Abstract
Background
Eribulin mesylate is a novel, nontaxane, microtubule dynamics inhibitor. In this study, we assessed the efficacy and safety of eribulin versus eribulin plus the oral small-molecule tyrosine kinase inhibitor anlotinib in patients with locally recurrent or metastatic breast cancer.
Patients and methods
In this single-center, open-label, phase II clinical study (NCT05206656) conducted in a Chinese hospital, patients with human epidermal growth factor receptor 2 (HER2)-negative, locally recurrent or metastatic breast cancer previously treated with anthracycline- or taxane-based chemotherapy were randomized (1 : 1) to receive eribulin alone or in combination with anlotinib. The primary efficacy endpoint was investigator-assessed progression-free survival (PFS).
Results
From June 2020 to April 2022, a total of 80 patients were randomly assigned to either eribulin monotherapy or eribulin plus anlotinib combination therapy, with 40 patients in each group. The data cut-off was 10 August 2022. The median PFS was 3.5 months [95% confidence interval (CI) 2.8-5.5 months] for eribulin and 5.1 months (95% CI 4.5-6.9 months) for eribulin plus anlotinib (hazard ratio = 0.56, 95% CI 0.32-0.98; P = 0.04). The objective response rates were 32.5% versus 52.5% (P = 0.07), respectively, and disease control rates were 67.5% versus 92.5% (P = 0.01), respectively. Patients <50 years of age, with an Eastern Cooperative Oncology Group performance status score of 0, visceral metastasis, number of treatment lines of four or more, hormone receptor negative (triple-negative), and HER2 low expression appeared to benefit more from combined treatment. The most common adverse events in both groups were leukopenia (n = 28, 70.0%, patients in the eribulin monotherapy group versus n = 35, 87.5%, patients in the combination therapy group), aspartate aminotransferase elevations (n = 28, 70.0%, versus n = 35, 87.5%), neutropenia (n = 25, 62.5%, versus n = 31, 77.5%), and alanine aminotransferase elevations (n = 25, 62.5%, versus n = 30, 75.0%).
Conclusion
Eribulin plus anlotinib can be considered an alternative treatment option for HER2-negative locally advanced or metastatic breast cancer.
Key words: breast cancer, eribulin, anlotinib, efficacy, safety, biomarker
Highlights
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Eribulin combined with anlotinib can significantly improve the PFS of eribulin monotherapy.
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Combination therapy group has manageable toxicity with similar adverse event spectrum compared with the monotherapy group.
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Circulating tumor DNA aberrations in PIK3CA, ESR1, GATA3 (PEG) were marginally related to the higher objective response rate in the eribulin plus anlotinib group.
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Eribulin plus anlotinib can be considered an alternative treatment option for HER2-negative advanced breast cancer.
Introduction
Female breast cancer was the most commonly diagnosed cancer in 2020,1 with human epidermal growth factor receptor 2 (HER2)-negative tumors accounting for ∼70%-80% of all breast cancers.2 Although anthracycline- or taxane-based regimens are commonly used in the treatment of breast cancer, for patients with HER2-negative metastatic breast cancer (MBC), particularly those with heavily pretreated disease and limited treatment options, there is an urgent need for new therapeutic drugs, and strategies to increase access to treatment, to improve overall survival (OS).3
Eribulin is an inhibitor of microtubule dynamics that belongs to the halichondrin class of antineoplastic agents. It has a novel and distinct mode of action compared with taxanes and vinca alkaloids and binds predominantly to a small number of high-affinity sites on the growing (plus) ends of microtubules.4 Eribulin also has several noncytotoxic effects, including vascular remodeling, reversal of the epithelial-to-mesenchymal transition, induction of differentiation, and suppression of migration and invasion.5 Based on results from several phase III clinical trials,5, 6, 7 eribulin has become an established therapy for patients with previously treated MBC. In EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin), the first phase III clinical trial of eribulin, patients treated with eribulin had significantly longer OS compared with those receiving treatment of the physician’s choice (13.1 versus 10.6 months).7 The most common adverse events (AEs) to eribulin were neutropenia (52.0%), asthenia/fatigue (54.0%), and alopecia (45.0%).7 Eribulin not only can improve patients’ OS with manageable adverse reactions, but also can bring a new breakthrough for the treatment of patients with advanced breast cancer.
