statistical power and generalizability of our findings, and results should be interpreted as exploratory. As a retrospective analysis, OS could not be analyzed due to incomplete follow-up data, limiting comparisons with phase III trial outcome. Secondly, as a single-center retrospective study, our findings are subject to selection bias and unmeasured confounding, which may affect the robustness of the conclusions. Lastly, given that 90% of patients received concurrent anti-angiogenic therapy, the independent contribution of utidelone to clinical outcomes cannot be definitively determined. Future prospective trials should aim to isolate its effect.
Conclusions
Utidelone demonstrates favorable efficacy and safety in refractory ABC patients, particularly in HR+/HER2− subtypes. Its combination with anti-angiogenic therapy shows promising intracranial activity, making it a valuable option for subsequent-line treatment in MBC.
Acknowledgments
We would like to thank the patients for their participation.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2884/rc
Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2884/dss
Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2884/prf
Funding: This study was supported by
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2884/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College (No. YW2023-53-1, date of approval: January 17, 2024). Due to the retrospective design of this study and patient anonymization, the Ethics Committee determined that informed consent was not required.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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