Eribulin and trastuzumab in early-line HER2-positive metastatic breast cancer: evaluating an active chemotherapy partner in an evolving treatment landscape

Introduction

It is estimated that 18–20% of invasive breast cancers overexpress the human epidermal growth factor receptor 2 (HER2) protein and/or have amplification of the erb-b2 receptor tyrosine kinase 2 (ERBB2) gene (1). While HER2 positive disease is biologically aggressive, outcomes in both the early stage and metastatic setting have seen dramatic improvements in survival due to treatment with the combination of chemotherapy [and endocrine therapy (ET)] with HER2 targeted therapies (2-4). The current frontline standard of care regimen for locally advanced or metastatic HER2 positive breast cancer is comprised of dual HER2 targeted blockade paired with a taxane, as established by the phase III CLEOPATRA trial, where the addition of pertuzumab to docetaxel and trastuzumab improved both progression-free survival (PFS) and overall survival (OS) (5). However, use of taxane therapy may be limited by toxicities such as hypersensitivity reactions, peripheral neuropathy, and myelosuppression, and many patients may have previously received a taxane in the early stage setting. As a result, there remains an unmet need to define alternative chemotherapy partners to optimize combination therapy with HER2 targeted agents.

Eribulin is a highly effective microtubule inhibitor that has become a standard of care as late-line treatment for HER2 negative breast cancer due to its demonstrated survival benefit compared to standard chemotherapy in heavily pretreated patients with metastatic breast cancer (6). Phase II studies in the first line setting suggested similar efficacy of eribulin combined with trastuzumab compared to docetaxel with trastuzumab, leading to interest exploring eribulin as a potential alternative to taxane chemotherapy in this setting (3,7).

Study design and demographics

The phase III EMERALD trial was a multicenter, randomized trial designed to answer the question of whether eribulin combined with trastuzumab and pertuzumab (eribulin-HP) would be noninferior to taxanes (weekly paclitaxel or every 3 week docetaxel) combined with trastuzumab and pertuzumab (THP) as first-line therapy for HER2-positive locally advanced breast cancer (LABC) or metastatic breast cancer (MBC), with a primary endpoint of PFS (8). Of note, prior treatment with trastuzumab emtansine (T-DM1) in the advanced setting was allowed. The trial enrolled 446 patients, 59% had de novo metastatic disease while 41% of the patients had recurrent disease. In the study population, 57.6% of the patients had estrogen receptor (ER) positive disease and 42% had ER negative disease, consistent with the expected distribution of HER2-positive breast cancer. Notably, 31% of the patients received prior taxanes in the perioperative setting and 30% had received perioperative anti-HER2 therapy. In the recurrent disease setting, 2.2% of the patients had previously received T-DM1, 4.3% of patients of patients had received anti-HER2 therapy, and 10.1% patients had received ET.

Key findings

The EMERALD trial results demonstrated noninferiority of eribulin-HP compared to THP, with a median PFS of 14 versus 12.9 months respectively. The overall response rates were comparable between arms (75.8% with eribulin and 75.2% with taxane). At the time of analysis, OS had not been reached in the eribulin arm, compared with 65.3 months in the taxane arm, with no statistically significant difference seen. Noninferiority was maintained across subgroups, including patients with prior perioperative taxane exposure and hormone receptor positive status. Eribulin also preserved quality of life (QoL) for a greater proportion of patients, with a higher percentage of patients maintaining their global health status (GHS) score at 6 months (62.7% vs. 43.7%) and 12 months (30.3% vs. 25.7%) compared to taxanes. Importantly, median time to deterioration in QoL was longer with eribulin (7.16 months) compared to taxane (4.56 months).

With regards to toxicity, eribulin was associated with higher rates of neutropenia (61.6% vs. 30.7%) and peripheral neuropathy, particularly grade 3 peripheral neuropathy (9.8% vs. 4.1%) and taxane therapy was more frequently associated with infusion reactions (24.8% vs. 13.4%), diarrhea (54.1% vs. 36.6%), febrile neutropenia (8.7% vs. 4.9%) and edema (42.2% vs. 8.5%). The inclusion criteria specified a minimum of six cycles of chemotherapy before continuing with antibody therapy alone, but decisions regarding treatment duration are generally impacted by response and toxicity. In EMERALD, the median duration of treatment with eribulin was longer than that of docetaxel and paclitaxel treatment (28.1 vs. 18.1 and 20.5 weeks respectively). OS data from this study are not yet reported.

Strengths and limitations

These outcomes suggest that eribulin can be used as a chemotherapy partner with HER2 targeted therapy, especially in patients who are intolerant to taxane therapy. However, there are several important considerations.

In the EMERALD trial, treatment was not given in the strictly defined first-line setting as 52 (11.6%) patients received HER2 directed therapy and/or ET for recurrent disease and 10 patients (2.2%) received T-DM1 for recurrent disease, allowed by the study protocol. However, the number of patients with exposure to therapy in the metastatic setting was small and is unlikely to have impacted the non-inferiority results.

The median PFS observed in EMERALD (13–14 months) was shorter than reported in CLEOPATRA (18.7 months, 10% with prior trastuzumab exposure) (3,9). This difference likely reflects the more heavily treated population enrolled in EMERALD, in which prior trastuzumab and chemotherapy exposure might have contributed to reduced treatment sensitivity. In addition, it is not clear whether patients with ER positive disease received ET as maintenance, which clearly impacts PFS in the first-line setting for patients with ER positive, HER2 positive advanced disease. It is possible that mandated ET for this subgroup would have further improved PFS results on study.