Tumor angiogenesis plays an important role in tumor growth and invasion.8 Bevacizumab is the first antiangiogenic monoclonal antibody. Multiple studies have confirmed that the combination of bevacizumab with chemotherapy can significantly improve progression-free survival (PFS) in patients with MBC.9,10 Several clinical studies have also confirmed the efficacy of eribulin combined with bevacizumab, with a median PFS of 8.3 months as first-line treatment11 and 6.2 months as second-line treatment12 in patients with HER2-negative MBC, with an acceptable safety profile.11,12 In a multicenter, real-world study from China, treatment with eribulin plus bevacizumab resulted in a longer median PFS compared with eribulin alone (5.4 versus 3.5 months; P = 0.046) in patients with MBC.13 However, currently there is no evidence that bevacizumab can improve OS when added to either chemotherapy or eribulin in patients with MBC.9,11
Anlotinib is a new antiangiogenic small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptors (VEGFRs) 1-3, fibroblast growth factors receptors (FGFRs) 1-4, platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β, and stem cell factor receptors, resulting in inhibition of tumor angiogenesis and growth and promotion of autophagy and apoptosis.3,14, 15, 16, 17 Anlotinib has demonstrated strong antitumor efficacy in a range of solid tumors in several phase II and III clinical trials, including in HER2-negative breast cancer.3 The most common AEs were hypertension (57.8%), elevated thyroid-stimulating hormone (34.6%), and hand-foot syndrome (23.1%).3
Based on the efficacy of eribulin and anlotinib and their different AEs profiles, we deemed it appropriate to use the two drugs in combination. A previous case report has shown that this combination yielded promising efficacy and safety.18 However, no randomized, controlled trials of eribulin plus anlotinib have been carried out to date. Therefore this study was undertaken to explore the efficacy and safety of eribulin combined with anlotinib in patients with HER2-negative, locally recurrent breast cancer or MBC. The potential predictive value of several biomarkers was also evaluated.
Patients and methods
Patients
Eligible patients were aged ≥18 years with histologically or cytologically confirmed locally recurrent or MBC. Patients had to have HER2-negative tumors, as confirmed by immunohistochemistry (score 0 to 2) or fluorescence in situ hybridization (negative); to be previously treated with anthracycline- or taxane-based chemotherapy regimens (at least one line of chemotherapy in the metastatic setting or a recurrence time of <1 year from the end of adjuvant or neoadjuvant chemotherapy); to have progression after at least one line of endocrine therapy for hormone receptor-positive/HER2-negative patients; to never receive eribulin mesylate treatment or antiangiogenetic therapy; to have measurable disease according to RECIST version 1.119; and to have an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-2. Brain metastases with stable disease or without clinical symptom were permitted.
Exclusion criteria were serious heart disease, uncontrollable hypertension, history of heavy hemorrhage, and recent operation within 3 months.
All enrolled patients provided informed consent. The study was approved by an institutional research ethics board and conducted in accordance with the Declaration of Helsinki, guidelines of the International Conference on Harmonisation Good Clinical Practice and local ethical and legal requirements. The trial was registered with the ClinicalTrials.gov registry (NCT05206656).
Study design
This was a prospective, single-center, open-label, randomized phase II clinical study carried out at the Hunan Cancer Hospital, Changsha, Hunan, China. Patients were randomized (1 : 1) to receive eribulin (1.4 mg/m2, intravenously, on days 1 and 8), either alone or in combination with anlotinib (fixed dose, 10 or 12 mg, orally, once daily for 14 consecutive days), in 21-day cycles. Randomization was stratified according to visceral metastases, HR status (positive or negative), and disease characteristics (recurrent disease or de novo stage IV).
Assessments and endpoints
Computed tomography or magnetic resonance imaging was used to evaluate treatment efficacy every 6 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Safety was monitored with AE reporting based on Common Terminology Criteria for Adverse Events version 5.0, regular clinical laboratory tests, and physical examinations. The primary endpoint was PFS, defined as the time between randomization and the date of first documentation of disease progression or death from any cause, whichever occurred first, with progression determined by the investigator according to RECIST version 1.1. PFS was also evaluated in a post hoc analysis in subgroups defined by age, ECOG PS, visceral metastases, HR status, and treatment history. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. ORR was defined as the proportion of patients who achieved a best overall response of complete response or partial response. DCR was defined as the proportion of patients who achieved a best overall response of complete response, partial response, or stable disease. Exploratory endpoints included the evaluation of circulating tumor DNA (ctDNA) and blood tumor mutation burden (bTMB) biomarkers.
