Oey O, Wijaya W, Redfern A. Eribulin in breast cancer: Current insights and therapeutic perspectives. World J Exp Med 2024; 14(2): 92558 [PMID: 38948420 DOI: 10.5493/wjem.v14.i2.92558]
Corresponding Author of This Article
Wynne Wijaya, MD, Master’s Student, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom. wynne.wijaya@oncology.ox.ac.uk
Research Domain of This Article
Oncology
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Minireviews
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Oey O and Wijaya W contributed equally to this work; Oey O and Wijaya W performed literature searching and wrote the manuscript; Redfern A supervised and contributed substantial inputs for the improvement of the manuscript; All authors have read and approved the final manuscript.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wynne Wijaya, MD, Master’s Student, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom. wynne.wijaya@oncology.ox.ac.uk
Received: January 29, 2024 Revised: February 21, 2024 Accepted: March 20, 2024 Published online: June 20, 2024 Processing time: 141 Days and 19.2 Hours
Abstract
Eribulin is a non-taxane synthetic analogue approved in many countries as third-line treatment for the treatment of patients with metastatic breast cancer. In addition to its mitotic property, eribulin has non-mitotic properties including but not limited to, its ability to induce phenotypic reversal of epithelial to mesenchymal transition, vascular remodelling, reduction in immunosuppressive tumour microenvironment. Since approval, there has been a surge in studies investigating the application of eribulin as an earlier-line treatment and also in combination with other agents such as immunotherapy and targeted therapy across all breast cancer sub-types, including hormone receptor positive, HER2 positive and triple negative breast cancer, many demonstrating promising activity. This review will focus on the application of eribulin in the treatment of metastatic breast cancer across all subtypes including its role as an earlier-line agent, its toxicity profile, and potential future directions.
Core Tip: Eribulin is a non-taxane chemotherapeutic agent which is utilised for the treatment of locally advanced or metastatic breast cancer patients who have progressed after 2-3 lines of taxane or anthracycline-based regimen. Eribulin’s non-mitotic properties which include its anti-mesenchymal, immunomodulating and vascular remodelling features could make it a perfect candidate in becoming adjuncts to standard treatment regimen for breast cancer across different subtypes. In the era of targeted therapy, immunotherapy and antibody-drug conjugates, we review current evidence to elucidate whether eribulin still has a role to play in earlier and later-line settings both as a single agent and in combination with other agents in patients with metastatic breast cancer across all subtypes of breast cancer.
Citation: Oey O, Wijaya W, Redfern A. Eribulin in breast cancer: Current insights and therapeutic perspectives. World J Exp Med 2024; 14(2): 92558
Breast cancer is the most common cancer affecting females with around 2 million cases annually worldwide[1]. Despite improvement in survival rates of patients with breast cancer, survival outcomes for patients with advanced and metastatic breast cancer remains dismal, reflecting the need for novel and alternative therapies. While novel agents such as cyclin-dependent kinase (CDK) 4/6 inhibitors and antibody-drug conjugates have revolutionised the treatment of metastatic breast cancer, particularly estrogen-receptor positive (ER+) and triple negative breast cancer (TNBC) respectively, survival outcomes especially for patients with metastatic TNBC remains poor. Many factors account for the poor survival including but not limited to lack of apparent tumor-specific receptor or pathway to target in TNBC, drug intolerance and development of treatment resistance. Mechanistic insights into the pathophysiology of TNBC is crucial to allow development of novel therapeutic strategies. With increasing understanding of the complexity of the tumour microenvironment, there is developing interest in the utilisation of agents that are not only cytotoxic but also ones that could modulate the tumour microenvironment to mount an effective anti-tumoral response[2]. One such therapeutic agent is eribulin.
Eribulin is a synthetic analogue of halichondrin B (Figure 1) that binds to the positive ends of the microtubule through the vinca domain on the polymerization surface of b-tubulin[3-5]. Halichondrin B is a natural large polyether macrolide originally isolated in 1985 from Halichondria okadai, a rare black sea sponge off the coast of Japan[6]. Due to its complex structure and the presence of contaminants, it was difficult to use until 1998 when the complete synthesis of halichondrin B was developed by Dr. Yoshito Kishi at Harvard. Kishi discovered that the anticancer activity of halichondrin resided on the right side macrolactone as macrolactone 1 shows inhibitory activity against certain cancer cell lines[7]. Afterwards, Eisai Research Institute licensed the technology and carried out the synthesis and future development of eribulin[5].
