Editor’s Note: Trastuzumab deruxtecan (T-DXd) has dramatically reshaped the treatment landscape for advanced HER2-positive breast cancer because of its outstanding efficacy. It is now considered the standard second-line treatment for HER2-positive advanced breast cancer and has also demonstrated remarkable activity in both the first-line metastatic and early breast cancer settings.However, for patients who develop resistance or disease progression following T-DXd treatment, there remains no globally established standard of care or high-level evidence-based treatment strategy. This challenge is particularly pressing in the Chinese population, where the optimal sequencing and post–T-DXd therapeutic approach urgently require further investigation.
At the 2026 ESMO Breast Cancer Congress (ESMO BC 2026), the team led by Professor Nanlin Li from Xijing Hospital, Air Force Medical University, presented the design of a prospective, multicenter, single-arm exploratory study (Abstract No. 596eTiP). The study is the first to evaluate the efficacy and safety of neratinib combined with fulvestrant and eribulin in patients with HR+/HER2+ advanced breast cancer previously treated with T-DXd, offering a mechanistically driven and potentially promising new therapeutic strategy for this difficult-to-treat population.
Oncology Frontier invited the principal investigator, Professor Nanlin Li, to provide an in-depth interpretation of the study design and its clinical significance.
Study Overview
Background
A landmark study published in Nature Cancer in June 2025 revealed that HER2-positive breast cancers resistant to T-DXd may express p95HER2, a truncated form of HER2 that lacks part of the extracellular domain. This altered receptor not only interferes with drug binding to HER2 but also induces the expression of immunosuppressive molecules such as PD-L1 and IL-6, thereby creating an immunosuppressive tumor microenvironment that contributes to T-DXd resistance.
Although this mechanism shares similarities with trastuzumab resistance, it also possesses unique biological characteristics.
Importantly, the study demonstrated that the tyrosine kinase inhibitor (TKI) neratinib can effectively degrade p95HER2, reverse the immunosuppressive microenvironment, restore antitumor immunity, and potentially resensitize tumors to T-DXd.
In parallel, earlier studies have suggested that in triple-positive breast cancer, targeting HER2 alone may activate the hormone receptor (HR) pathway because of the complex crosstalk between HR and HER2 signaling. This adaptive signaling may allow tumor cells to evade therapy and ultimately contribute to resistance to anti-HER2 treatment. Consequently, effective HER2 targeting is considered a key strategy for overcoming estrogen receptor (ER)-mediated resistance.
A clinical case report published in Frontiers in Oncology in 2025 described a 38-year-old patient with HR+/HER2+ advanced breast cancer who achieved a remarkable response after developing resistance to T-DXd and subsequently receiving neratinib combined with fulvestrant and paclitaxel. The regimen demonstrated favorable tolerability, with only mild fatigue and appetite loss reported.
This case provided preliminary clinical proof-of-concept that neratinib may reverse T-DXd resistance while endocrine therapy simultaneously addresses HR-pathway crosstalk in triple-positive disease. However, larger-scale clinical validation remains necessary.
Neratinib is an irreversible dual tyrosine kinase inhibitor primarily targeting epidermal growth factor receptor (EGFR) and HER2. By covalently binding to ATP-binding sites within the intracellular kinase domains of EGFR and HER2, neratinib inhibits receptor homo- and heterodimerization, suppresses autophosphorylation, blocks downstream signaling pathways, and ultimately inhibits tumor cell proliferation.
Multiple previous studies have confirmed the efficacy and safety of neratinib-based regimens in HER2-positive advanced breast cancer. In the NALA trial, neratinib plus capecitabine achieved a median progression-free survival (PFS) of 8.8 months, overall survival (OS) of 21 months, and an objective response rate (ORR) of 32.8% in patients previously treated with more than two HER2-targeted therapies.
In addition, a phase II study evaluating neratinib with or without fulvestrant in HER2-positive, hormone receptor-positive metastatic breast cancer demonstrated the safety of the neratinib-fulvestrant combination. In HR-positive, HER2-mutant metastatic breast cancer, both the SUMMIT and MutHER studies further confirmed the efficacy and safety of neratinib combined with fulvestrant and trastuzumab.
Eribulin, a microtubule inhibitor, not only exerts direct antitumor effects but may also reverse epithelial-mesenchymal transition (EMT) and improve the tumor microenvironment, making its potential synergy with neratinib particularly worthy of investigation.
The EMERALD study demonstrated that eribulin combined with trastuzumab and pertuzumab (HP) as first-line treatment for HER2-positive breast cancer was noninferior to taxane plus HP therapy, further supporting the efficacy and safety of eribulin in HER2-positive disease.
Fulvestrant is a selective estrogen receptor degrader (SERD). Unlike traditional estrogen receptor modulators such as tamoxifen, fulvestrant completely suppresses estrogen receptor signaling. Its key mechanisms include binding to the estrogen receptor with substantially greater affinity than tamoxifen, blocking estrogen-receptor interaction, promoting receptor degradation, reducing estrogen receptor expression, and downregulating downstream estrogen signaling pathways.
