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Complexities in HER2+ MBC
Expert Thoughts on Navigating Complexities in HER2+ MBC Sequencing

Released: May 07, 2025

Expiration: November 06, 2025

Ian Krop
Ian Krop, MD, PhD
Sarah L. Sammons
Sarah L. Sammons, MD
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Key Takeaways
  • First-line systemic therapy for patients with HER2-positive metastatic breast cancer is a taxane plus trastuzumab and pertuzumab followed by trastuzumab and pertuzumab maintenance
  • Second-line treatment is primarily T-DXd, but tucatinib/trastuzumab/capecitabine can also be considered for patients with central nervous system disease progression
  • Later treatment is usually tucatinib/trastuzumab/capecitabine followed by T-DM1, but subsequent treatment sequencing is dependent on patient preference and treatment history

Introduction
The treatment landscape for HER2-positive metastatic breast cancer (MBC) has continued to evolve, as new and effective HER2-targeted therapies have become available. Recent clinical trial data continue to reshape the foundation of sequencing therapy for patients with HER2-positive MBC. This commentary answers some frequently asked questions from recent live events and discusses some of the nuanced decisions oncologists face in clinical practice.

What is standard of care in the first-line and second-line settings? 

Ian Krop, MD, PhD:
In the first-line setting, standard of care remains the combination of a taxane plus trastuzumab and pertuzumab (THP), as established by the phase III CLEOPATRA trial, followed by trastuzumab and pertuzumab (HP) maintenance. Although docetaxel was used as the taxane backbone in the study, subsequent trials demonstrated that paclitaxel is also very effective, and many healthcare professionals (HCPs) find it to be better tolerated. Whereas THP has been a standard approach since 2012, new data from the randomized phase III PATINA trial presented at the 2024 San Antonio Breast Cancer Symposium suggest that this approach could be modified. In this trial, participants were randomized to receive HER2-targeted therapy (trastuzumab ± pertuzumab) and endocrine therapy with or without palbociclib, a CDK4/6 inhibitor, as first-line maintenance therapy for endocrine receptor–positive patients with no evidence of disease after 6-8 cycles of induction chemotherapy with HER2-targeted therapy. The addition of palbociclib led to a statistically significant 15-month improvement in median progression-free survival (PFS) (HR: 0.74; P = .0074). Although overall survival (OS) data are immature, they appear promising. There was a substantial increase in the incidence of neutropenia and a modest increase in diarrhea. However, overall, these are manageable toxicities. We anticipate FDA approval of this regimen, which would change clinical practice to include palbociclib and endocrine therapy with HP maintenance for patients with endocrine receptor–positive and HER2-positive MBC.

In the second-line setting, standard of care has evolved from the HER2-targeting antibody–drug conjugate (ADC) trastuzumab emtansine (T-DM1), which gained approval based on the randomized phase III EMELIA trial, to trastuzumab deruxtecan (T-DXd) based on the DESTINY-Breast03 trial. The randomized phase III DESTINY-Breast03 trial compared the 2 ADCs in patients with HER2-positive MBC after previous treatment with trastuzumab and a taxane, with or without pertuzumab. T-DXd demonstrated significantly improved median PFS and OS and increased but manageable toxicity compared with T-DM1 in this trial, leading to the adoption of T-DXd as a second-line treatment standard of care. 

However, in some cases, tucatinib, a HER2-directed kinase inhibitor, plus trastuzumab/capecitabine can be used in the second line for patients with both systemic and central nervous system (CNS) disease progression. The phase II HER2CLIMB trial enrolled patients with heavily pretreated HER2-positive MBC, including those with active or stable brain metastases, and randomized them to receive trastuzumab/capecitabine with tucatinib or with placebo. Of importance, this was the first large trial to include a significant number of patients with active or stable CNS disease, and the addition of tucatinib resulted in improved median PFS and OS both in the overall population and in those with brain metastases. Intracranial response was also improved in patients with measurable brain metastases who received tucatinib. Most of the adverse events associated with the tucatinib combination in this trial were low grade and manageable, and in general, tucatinib tends to have a more favorable toxicity profile than other kinase inhibitors. Now, the combination of tucatinib/trastuzumab/capecitabine is generally used in the third-line setting for patients with HER2-positive MBC after THP and T-DXd but can be used in the second line for patients with brain metastases. However, more recent data from the phase IIIb/IV DESTINY-Breast12 trial in patients with or without stable/active brain metastases has shown that T-DXd also has durable intracranial activity in patients with brain metastases.

What challenges do HCPs face in third-line and later-line therapy? 

Ian Krop, MD, PhD:
Unlike earlier lines, standard of care in third- and later-line therapies is less clear. There are currently several potential third-line regimens, including T-DM1, tucatinib/trastuzumab/capecitabine, or other HER2-targeted therapies.

In most cases when patients receive THP followed by T-DXd, tucatinib/trastuzumab/capecitabine is considered in the third-line setting followed by T-DM1 as fourth-line therapy. There are no explicit data for this sequencing order, but because T-DXd and T-DM1 are both HER2-targeting ADCs, resistance to T-DXd resulting in disease progression during second-line treatment could theoretically affect the efficacy of subsequent T-DM1. Tucatinib/trastuzumab/capecitabine has a different mechanism of action and proven CNS activity, so it is more frequently considered after progression on T-DXd.