Eribulin inhibits polymerization and consequent microtubule extension without affecting microtubule shortening[8-10]. It binds to the plus ends of microtubules, halts microtubule growth in the interphase cells without affecting the shortening phase, and forms non-productive aggregates of tubulin, leading to G2/M cell-cycle block and eventually apoptosis after prolonged mitotic blockage[11]. This mechanism is in contrast to other microtubule-targeting agents such as taxanes, epothilones and vinca alkaloids, which influence both microtubule growth and shortening[8]. This averts the assembly of mitotic spindle during prometaphase, leading to cell cycle arrest and, ultimately, to apoptosis[8]. As cancer cells divide at a more rapid rate than normal cells, they have increased susceptibility to this microtubule-targeted mechanism relative to healthy cells. In addition to its anti-mitotic mechanism of action, eribulin possesses several non-mitotic activities, many affecting the tumour microenvironment (Figure 2). This includes the phenotypic reversal of epithelial to mesenchymal transition (EMT), potentially via suppressed transforming growth factor-beta (TGF-β)/Smad signalling, with consequent inhibition of tumour invasion and metastasis. Also potentially interlinked with EMT reversal, in-vitro studies reveal substantially decreased proportions of cancer stem cells (CSC) in both ER+ and ER-negative breast cancer cell lines after eribulin exposure[12,13]. Additionally, reduction of the immunosuppressive tumour microenvironment and vascular remodelling have been described[14-17].
Figure 2 Eribulin non-mitotic mechanisms of action in cancer.
Eribulin induces phenotypic reversal of epithelial to mesenchymal transition, decreases proportions of cancer stem cells, reduces the immunosuppressive tumour microenvironment and promotes vascular remodelling.
Apart from breast cancer, eribulin is approved for the treatment of advanced or metastatic liposarcoma after progression on anthracycline therapy, where impressive survival benefits have also been observed[18]. Furthermore, significant antitumor activity has been observed against a range of preclinical cancer models, including colorectal, non-small cell lung cancer, melanoma, glioblastoma and ovarian cancer[19-23]. However, this review will concentrate on eribulin activity in breast cancer across different stages and subtypes, including discussion on its utilisation as an earlier-line treatment, toxicity profile and future directions.
ERIBULIN IN METASTATIC BREAST CANCER
The evidence supporting the approval of eribulin for the treatment of metastatic breast cancer is based on results from several trials summarized in Table 1. In an open-label, randomised multicentre phase 3 study – EMBRACE trial[24] – 762 patients who received 2-5 prior lines of chemotherapy, including a taxane and anthracycline were randomised in a 2:1 ratio to receive either eribulin mesylate 1.4 mg/m2 days 1 and 8 every 21 d, or treatment of physician choice (TPC), which was defined as any single-agent chemotherapy, targeted therapy, radiotherapy or symptomatic treatment[24]. Ninety-seven percent (97%) of patients in the TPC arm received chemotherapy – 26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 22% other chemotherapy[24]. While median progression free survival (PFS) was not significantly different between eribulin and TPC arms (3.7 months vs 2.2 months respectively; P = 0.137), overall survival (OS) was significantly longer in the eribulin arm (13.1 months vs 10.6 months respectively; P = 0.041)[24], making eribulin one of the few single agents available today, in addition to antibody-drug conjugates, demonstrated to prolong OS in the refractory setting and defying the presumption that improved OS is an improbable outcome from chemotherapy in refractory metastatic breast cancer[24-26].
Table 1 Summary of studies investigating the role of eribulin in metastatic breast cancer.