The MonarcHER study demonstrated that fulvestrant combined with a CDK4/6 inhibitor and trastuzumab numerically improved overall survival compared with trastuzumab plus chemotherapy in heavily pretreated triple-positive advanced breast cancer, with manageable safety consistent with prior mechanistic findings.
Based on these scientific and clinical observations, our study was designed to address the major challenge of T-DXd resistance in HER2-positive breast cancer by leveraging the latest insights into p95HER2-mediated resistance mechanisms.
We innovatively proposed a combination strategy consisting of neratinib, eribulin, and fulvestrant. This regimen is supported by a strong mechanistic rationale: neratinib can degrade p95HER2 and reverse immune suppression, while preliminary clinical evidence suggests that this combination may induce substantial tumor regression in resistant patients.
Through a rigorously designed phase II study, we aim to systematically evaluate the efficacy and safety of this regimen, focusing on key endpoints including objective response rate, progression-free survival, and overall survival.
Positive findings from this study could provide a new standard treatment strategy for patients resistant to T-DXd and help address the current lack of clear recommendations in NCCN guidelines. If successful, a randomized phase III trial is planned to further validate the value of this combination approach.
Study Methods
This is a single-arm, multicenter, prospective exploratory study (NCT07333937) designed to evaluate the efficacy, safety, and biomarker characteristics of neratinib plus fulvestrant and eribulin in patients with T-DXd-pretreated HR+/HER2+ advanced breast cancer.
Key Eligibility Criteria
- Female patients aged 18–75 years
- ECOG performance status 0–1
- Locally recurrent or metastatic HR+/HER2+ breast cancer
- Disease progression following or intolerance to prior T-DXd treatment
Treatment Regimen
- Neratinib: Stepwise dose escalation to 240 mg once daily, with prophylactic loperamide
- Eribulin: 1.4 mg/m² intravenous infusion on Days 1 and 8 every 3 weeks
- Fulvestrant: 500 mg intramuscular injection on Days 1 and 15 during Cycle 1, followed by Day 1 every 4 weeks thereafter
Study Endpoints
Primary Endpoint
- Objective response rate (ORR) assessed by RECIST v1.1
Secondary Endpoints
- Progression-free survival (PFS)
- Disease control rate (DCR)
- Duration of response (DOR)
- Overall survival (OS)
- Safety (NCI-CTCAE v5.0)
Exploratory Endpoints
- p95HER2 expression (IHC/WB)
- Signaling and immune biomarkers
- Dynamic ctDNA changes
Statistical Hypothesis and Sample Size
Based on real-world post–T-DXd treatment data in HER2-positive advanced breast cancer, where historical ORRs ranged from 10% to 31%, the control ORR threshold was set at 21%.
The study hypothesizes that the neratinib-based combination regimen could achieve an ORR of 43%.
Using a single-arm proportion test with 80% power and a two-sided alpha of 0.05, 31 evaluable patients are required. Allowing for a 10% dropout rate, the target enrollment is 35 patients.
Investigator’s Perspective
Professor Nanlin Li
“I believe this study carries three major strengths and clinical values.
First, it directly addresses a major unmet clinical need. T-DXd has become a cornerstone therapy for HER2-positive advanced breast cancer, but the absence of a standard treatment strategy after resistance has emerged as a major clinical challenge. Our study specifically focuses on the post–T-DXd population and helps fill the gap in Chinese real-world and prospective data, making it highly relevant to current clinical practice.
Second, the study represents a mechanism-driven translational innovation. Based on cutting-edge discoveries regarding p95HER2-mediated immune suppression, we selected neratinib because of its ability to degrade p95HER2 and reverse immune resistance. The scientific rationale is strong and creates a complete translational pathway from mechanistic discovery to clinical application.
Third, the combination strategy itself is highly synergistic. Neratinib targets HER2 signaling, fulvestrant suppresses the hormone receptor pathway, and eribulin provides cytotoxic chemotherapy activity. Together, the three agents comprehensively target HER2 signaling, HR signaling, and tumor cell proliferation, making this regimen particularly well suited for HR+/HER2+ advanced breast cancer after T-DXd resistance, with the potential to deliver substantial clinical benefit.”
Future Perspectives
This study is the first prospective multicenter trial investigating the combination of neratinib, fulvestrant, and eribulin in HR+/HER2+ advanced breast cancer following T-DXd resistance.
With a clearly defined biological rationale and a scientifically rigorous design, the study has the potential to establish a new evidence-based treatment strategy for this unmet-need population. In addition, the planned biomarker analyses may further support the development of precision treatment approaches.
Patient enrollment is currently ongoing in an orderly manner, and we look forward to both interim and final results, which may ultimately provide more effective and accessible treatment options for patients with triple-positive advanced breast cancer after T-DXd resistance.”
Professor Nanlin Li