Biomarker analyses
All biomarker analyses were prospectively planned. Blood samples were obtained at baseline, with next-generation sequencing of 1021 genes and bTMB calculations carried out on ctDNA. Detailed protocols for ctDNA sequencing and bTMB calculation have been described in detail previously20, 21, 22 and are provided in the Supplementary Appendix, available at https://doi.org/10.1016/j.esmoop.2023.101563).
Statistical analyses
A two-sided log-rank test with an overall sample size of 69 patients (34 in the control group and 35 in the treatment group) achieves 80.4% power at a 0.05 significance level to detect a hazard ratio (HR) of 0.47 when the control group median survival time is 3.6 months.23 The study lasts for 18 months, in which patient accrual (entry) occurs in the first 6 months. Considering loss of follow-up, 40 patients in each group will be enrolled in this study.
To compare categorical variables, Pearson’s χ2 test or Fisher’s exact test were used. PFS was estimated by the Kaplan–Meier method and survival curves were compared using the log-rank test. HRs with corresponding 95% confidence intervals (CIs) were estimated from a Cox proportional hazards model. All statistical tests were two-sided, with P <0.05 were considered significant. Pearson’s χ2 test, log-rank test, and Cox regression analysis were conducted using SPSS software (version 23, IBM SPSS Inc., Armonk, NY). Kaplan–Meier survival curves were plotted using the R package ‘survival’ in R software (version 3.6.0; Institute for Statistics and Mathematics, Vienna, Austria).
Results
Patient characteristics
Between June 2020 and April 2022, 80 patients were enrolled into the study and randomized to receive and treatment. Of these, 40 were randomized to receive eribulin monotherapy and 40 patients were randomized to receive eribulin plus anlotinib combination therapy (Figure 1).
Figure 1.
Trial profile. Diagram indicating participant numbers and disposition through the course of the trial.
Baseline characteristics were generally balanced between the treatment groups (Table 1). Overall, 73.8% (59/80) of patients had visceral metastases and 51.3% (41/80) had hormone receptor-positive tumors. Study therapy was administered second line, third line, fourth line, and beyond fourth line in 31.3% (25/80), 22.5% (18/80), 16.3% (13/80), and 30.0% (24/80) of patients, respectively.
Table 1.
Demographics and disease characteristics
| Variable | Eribulin (n = 40), n (%) | Eribulin + anlotinib (n = 40), n (%) |
|---|---|---|
| Age (years) | ||
| <50 | 21 (52.5) | 23 (57.5) |
| ≥50 | 19 (47.5) | 17 (42.5) |
| Disease characteristic | ||
| Recurrent disease | 37 (92.5) | 35 (87.5) |
| De novo stage IV | 3 (7.5) | 5 (12.5) |
| Pathology | ||
| Invasive ductal carcinoma | 37 (92.5) | 39 (97.5) |
| Noninvasive ductal carcinoma | 3 (7.5) | 1 (2.5) |
| Side | ||
| Left | 19 (47.5) | 24 (60.0) |
| Right | 21 (52.5) | 16 (40.0) |
| Metastatic sites | ||
| Visceral | 29 (72.5) | 30 (75.0) |
| Lymph node | 28 (70.0) | 31 (77.5) |
| Chest wall | 12 (30.0) | 10 (25.0) |
| Liver | 19 (47.5) | 19 (47.5) |
| Lung | 19 (47.5) | 17 (42.5) |
| Bone | 25 (62.5) | 21 (52.5) |
| Brain | 6 (15.0) | 3 (7.5) |
| ECOG PS | ||
| 0 | 27 (67.5) | 30 (75.0) |
| 1-2 | 13 (32.5) | 10 (25.0) |
| Hormone receptor (most recent result) | ||
| Positive | 24 (60.0) | 17 (42.5) |
| Negative | 16 (40.0) | 23 (57.5) |
| ER status | ||
| Positive | 20 (50.0) | 15 (37.5) |
| Negative | 20 (50.0) | 25 (62.5) |
| PR status | ||
| Positive | 15 (37.5) | 7 (17.5) |
| Negative | 25 (62.5) | 33 (82.5) |
| HER2 status | ||
| Negative | 24 (60.0) | 20 (50.0) |
| Low expression | 16 (40.0) | 20 (50.0) |
| Number of prior therapy lines | ||
| 1 | 10 (25.0) | 15 (37.5) |
| 2 | 8 (20.0) | 10 (25.0) |
| 3 | 9 (22.5) | 4 (10.0) |
| ≥4 | 13 (32.5) | 11 (27.5) |
| Prior therapies | ||
| Surgery | 38 (95.0) | 35 (87.5) |
| Radiation therapy | 16 (40.0) | 20 (50.0) |
| Neoadjuvant therapy | 7 (17.5) | 10 (25.0) |
| Adjuvant chemotherapy | 34 (85.0) | 32 (80.0) |
| Endocrine therapy | 25 (62.5) | 22 (55.0) |
ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PR, progesterone receptor.