In another study by Yuan et al[27], eribulin displayed statistically significant superior PFS, although similar OS relative to vinorelbine in Chinese women with locally recurrent or metastatic breast cancer previously treated with 2-5 prior chemoregimens (PFS: HR 0.8, P = 0.036; Median OS: HR 1.03; P = 0.838). Moreover, toxicity profile of eribulin was more favourable compared to vinorelbine as the number of treatment-emergent adverse events leading to discontinuation was significantly lower in eribulin than vinorelbine (14% vs 7.2%).
Eribulin was also studied in combination with balixafortide, a chemokine receptor CXCR4 antagonist to unravel any synergy between these agents in HER2-negative metastatic breast cancer patients[28]. Balixafortide has been shown in several pre-clinical studies to exert anti-tumour, anti-metastastic and immunomodulatory effects, promoting a more favourable tumour microenvironment which is more sensitive to chemotherapy and immunotherapy[29-31]. As such, it has similar mechanism of action to eribulin and therefore could display a synergistic effect when used in combination. This is supported by the more superior PFS and clinical benefit response rate in the combination arm [PFS: 6.2 months; ORR: 38%; clinical benefit rate (CBR): 63%; 1-year OS: 75%][28] compared to the single-agent eribulin arm (PFS: 3.6 months; ORR: 13%; CBR: 28%; 1-year OS: 54%), although noting participant characteristics discrepancy in this inter-trial comparison[24]. Further clinical trials are warranted to confirm these findings.
Eribulin’s superior efficacy could be attributed to the non-mitotic effects of eribulin, most of which are absent in other alternative agents. Firstly, eribulin induces vascular remodelling leading to increased tumour perfusion and diminished hypoxia, as evidenced by the increased microvessel density and decline in hypoxia-associated protein expression of CA-9 and vascular endothelial growth factor following eribulin treatment in MX-1 and MDA-MB-231 human breast cancer xenograft models[16]. Diminished hypoxic conditions decreases the likelihood of extensive extracellular matrix remodelling, such as increased collagen deposition, which is associated with metastasis[32]. Additionally, increased tumour perfusion implies that an increased drug concentration would reach tumour cells and thus would be more susceptible to subsequent lines of therapy. Secondly, treatment with eribulin in MX-1 in vivo experimental mouse model reversed EMT as characterised by the increased expression of epithelial markers and decreased expression of mesenchymal markers[14]. EMT reversal may lead to reduced CSC regeneration and tendency to metastasise[12]. Simultaneous with EMT reversal was diminished lung metastasis and prolongation of OS in eribulin-treated mice compared to controls[14]. Combining eribulin’s non-mitotic properties together with its well-known mitotic mechanism, it is no surprise that eribulin improves survival outcomes.
DIFFERENTIAL EFFICACY OF ERIBULIN ACROSS SUB-TYPES
Eribulin in TNBC
Metastatic TNBC represents an aggressive and difficult to manage form of breast cancer, with a significant risk of distant relapse, after which median OS is only 13 months with treatment[33]. While antibody-drug conjugates such as trastuzumab-deruxtecan and sacituzumab-govitecan have recently been approved for use in metastatic TNBC given their promising effect on overall survival, these agents are expensive and display a fairly adverse toxicity profile, with grade 3-4 adverse events of up 52%[34]. Additionally, immune checkpoint inhibitors, also approved for use in metastatic TNBC in combination with chemotherapy produced fairly low objective response rate of less than 20%[35]. Efforts are currently ongoing to identify biomarkers to tailor therapy and identify the most optimal sequence and combination regimen for the treatment of TNBC.
Eribulin remains an important agent in TNBC either as a single-agent or in combination with other agents such as chemotherapy, immunotherapy and targeted therapy. Given the lack of receptor-specific targets and diverse heterogeneity in TNBC, agents that modulate the tumor microenvironment and target signal transduction, epigenetic modifications such as eribulin are urgently needed. Eribulin with its immunomodulatory effects has the potential to prime the tumor microenvironment to facilitate their counterpart agent utilised in combination to work more effectively. Several agents such as Olaparib and pembrolizumab have been explored in clinical trials in combination with eribulin[36,37].