The taxane comparator arm was heterogenous, which may influence treatment tolerability and duration, as toxicity differs depending on whether paclitaxel or docetaxel is administered. These differences are relevant as peripheral neuropathy is more commonly seen with weekly paclitaxel compared to docetaxel, while febrile neutropenia, edema and bone marrow suppression are more commonly seen with every 3-week docetaxel (10). The approximately 30% of patients with prior taxane exposure might have influenced the noninferiority analysis as preexisting taxane resistance could bias the results in favor of eribulin. However, subset analysis did not demonstrate differential impact based on prior exposure to taxanes or chemotherapy in the early-stage setting.

The limitations of EMERALD are mainly related to the rapidly evolving landscape in the treatment of HER2 positive breast cancer, as outlined below.

Implications for practice

The EMERALD trial definitively showed similar efficacy with eribulin, compared to taxane, as the chemotherapy partner for trastuzumab and pertuzumab treatment for minimally pre-treated metastatic HER2-positive breast cancer, important not just in this setting but as a sequential chemotherapy partner over the metastatic treatment course. This study demonstrated a noninferior PFS compared to taxane-HP, along with a clinically meaningful delay in deterioration of QoL. An eribulin-based regimen may be particularly suitable for patients with prior taxane exposure or those who are unable to tolerate taxanes.

Earlier studies, including MARIANNE, HERNATA, and VELVET, have shown that alternative regimens such as T-DM1 or vinorelbine-HP exhibit clinical activity but do not confer clearly equivalent or superior efficacy compared with a taxane-HP regimen (11-13). The results of EMERALD provide an important contribution to this body of evidence supporting use of an active chemotherapy partner for HER2-based therapy.

However, the therapeutic landscape for first-line treatment of advanced or metastatic HER2-positive breast cancer is rapidly evolving. Historically, combination therapy with THP has been the established standard of care in this setting. However, interim results from the DESTINY-Breast09 trial demonstrated a significant improvement in median PFS with the antibody drug conjugate trastuzumab deruxtecan (T-DXd) plus pertuzumab compared with THP in patients with advanced or metastatic HER2-positive disease pointing towards a potential shift in first line therapy (Table 1) (3,8,14). The use of maintenance strategies also effects efficacy in the first-line setting. In the PATINA study patients with hormone receptor positive, HER2-positive disease with responding or stable disease following 4-8 cycles of induction chemotherapy combined with HER2 targeted therapy were randomized to receive maintenance HP plus ET with or without palbociclib. The addition of palbociclib to maintenance therapy resulted in a significant PFS benefit and has already been incorporated into clinical practice (15). HER2CLIMB-05 is evaluating the addition of tucatinib to maintenance HP and recently reported improvements in PFS (16). An ongoing study, DemetHER, is evaluating maintenance with HP and ET as indicated following induction with T-DXd (17). These maintenance strategies will impact how therapies are used in the early line setting with continuous combination therapy such as eribulin-trastuzumab remaining viable options in the later line setting. In addition, treatment in the early-stage setting will clearly impact treatment decisions in the metastatic setting, although with greater efficacy in early-stage the proportion of metastatic patients with de novo disease will presumably increase. Recent data from DESTINY-Breast11 and Destiny-Breast05 demonstrating benefit from T-DXd in the high-risk neoadjuvant and post neo-adjuvant settings respectively will create new questions regarding optimal sequencing of treatment for those who develop recurrent disease (18,19).

In this context, eribulin combined with HER2 targeted therapy remains a limited but reasonable alternative for select patients in the early-line advanced stage setting. We would consider eribulin-HP for a patient who had progressed on neoadjuvant/adjuvant taxane and T-DXd with a short disease-free interval. Eribulin-trastuzumab also remains an effective and important option in combination with trastuzumab as later line treatment for patients who receive current standards (THP and/or T-DXd) in the earlier line setting.

Conclusions

The phase III EMERALD study demonstrated noninferiority of eribulin-HP compared to taxane-HP in the earlier line setting for advanced/metastatic HER2+ breast cancer, with patients receiving eribulin showing a longer time to QoL deterioration. Taking into context new treatment approaches demonstrating improved PFS, this regimen offers an alternative chemotherapy partner for trastuzumab and pertuzumab.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-162/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2025-aw-162/coif). H.L.C. is a member of City of Hope Data Safety Monitoring Board, an internal committee to review safety of ongoing clinical trials at her institution. This role does not conflict with this particular manuscript. I.M.K. reports research funding from Merck; and consulting fees from AstraZeneca, BioNTech, Daiichi Sankyo, Menarini Stemline, Pfizer, Gilead and Caris Life Sciences. H.S.R. reports research funding from AstraZeneca, Gilead Sciences, Lily, Merck, Daiichi Sankyo, Novartis, Pfizer, F. Hoffman-LaRoche/Genentech, Stemline Therapeutics, Ambryx, Bicycle Therapeutics; and consulting fees from Napo, Bristol Myers Squibb, Helsinn and BioNTech. The authors have no other 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.

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