Efficacy
At data cut-off (10 August 2022), 10 patients (12.5%) remained on treatment, 5 in the eribulin monotherapy group and 5 in the eribulin plus anlotinib group.
The primary endpoint was met and the median PFS was 5.1 months (95% CI 4.5-6.9 months) for patients receiving eribulin plus anlotinib versus 3.5 months (95% CI 2.8-5.5 months) for eribulin monotherapy (HR = 0.56, 95% CI 0.32-0.98; P = 0.04; Figure 2). The ORR was higher with eribulin plus anlotinib than eribulin alone (52.5% versus 32.5%; P = 0.07), as was the DCR (92.5% versus 67.5%; P = 0.01; Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2023.101563). The efficacy of different treatment lines (lines 2, 3, 4, and >4) is shown in Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2023.101563. Even among patients with breast cancer with more than four lines of treatment, there is still 54.5% ORR and 100.0% DCR in the eribulin plus anlotinib group (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2023.101563). Tumor shrinkage was noted in 82.5% (33/40) and 65.0% (26/40) of the patients in the eribulin plus anlotinib and eribulin monotherapy groups, respectively (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2023.101563). However, OS has not been reached at this stage.
Figure 2.
Kaplan–Meier curve for progression-free survival in patients treated with eribulin monotherapy or eribulin plus anlotinib. E, eribulin; E+A, eribulin plus anlotinib; PFS, progression-free survival.
In the post hoc analysis of PFS, HRs favored the combination of eribulin plus anlotinib over eribulin monotherapy in most subgroups (Figure 3). Patients <50 years of age and those with an ECOG PS score of 0, visceral metastases, four or more treatment lines, hormone receptor-negative status, and HER2 low expression appeared to gain the most benefit from combination treatment. For patients with hormone receptor-positive/HER2-negative cancer, the median PFS was 4.7 months for eribulin plus anlotinib and 4.2 months for eribulin alone (HR = 0.80, 95% CI 0.35-1.80; P = 0.58; Supplementary Figure S2A, available at https://doi.org/10.1016/j.esmoop.2023.101563). For patients with triple-negative breast cancer, the median PFS was 5.7 months for eribulin plus anlotinib and 2.8 months for eribulin alone (HR = 0.39, 95% CI 0.02-0.87; P = 0.02; Supplementary Figure S2B, available at https://doi.org/10.1016/j.esmoop.2023.101563).
Figure 3.
Forest plot of hazard ratios for progression-free survival. CI, confidence interval; E, eribulin; E+A, eribulin plus anlotinib; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; HR, hazard ratio; PR, progesterone receptor.
Safety
The incidence of treatment-emergent AEs of any grade was 97.5% in the eribulin monotherapy group and 100% in the eribulin plus anlotinib combination therapy group. The most common AEs of any grade were leukopenia (n = 28, 70.0%, patients in the eribulin monotherapy group versus n = 35, 87.5%, patients in the combination therapy group), aspartate aminotransferase elevations (n = 28, 70.0% versus n = 35, 87.5%), neutropenia (n = 25, 62.5% versus n = 31, 77.5%), and alanine aminotransferase elevations (n = 25, 62.5% versus n = 30, 75.0%; Table 2). The incidence of grade 3-4 AEs was 50.0% in both groups, the most common of which were neutropenia (n = 15, 37.5%, patients in the eribulin monotherapy group versus n = 15, 37.5%, patients in the combination therapy group), leukopenia (n = 6, 15.0% versus n = 6, 15.0%), and aspartate aminotransferase elevations (n = 3, 7.5% versus n = 7, 17.5%). Of the 80 patients, only 1 patient discontinued treatment, and was assigned to eribulin monotherapy. No deaths related to an AE were reported in this study.