Subgroup analyses from Study 301, a phase 3 trial investigating the efficacy of eribulin compared to capecitabine in taxane and anthracycline pre-treated patients who had ≤ 3 prior chemotherapies revealed a statistically significant improvement in OS for metastatic TNBC patients treated with eribulin compared to those with capecitabine (14.4 months vs 9.4 months respectively; P = 0.01)[38]. However, the PFS was not significantly different between the two groups (2.9 months vs 2.3 months respectively; P = 0.112)[38]. Similar results were observed in a pooled subgroup analysis of study 301 and 305, involving 352 TNBC patients conducted by Pivot et al[39]. In this analysis, OS and PFS were significantly longer in the eribulin arm relative to the control arm (OS: 12.4 months vs 8.1 months respectively; P < 0.01) (PFS: 2.8 months vs 2.5 months; P < 0.05)[39].
The interest in combining eribulin with immune checkpoint inhibitor in TNBC came about from the IMPASSION130 trial which demonstrated a significant improvement in PFS in metastatic TNBC patients with PD-L1+ tumours treated using a combination of atezolizumab, an anti-programmed death-ligand-1 (anti-PD-L1), and nab-paclitaxel relative to nab-paclitaxel only (7.5 vs 5 months respectively; P < 0.0001), leading to the accelerated United States Food and Drug Administration approval[40]. Eribulin was combined with pembrolizumab in a phase Ib/II study – ENHANCE1/KEYNOTE-150 – involving 106 patients with metastatic TNBC pre-treated with ≤ 2 lines of chemotherapy[37]. Outcomes were promising, with a CBR of 36.8%, median PFS and OS of 4.1 months and 16.1 months respectively[37]. Safety for the combination was acceptable and comparable to the two drugs when used as monotherapy[37]. While clinical activity was preserved regardless of PD-L1 status, RR in PD-L1+ive tumours was superior at 30.6% compared to 22.4% in PD-L1-negative disease[37]. These results were consistent with work by Goto et al[15] demonstrating that eribulin mitigates PD-L1 and FOXP3 expression in eribulin-treated breast cancer samples, likely via EMT-reversal, as shown by the inverse correlation between the two proteins and the epithelial marker, E-cadherin. Considering that the anti-programmed cell death protein 1 (PD-1) pembrolizumab modulates the activity of cytotoxic T lymphocytes via its immune-checkpoint blockade, the combination with eribulin warrants further exploration in larger trials. It is crucial to remember that population response rate (RR) to immunotherapy is variable and as such, utilising a composite index which incorporates biomarkers such as tumour-infiltrating lymphocytes number, tumour mutational burden and PD-L1 expression, that predict response to immunotherapy can be helpful.
Promising efficacy has also been demonstrated for eribulin when combined with targeted therapy in metastatic TNBC. In a phase 2 Japanese study involving 24 patients previously treated with both anthracycline and taxanes treated with a combination of olaparib and eribulin, the median PFS and OS were 4.2 (95%CI, 3.0-7.4) and 14.5 (95%CI, 4.8-22.0) months, respectively[36]. These survival data were superior to data from a similar Japanese patient population treated with eribulin alone[41]. However, there was some concern on toxicity with 83.3% of patients experiencing neutropenia, 41.7% anemia and 33% febrile neutropenia[36]. A phase 1 trial investigating the combination of everolimus and eribulin in metastatic TNBC patients who had ≤ 4 Lines of prior chemotherapy showed modest efficacy, with 36% of patients achieving partial response, 36% of patients having stable disease and 27% of patients progressing. The median OS was 8.3 months (95%CI: 5.5 to undefined) and PFS was 2.6 months (95%CI: 2.1 to 4.0)[42].
Eribulin in estrogen receptor-positive breast cancer
While selective ER modulators, aromatase inhibitors, and selective ER down-regulators, especially in combination with CDK4/6 inhibitors provide substantial clinical benefit by reducing the risk of disease recurrence and mortality, a subset of patients with ER+ breast cancer particularly luminal B tumor experience more aggressive disease with poorer survival outcomes relative to luminal A tumor[43]. Furthermore, resistance to endocrine therapies represents a major challenge, limiting the success of management of ER + breast cancer. Fortunately, in vitro studies have revealed that eribulin has the potential to induce luminal type conversion and expression of genes implicated in hormonal sensitivity, thereby potentially improving response and survival in ER+ breast cancer patients[14]. In regards to the latter, eribulin has also been shown to overcome resistance in hormone-resistant breast cancer cells. Previous clinical trials have investigated the role of eribulin in combination with endocrine therapy demonstrated promising results[44-48].