Table 2.
Adverse events of all grades
| Adverse events | Eribulin (n = 40) |
Eribulin + anlotinib (n = 40) |
||||
|---|---|---|---|---|---|---|
| All grades, n (%) | Grade 3, n (%) | Grade 4, n (%) | All grades, n (%) | Grade 3, n (%) | Grade 4, n (%) | |
| Hematologic | ||||||
| Leukopenia | 28 (70.0) | 6 (15.0) | 0 (0.0) | 35 (87.5) | 6 (15.0) | 0 (0.0) |
| Neutropenia | 25 (62.5) | 14 (35.0) | 1 (2.5) | 31 (77.5) | 8 (20.0) | 7 (17.5) |
| Anemia | 20 (50.0) | 2 (5.0) | 0 (0.0) | 9 (22.5) | 0 (0.0) | 0 (0.0) |
| Thrombocytopenia | 5 (12.5) | 0 (0.0) | 1 (2.5) | 3 (7.5) | 0 (0.0) | 0 (0.0) |
| Nonhematologic | ||||||
| Aspartate transaminase increased | 28 (70.0) | 3 (7.5) | 0 (0.0) | 35 (87.5) | 7 (17.5) | 0 (0.0) |
| Alanine aminotransferase increased | 25 (62.5) | 2 (5.0) | 0 (0.0) | 30 (75.0) | 3 (7.5) | 0 (0.0) |
| Hypertriglyceridemia | 9 (22.5) | 0 (0.0) | 0 (0.0) | 16 (40.0) | 0 (0.0) | 0 (0.0) |
| Nausea/decreased appetite | 12 (30.0) | 0 (0.0) | 0 (0.0) | 13 (32.5) | 0 (0.0) | 0 (0.0) |
| Pain | 20 (50.0) | 1 (2.5) | 0 (0.0) | 13 (32.5) | 1 (2.5) | 0 (0.0) |
| Hypertension | 2 (5.0) | 0 (0.0) | 0 (0.0) | 12 (30.0) | 0 (0.0) | 0 (0.0) |
| Hypercholesterolemia | 7 (17.5) | 1 (2.5) | 0 (0.0) | 12 (30.0) | 0 (0.0) | 0 (0.0) |
| Peripheral neuropathy | 6 (15.0) | 0 (0.0) | 0 (0.0) | 10 (25.0) | 0 (0.0) | 0 (0.0) |
| Hyperglycemia | 7 (17.5) | 0 (0.0) | 0 (0.0) | 8 (20.0) | 0 (0.0) | 0 (0.0) |
| Proteinuria | 3 (7.5) | 0 (0.0) | 0 (0.0) | 8 (20.0) | 0 (0.0) | 0 (0.0) |
| Hypocalcemia | 12 (30.0) | 0 (0.0) | 0 (0.0) | 7 (17.5) | 0 (0.0) | 0 (0.0) |
| Hypokalemia | 9 (22.5) | 0 (0.0) | 0 (0.0) | 6 (15.0) | 1 (2.5) | 0 (0.0) |
| Blood bilirubin increased | 3 (7.5) | 0 (0.0) | 0 (0.0) | 6 (15.0) | 0 (0.0) | 0 (0.0) |
| Fatigue | 9 (22.5) | 0 (0.0) | 0 (0.0) | 5 (12.5) | 0 (0.0) | 0 (0.0) |
| Pyrexia | 2 (5.0) | 0 (0.0) | 0 (0.0) | 1 (2.5) | 0 (0.0) | 0 (0.0) |
| Infection | 2 (5.0) | 2 (5.0) | 0 (0.0) | 3 (7.5) | 2 (5.0) | 0 (0.0) |
| Cough | 4 (10.0) | 0 (0.0) | 0 (0.0) | 3 (7.5) | 0 (0.0) | 0 (0.0) |
| Dizziness | 1 (2.5) | 0 (0.0) | 0 (0.0) | 3 (7.5) | 0 (0.0) | 0 (0.0) |
| Vomiting | 2 (5.0) | 0 (0.0) | 0 (0.0) | 2 (5.0) | 0 (0.0) | 0 (0.0) |
| Hypoalbuminemia | 2 (5.0) | 0 (0.0) | 0 (0.0) | 2 (5.0) | 0 (0.0) | 0 (0.0) |
| Dental ulcer | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (5.0) | 0 (0.0) | 0 (0.0) |
| Insomnia | 3 (7.5) | 0 (0.0) | 0 (0.0) | 1 (2.5) | 0 (0.0) | 0 (0.0) |
| Constipation | 2 (5.0) | 0 (0.0) | 0 (0.0) | 1 (2.5) | 0 (0.0) | 0 (0.0) |
| Hoarseness | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (2.5) | 0 (0.0) | 0 (0.0) |
| Dyspnea | 3 (7.5) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Hyponatremia | 2 (5.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
The different incidence rates of AEs between the two groups were mainly due to AEs that have previously been associated with anlotinib; for example, hypertension (n = 9, 22.5%, patients versus n = 16, 40.0%, patients) and proteinuria (n = 3, 7.5% versus n = 8, 20.0%).