A phase II single-arm study has shown that eribulin could be beneficial especially among luminal B breast cancer patients by its ability to induce a phenotypic shift to the luminal A subtype[44] which tends to be less aggressive, lower grade and more sensitive to anti-estrogen therapy than luminal B subtype[45,46] with a consequently better prognosis[46,47]. In the SOLTI1007 study, Prediction Analysis of Microarray 50-gene classifier (PAM50) gene-expression profiling conducted on breast tumours obtained from 101 early-stage ER+, HER2-negative breast cancer patients post-treatment with eribulin for 4 cycles revealed 44.1% of luminal B subtype tumour underwent complete (100%) phenotypic transformation to the luminal A subtype. This phenotypic change was associated with the increased expression of luminal-related genes (ESR1 and NAT1), genes implicated in negative regulation of apoptosis (BCL2 and IL6), and angiogenesis (ANGPTL4 and HIF1A), and reduced expression of cell-cycle related genes (CCNB1, RAD17, MKI67) and genes related to microtubule cytoskeleton organization (AURKA, CENPA, KIF23)[48]. This is consistent with an earlier study which also showed upregulation in expression of genes implicated in hormonal sensitivity – ESR1, BCL2 and ERBB4[44]. Hence, eribulin may induce increased hormonal sensitivity in luminal B patients. This provides a rationale for the investigation of combination of eribulin with hormonal/anti-estrogen therapy for patients who present with luminal B subtype at baseline. Lending clinical support to this hypothesis, Kobayashi and colleagues (2016) identified an increase in time to treatment failure (TTF) when endocrine therapy was started immediately following eribulin treatment as compared to prior (mean: 1.4 months). While there was no significant difference in TTF for endocrine therapy in pre- and post-eribulin treated patients, the proportion of patients with longer TTF was significantly higher in patients who received eribulin prior to endocrine therapy (64% vs 24%; P = 0.018)[49]. This further emphasises the idea that eribulin could improve sensitivity to anti-estrogen therapy and potentially could be incorporated as a combination first-line therapy for ER+ breast cancer.
Eribulin has a potential role in overcoming resistance to endocrine therapy. In vitro study by Goto et al[15] showed that treatment with eribulin increased vascular remodelling and improved tumor hypoxia which enhanced the expression of epithelial and ER-related genes and proteins in hypoxia-resistant cell lines and tumor, leading to an enhanced anticancer effect of tamoxifen. While endocrine therapy-resistant breast cancer is relatively common, a proportion of HR-positive breast cancer eventually exhibit resistance to CDK4/6 inhibitors[50]. In a study by Pandey et al[51], treatment with eribulin followed by abemaciclib, a CDK4/6 inhibitor overcame resistance in CDK4/6 inhibitor-resistant cells. This is postulated to occur via synergistic pole-like kinase 1 inhibition in the G2/M phase by eribulin. The synergistic anti-tumor effect of eribulin in combination with abemacilib was confirmed in-vivo and certainly merits further investigation in clinical trials.
Eribulin in HER2-positive breast cancer
Eribulin has also been studied in HER2+ breast cancer. While prognosis has significantly improved in HER2+ breast cancer since the advent of anti-HER2 therapy and more recently, antibody drug conjugates such as TDM-1 and trastuzumab-deruxtecan, around 20% of patients still experience progressive disease[25,26]. Intolerance to taxanes which is often used in combination with anti-HER2 therapy is not uncommon and the recommended combination of trastuzumab with pertuzumab is often not available in many countries, making the availability of alternative agents valuable[52,53]. Given it is prudent to combine trastuzumab with pertuzumab and chemotherapy to avoid treatment resistance, a chemotherapeutic agent with proven efficacy in HER2+ breast cancer would be useful. Eribulin has been studied in the setting of HER2+ breast cancer in numerous clinical trials previously.