Biomarker analysis
Blood samples collected from 22 patients at baseline were available for ctDNA detection (13 patients in the eribulin monotherapy group and 9 patients in the eribulin plus anlotinib combination therapy group). According to ctDNA analysis, 19 (83.4%) patients had ctDNA alterations. The median number of alterations was 6 (range 1-23). The gene mutation profiles varied by treatment line, response, and hormone receptor status (Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2023.101563). Estrogen Receptor 1 (ESR1, 8/22, 36.4%), TP53 (7/22, 31.8%), GATA Binding Protein 3 (GATA3, 5/22, 22.7%), and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA, 4/22, 18.2%) were the most frequently mutated genes. In ctDNA mutational analysis, no single gene was significantly related to the efficacy of eribulin monotherapy or eribulin plus anlotinib combination therapy (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2023.101563). However, PEG aberrations (any ctDNA aberrations in PIK3CA, ESR1, GATA3) were marginally related to the higher ORR observed in the group treated with eribulin plus anlotinib (double-sided Fisher’s exact test, P = 0.17, Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2023.101563). By contrast, PEG aberrations were not related to the ORR in the eribulin monotherapy group. In patients with PEG aberrations, a partial response was achieved by 100% of patients in the combination therapy group versus only 33% in the eribulin monotherapy group (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2023.101563). These PEG alterations appear to be sensitive to anlotinib treatment (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2023.101563).
TMB was calculated for 20 patients and included 12 (60.0%) patients with a low TMB, 7 (35.0%) patients with a high TMB, and 1 (5.0) patient with an unknown TMB (no ctDNA alternation found). The median TMB was 6.24 (range 0.00-27.84). There was no association between TMB and the efficacy of eribulin or anlotinib treatment.
Discussion
The primary endpoint of this randomized, phase II study was achieved, with a statistically significant 44% reduction in the risk of disease progression or death in patients with advanced HER2-negative breast cancer randomized to eribulin plus anlotinib combination therapy versus eribulin monotherapy (P = 0.042). Compared with patients treated with eribulin monotherapy, patients in the combination therapy group also achieved a higher ORR (52.5% versus 32.5%; P = 0.07) and a higher DCR (92.5% versus 67.5%; P = 0.01). Furthermore, the addition of anlotinib to eribulin did not increase the incidence of all grades AEs, including grade 3-4 AEs compared with eribulin alone. To the best of our knowledge, this is the first clinical trial in which the efficacy and safety of eribulin combined with anlotinib were evaluated. The results of this study indicate that this combination is superior to eribulin alone, with manageable toxicity, in patients with advanced HER2-negative breast cancer.