Several phase 2 trials have also examined the efficacy and safety of eribulin among HER2-positive breast cancers[54-56]. In a multicentre phase 2, single arm study conducted by Sakaguchi et al[55], the combination of trastuzumab and eribulin first-line produced a RR of 53.6%, CBR of 64.0% and median PFS of 11.3 months (344 d) in advanced or metastatic HER2+ breast cancer patients. 42.9% of patients experienced a grade 3/4 adverse event, with neutropenia being the most common (28.6%)[55]. The same combination was tested in advanced HER2+ breast cancer patients pre-treated with a median of 3 lines of previous treatment, including pertuzumab, lapatinib, and trastuzumab[54]. The results of this study, with an ORR of 41.7%, median OS and PFS of 8 and 5.4 months respectively, suggests that eribulin and trastuzumab combination could be considered for the treatment of pre-treated HER2-positive breast cancers[54]. Furthermore, eribulin has been studied as the first-line treatment in a triple combination therapy with trastuzumab and pertuzumab (ETP) in metastatic HER2+ breast cancer patients in a multicentre phase 2, single arm study[56]. Here, the ORR, CBR and median PFS were 80%, 84% and 23.1 months, clearly demonstrating an auspicious level of efficacy, comparable to the phase 3 CLEOPATRA trial (ORR 68.4%, OS 56.6 months, PFS 18.7 months, duration of response 20.2 months) which investigated the combination of trastuzumab, pertuzumab and docetaxel (DTP)[41,57]. Additionally, toxicity profile of the ETP regimen appeared favourable relative to the DTP regimen, with less severe neutropenia (32% vs 52.8%), and grade 3 peripheral neuropathy (0% vs 2.7% respectively)[41,57] - again paving the way for phase 3 trials. The application of eribulin combined with trastuzumab could offer alternative options to the current standard eviQ first-line of trastuzumab/pertuzumab, T-DM1, trastuzumab/capecitabine and DTP regimen, especially in cases where toxicity with capecitabine and paclitaxel are major issues[58]. Of note, allergy and intolerance and the development of acute and cumulative toxicities is common with taxanes[59-61]. Therefore, ETP could potentially be utilised as a first-line therapy or perhaps subsequent lines of therapy, for patients who have failed to respond to DTP and trastuzumab/capecitabine.
ERIBULIN AS AN EARLIER-LINE AGENT IN METASTATIC DISEASE
Recently, there has been increasing number of studies evaluating the use of eribulin as earlier-line therapy in the treatment of metastatic breast cancer. A prospective study investigating the efficacy of eribulin in first-/second-line compared to third-/fourth-line setting in women with advanced/metastatic breast cancer demonstrated that use in the former setting resulted in more superior TTF and OS compared to the latter setting (TTF: 135 d vs 119 d; OS: 555 d vs 383 d)[62]. These encouraging results of eribulin when used first-line concur with data from a recent multicentre, phase 2, single-arm trial – MERIBEL study – which explored the role of eribulin as a first-line agent in patients with metastatic HER2-negative breast cancer who were pre-treated with taxanes in early-stage and had a DFI < 36 months[48]. In this study, the median investigator-assessed TTF, ORR and CBR were 4.1 months, 20.8% and 26.4% respectively – comparable to phase 2 studies of taxanes and anthracyclines in metastatic breast cancer. Additionally, the trial showed non-cross-resistance with eribulin and taxanes and viable responses regardless of ER status – shown by the non-significant difference in median TTF between TNBC and luminal phenotype (3.9 vs 6.2 months, HR 1.7, 95%CI: 0.9 to 3.4, P = 0.111)[48]. Furthermore, a phase 2 Japanese study demonstrated that eribulin in the first- or second-line setting in Japanese patients with metastatic breast cancer produced an ORR and CBR of to 43.8% and 56.3% respectively, and PFS of 8.3 months. However, the PFS in this study might be overestimated because radiographic evaluation was conducted after every 3 cycles of eribulin treatment, instead of every 2 cycles as performed in other first-line trials[63]. Additionally, the discrepancy in efficacy might also be accounted for by the fewer proportion of patients with TNBC subtypes compared to the study[48,63]. Another phase 2 study in Japan also evaluated the efficacy and safety of eribulin as the first-line treatment for HER2-negative metastatic breast cancer[64]. After receiving a median of 8 cycles of eribulin treatment, ORR and CBR were 54.3% and 62.9% respectively. The median PFS and OS was 5.8 (95%CI 4.8 to 8.1) and 35.9 months. A multicentre phase 2 study in the United States demonstrated the ORR, CBR, and PFS of 28.6% (95%CI 17.3-42.2), 51.8%, and 6.8 months (95%CI 4.4-7.6) after receiving a median of 7 cycles of eribulin therapy[65]. These findings suggest good antitumor activity of eribulin as first- or second-line treatment of locally advanced and metastatic breast cancer, warranting further exploration in phase 3 clinical trials.