In this study, patients receiving eribulin plus anlotinib had a longer median PFS (5.1 months; 95% CI 4.5-6.9 months) than those receiving eribulin monotherapy (3.5 months; 95% CI 2.8-5.5 months) These results are consistent with those reported from a previous multicenter, real-world study conducted in China, in which patients with MBC treated with eribulin plus bevacizumab (representing 21.3% of all patients treated with eribulin) achieved a longer median PFS compared with patients treated with eribulin monotherapy (5.4 versus 3.5 months; P = 0.046),13 confirming the reliability of the results of this study.
In a post hoc analysis of PFS in this study, patients <50 years of age, and those with an ECOG PS score of 0, visceral metastases, four or more treatment lines, and hormone receptor-negative status were more likely to benefit from combined treatment. These results suggest that better efficacy may be achieved using eribulin combined with anlotinib in a population of younger patients with good general condition, a high tumor burden, who had been heavily pretreated, and had triple-negative breast cancer. This is helpful to guide the selection of clinical treatment strategies, but because post hoc analysis belongs to subgroup analysis, its specific clinical application value needs to be further explored.
Although promising results with eribulin plus anlotinib were achieved in this study, the strategy of combining chemotherapy and an antiangiogenic agent remains controversial, with inconsistent results reported across clinical trials. For example, in two randomized controlled trials, no significant improvements in PFS or OS were observed with the antiangiogenic VEGFR2 inhibitor ramucirumab combined with chemotherapy, compared with chemotherapy alone.24,25 Furthermore, while treatment with the VEGF inhibitor bevacizumab, which is widely used clinically, resulted in significant improvements in PFS when combined with chemotherapy for HER2-negative MBC versus chemotherapy alone, OS was not improved.9 OS data are not yet available for this study; thus further follow-up is required to determine whether the combination of eribulin plus anlotinib is associated with an OS benefit.
In addition to the novel therapeutic strategy of eribulin combined with anlotinib explored in this study, previous studies have focused on the feasibility of eribulin combined with programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors. In a phase II clinical trial in patients with hormone receptor-positive, HER2-negative MBC, eribulin combined with pembrolizumab did not improve PFS or OS in either the general population or in patients with PD-L1-positive MBC.26 In another multicenter, phase II study, a median PFS of 8.1 months was achieved with camrelizumab combined with apatinib and eribulin in patients with heavily pretreated triple-negative breast cancer. However, as this study had a single-arm design and a small study population, this treatment strategy requires further exploration.27
Neuropathy is a well-known side-effect of microtubule inhibitors and can have a significant impact on patients’ health-related quality of life. In recent studies, paclitaxel in particular has been shown to be associated with delayed recovery from chemotherapy-induced peripheral neuropathy, resulting in severe, pervasive, and long-term effects.11,28 Eribulin has a similar mechanism of action to paclitaxel, but may potentially be less neurotoxic given the more pronounced neurodegenerative effects observed with paclitaxel and greater microtubule-stabilizing effects induced by eribulin.29 An alternative approach to reduce the risk of side-effects such as neuropathy is to use a different chemotherapy combination partner. Our therapeutic strategy of eribulin combined with anlotinib may reduce the adverse reactions associated with both drugs. Our study demonstrated a similar AE spectrum and incidence, and a similar incidence of grade 3-4 AEs as reported in a prior real-world study,13 and there was no significant increase in the incidence of AEs with eribulin plus anlotinib compared with eribulin monotherapy.
Previous studies exploring therapeutic markers for chemotherapy or antiangiogenesis TKIs were generally small or retrospective in nature, thus providing limited evidence. In this study, we also attempted to identify biomarkers that may predict the efficacy of eribulin-based therapy. As we did not require patients to undergo ctDNA tests, ctDNA results were only available for 22 patients. No single gene mutation, including ESR1, TP53, GATA3, and PIK3CA, nor bTMB, was associated with efficacy. These results are unsurprising, as historically it has been difficult to identify predictive markers for the efficacy of chemotherapy. However, the small number of patients who had ctDNA and TMB tests in this study could also explain these negative results.
Previous studies have found that the low baseline neutral lymphocyte ratio is associated with better tumor response and longer PFS of arotinib.30 However, there are currently no reports on the gene biomarker of anlotinib. We found that PEG alterations may be sensitive to anlotinib treatment in this study, consistent with previous research31; however, further studies with larger sample sizes are needed.