First-line usage could be beneficial for a number of reasons. Firstly, it leaves the tumour in a less aggressive state post-therapy, considering that eribulin reverses the mesenchymal phenotype, may diminish stem-like cells and promote the luminal A phenotype, rendering the tumour more susceptible to subsequent lines of endocrine and chemotherapy. An augmented cytotoxic effect could also arise via the induction of vascular remodelling which allows higher drug concentrations to reach the tumour post-eribulin treatment. Enhanced infiltration into tumours of cytotoxic T-cells is also a possibility enhancing immunotherapy. Further phase 3 studies incorporating immunohistochemical analysis of serial biopsies and taking careful account of outcomes from later line therapies.
SAFETY OF ERIBULIN
In terms of safety, eribulin has demonstrated an acceptable level of toxicity in the treatment of patients with breast cancer. Safety data from the EMBRACE trial showed that serious adverse effects (AE) occurred at a similar proportion in the eribulin group compared with the control group – treatment of physician choice (96% received either capecitabine, vinorelbine or gemcitabine) – 25% vs 26% respectively[24]. Of these patients, 13% of eribulin-treated patients discontinued therapy relative to 15% of patients in the control group[24]. A closer look into specific AEs reveals that grade 3 and 4 were more common in the eribulin group including neutropenia (grade 3: 21% vs 14%; grade 4: 24% vs 7% respectively), leukopenia (grade 3: 12% vs 5%; grade 4: 2% vs 1% respectively) and peripheral neuropathy (grade 3: 8% vs 2%; grade 4: < 1% vs 0 respectively)[24]. A drawback with eribulin tends to be greater myelosuppression compared to other agents such as gemcitabine and vinorelbine, especially in heavily pre-treated patients[66,67]. leading to the need for either administration of granulocyte-colony stimulating factor or dose reduction from 1.4 mg/m2 to 1.2 mg/m[63,68]. Interestingly, a retrospective analysis revealed that dose reduction was associated with better clinical outcomes compared to dose-interval prolongation, in cases where adjustments are necessary owing to toxicity[68]. Considering eribulin-induced peripheral neuropathy, similar dose reduction and/or duloxetine administration, and more recently, photobiomodulation may be employed to alleviate the effect[69,70]. Interestingly, eribulin has been shown to be less neurotoxic than ixabepilone in a randomised phase 2 study (incidence: 31% vs 44%)[71]. Of these patients who experienced peripheral neuropathy, 3.9% discontinued treatment with eribulin relative to 18% who were treated with ixabepilone[71]. Furthermore, quality of life assessment, assessed as a secondary end point in study 301 showed patients receiving eribulin treatment had better cognitive function (P < 0.001) than those receiving capecitabine[72]. However, patients receiving eribulin had inferior emotional function relative to those receiving capecitabine (P = 0.033)[72]. The difference in the effect on quality of life could be ascribed to the toxicity profile of the two drugs where eribulin had lower gastrointestinal toxicities such as nausea, vomiting and diarrhea while capecitabine had in general, less mucositis and alopecia[72].
Unlike capecitabine, special precaution must be exercised in patients on eribulin with mild to moderate hepatic impairment, as for taxanes and ixabepilone[73]. With regards to with renal impairment, pharmacokinetic studies suggest a dose reduction similar to those patients with hepatic impairment, tailored to the level of GFR[74]. As such, to avoid potential toxicity, clinicians may opt for a different agent for patients with comorbid hepatic and/or renal impairment, for instance, resorting to agents such as paclitaxel, doxorubicin and vinorelbine in patients with renal impairment. Considering the impact of age, pooled exploratory analysis of two single-arm phase 2 and one phase 3 trial in the metastatic setting revealed the incidence of adverse events, OS (P = 0.82), PFS (P = 0.42), ORR and CBR were completely independent of age[75]. In fact, an observational Italian study exploring the use of eribulin in elderly patients with metastatic breast cancer revealed that eribulin preserved quality of life regardless of geriatric status, except for a decline in instrumental activities of daily living and increase in geriatric depression[76].
FUTURE DIRECTIONS
Recent data from clinical trials emphasise that eribulin has potential as an earlier-line agent in the management of patients with metastatic breast cancer, especially in the area of TNBC where options are limited and prognosis is dismal[62,63]. This could have the added advantage of leaving tumours in a less aggressive and more treatment responsive state post-therapy – with a less mesenchymal phenotype, less immunosuppressive environment and better vascularisation – potentially rendering tumours more susceptible to further lines of therapy, translating to improved OS[14,16,17]. To confirm this, further clinical trials investigating eribulin as a first-/second- line agent in metastatic TNBC are warranted. One such a study is ongoing in the Dana Farber Cancer Institute in Boston, where eribulin is followed by doxorubicin and cyclophosphamide administration in patients with invasive HER2-negative inflammatory breast cancer in the neoadjuvant setting[77]. However, interestingly, recent data from early phase trials suffice to consider use of eribulin as a first-line and second-line agent in Japan and Europe respectively in the management of metastatic TNBC[78,79]. Observational study in Japan which investigated eribulin as first-/second line or later-line chemotherapy in HER2-negative, hormone resistant mBC demonstrated that median OS were 22.8 (17.3-31.0), 16.3 (12.4-19.9), and 12.6 (11.2-15.1) months respectively[78]. While median OS was superior in first-line compared to later-lines of therapy, it is statistically non-significant[78]. This could be attributed to the limited sample size in the study and the fact that the follow-up time was limited to 2 years. Furthermore, combination therapy involving eribulin and other agents such as immunotherapy, targeted therapy in mTNBC setting should further be explored. Such studies are currently ongoing – first is a phase 1b/2 study investigating the combination of rebastinib and eribulin or paclitaxel and second, a phase 3 trial exploring the combination of eribulin and balixafortide compared to eribulin monotherapy[80,81]. In the area of ER+ breast cancer, promising preclinical and early phase study discussed above suggests that future studies could explore pre-treating patients with metastatic ER+ breast cancer with eribulin prior to endocrine therapy. A potential study could investigate eribulin administration prior to current gold standard treatment with combination CDK4/6 inhibitors and aromatase inhibitors in patients with ER+, HER2-negative mBC. In the setting of HER2+ breast cancer, further phase 3 trials investigating the combination of eribulin, trastuzumab and pertuzumab ought to be conducted to confirm the promising efficacy and safety data from earlier phase trials.
CONCLUSION
Eribulin is a non-taxane chemotherapy agent which is utilised for the treatment of locally advanced or metastatic breast cancer patients who have progressed after 2-3 lines of taxane or anthracycline-based regimen. Eribulin’s non-mitotic properties which include its anti-mesenchymal, immunomodulating and vascular remodelling features could make it a perfect candidate in becoming adjuncts to standard treatment regimen for breast cancer across different subtypes. In the era of targeted therapy, immunotherapy and antibody-drug conjugates, eribulin likely still has a role to play in earlier and later-line settings both as a single agent and in combination with other agents in patients with metastatic breast cancer across all subtypes of breast cancer, pending further phase 3 trials. Further studies exploring combination with targeted therapy and immunotherapy are warranted to further add to the available pharmacological armamentarium for metastatic breast cancer.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
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