While lower expression of epithelial–mesenchymal transition pathway genes has previously been associated with prolonged PFS with eribulin,32 no gene mutations have been identified that are clearly associated with the efficacy of eribulin. In addition, although there is some controversy, it is currently believed that higher TMB is associated with higher sensitivity to immune checkpoint inhibitor therapy. However, no studies have found a correlation between TMB and the efficacy of chemotherapy drugs, including eribulin and gemcitabine.26,32, 33, 34 In a study of predictive biomarkers for antiangiogenic TKIs, patients with breast cancer susceptibility gene A mutations had a longer PFS and OS with apatinib.35 In addition, in a small study in patients treated with anlotinib, the presence of TP53 and PIK3CA mutations were associated with significantly shorter PFS than that in patients without these mutations.3 These data appear to contradict the current finding that PEG alterations increased the efficacy of anlotinib, possibly due to the smaller sample size and the different use of anlotinib in combination with eribulin. A possible mechanism for this observation might be the antiangiogenic effect of anlotinib. Anlotinib is an inhibitor of FGFR. FGFR overexpression could activate the phosphatidylinositol-3-kinase–mammalian target of rapamycin (PI3K–mTOR) pathway and lead to endocrine therapy resistance.36 By inhibiting FGFR, anlotinib is supposed to suppress the PI3K–mTOR pathway and limit treatment resistance. Because of the relatively small sample size of ctDNA testing, we did not carry out a statistical analysis to investigate the relationship between PEG alterations and hormone receptor status. However, in the eribulin plus anlotinib group, three of four (75%) patients with PEG alterations were hormone receptor-positive and in the eribulin monotherapy group, five of six (83%) patients with PEG alterations were hormone receptor positive. These data suggest that PEG alterations were associated with hormone receptor-positive cancers. In the eribulin plus anlotinib group, more patients with PEG alterations achieved an objective response (100% versus 33.3% in the erlotinib monotherapy group), suggesting that anlotinib might be useful in suppressing PEG-activated treatment resistance in patients with hormone receptor-positive tumors. There have been no previous studies undertaken to investigate the association between TMB and the efficacy of anlotinib.
The current study has several limitations. Because of the preliminary nature of most phase II studies, the study had a small sample size. In addition, the open-label study design may have increased the risk of bias. There were also some differences in baseline characteristics between the treatment groups (no statistical difference), which may have affected the robustness of the results; however, these potential confounders did not appear to influence the efficacy of treatment (Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2023.101563). OS data are not currently available—OS will be evaluated in subsequent follow-up analyses. Because of the 100% Chinese population included in our study, the results may not be fully generalizable to broader populations. Finally, as patients were not required to take a ctDNA test at enrollment, ctDNA data were only available for 22 patients.
Conclusion
In summary, this study provides valuable data supporting the use of eribulin plus anlotinib in Chinese patients with advanced HER2-negative breast cancer. The primary endpoint was met: eribulin plus anlotinib led to a statistically significant improvement in PFS versus eribulin monotherapy in patients with HER2-negative, locally recurrent breast cancer or MBC previously treated with anthracycline- or taxane-based chemotherapy. In addition, combination therapy did not increase the incidence of AEs versus eribulin monotherapy.
Acknowledgements
We thank the patients, their families, and caregivers for their participation in the study.
Funding
This work was supported by the Hunan Provincial Natural Science Foundation of China [grant numbers 2023JJ60464], Hunan Provincial Science and Technology Department Project [grant numbers 2018SSK2120, 2018SK2124, 2019SK2032, and 2019JJ50360], the Health and Family Planning Commission of Hunan Province [grant numbers C2019070 and B2019089], the Changsha Science and Technology Project [grant numbers kq1901076, kq2004125 and kq2004137], the Chinese Anti-Cancer Association HER2 target Chinese Research Fund [grant number CORP-239-S5], and Climb Plan of Hunan Cancer Hospital [grant number ZX2021005].
Disclosure
The authors have declared no conflicts of interest.
Ethics approval and consent to participate
The study was approved by the Ethics Committee at the Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University (YYS-20200305) and registered with the ClinicalTrials.gov registry (NCT05206656).
Consent for publication
Informed consent was obtained from each patient prior to study onset.
Data availability
All data supporting the findings of this study are available from the corresponding author upon reasonable request.
Supplementary data
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data supporting the findings of this study are available from the corresponding author upon reasonable request.