Of note, the HER2CLIMB study included patients who received prior trastuzumab, pertuzumab, and T-DM1 treatment but did not include patients who received prior T-DXd, which was not the standard of care at the time the trial was designed. In fact, we do not have any large, randomized trials for optimal therapy after T-DXd, but there are some real-world data. One retrospective, real-world study from the Dana-Farber Cancer Institute suggested that there is modest activity with a number of regimens, but currently there is no obvious best choice. Later-line therapy selection primarily depends on patient preference regarding type of treatment along with adverse effect profiles.

Therapies to consider beyond the fourth-line metastatic setting include 2 potent HER kinase inhibitors that also inhibit EGFR—neratinib (approved in combination with capecitabine after ≥2 prior HER2-targeted regimens for MBC) and pyrotinib (approved in combination with capecitabine in China). In addition, we can consider margetuximab, a monoclonal antibody similar to trastuzumab with a modified Fc region to mediate activation of the immune system, which is approved in combination with chemotherapy for HER2-positive MBC after ≥2 prior HER2-targeted regimens (≥1 for MBC). 

How do brain metastases affect optimal treatment sequencing?

Sarah L. Sammons, MD:
Some of the most challenging clinical decisions HCPs make in the clinic for patients with HER2-positive MBC involve brain metastases. Brain metastases are extremely common in HER2-positive MBC, occurring in approximately 30% to 50% of patients. Among these patients, 10% will have brain metastases when they first develop metastatic disease, and throughout subsequent lines of therapy, the incidence of brain metastases increases. Current National Comprehensive Cancer Network and American Society of Clinical Oncology (ASCO) guidelines do not recommend screening asymptomatic patients with MBC for brain metastases. However, the European Society for Medical Oncology guidelines do recommend screening patients with HER2-positive MBC and metastatic triple-negative breast cancer if it would lead to a treatment change. 

Regarding treatment sequencing, our goal for patients with stable brain metastases is to prevent both extracranial and intracranial progression, so standard sequencing algorithms are recommended. Active brain metastases are more clinically challenging, and the approach to these cases depends on whether the patient has received prior treatment. HCPs should rely on literature, clinical trials, and regimens that will result in an intracranial response to spare patients from the morbidity associated with brain metastases.

For patients with CNS disease and systemic progression, systemic therapies with the best intracranial response include tucatinib/capecitabine/trastuzumab and T-DXd. Both have demonstrated excellent intracranial activity in the HER2CLIMB and DESTINY-Breast12 studies, respectively, and should be the prioritized systemic therapies for patients with active brain metastases.

For patients with brain metastases who continue to experience progression after these therapies, T-DM1 can also be considered. The phase IIIB KAMILLA study showed that T-DM1 has some intracranial activity in patients with HER2-positive MBC after both chemotherapy and anti-HER2 therapy (intracranial overall response rate: 21.4%). Data from the phase III NALA study also showed that the addition of neratinib to capecitabine and lapatinib in patients with HER2-positive MBC and at least 2 prior HER2-directed regimens significantly improved PFS and time to intervention for CNS disease compared with capecitabine and lapatinib alone. Despite meaningful activity, however, the combination of neratinib plus capecitabine is associated with substantial gastrointestinal toxicity, even when prophylactic loperamide is used.

The ongoing HER2CLIMB-02 trial also examined adding tucatinib to T-DM1 for patients with progression on trastuzumab plus taxane and no prior treatment with tucatinib, afatinib, or T-DXd, which moderately prolonged PFS in both the general patient population (9.5 vs 7.4 months for T-DM1 plus placebo) as well as those with baseline brain metastases (7.8 vs 5.7 months). OS and intracranial data for this study have not yet been published but may clarify the potential positioning of this regimen in the sequencing of treatments for HER2-positive MBC.

Additional phase II studies of interest for patients with active CNS disease and progression after multiple lines of treatment include the TBCRC 022 study exploring neratinib plus T-DM1 and the PATRICIA study of high-dose trastuzumab plus pertuzumab.

Are there data for using tucatinib without capecitabine for patients who may not tolerate capecitabine, for instance those with dihydropyrimidine dehydrogenase (DPD) germline deficiency?

Ian Krop, MD, PhD:
Data from a phase I study of tucatinib monotherapy suggests it has some efficacy in patients with HER2-positive MBC, so it could be reasonable to use tucatinib without capecitabine. There are similar data for single-agent neratinib, but both agents appear to be more effective when combined with a cytotoxic agent.

Sarah L. Sammons, MD:
There is a phase I dose-escalation trial of trastuzumab plus tucatinib that resulted in some intracranial responses, so the regimen likely has some CNS activity without capecitabine. In addition, the phase III HER2CLIMB-05 trial is currently investigating maintenance tucatinib with trastuzumab and pertuzumab, so we may get more data for this use case. Fortunately, DPD deficiency occurs in only 3% to 8% of the population, and my institution has strict guidelines to dose reduce capecitabine for these patients. In my clinical practice for patients with moderate DPD deficiency beginning the HER2CLIMB regimen, I start with a moderate dose reduction of capecitabine and if a patient does not tolerate it, I may treat without capecitabine.

How would you treat patients with progressive brain metastases but no other systemic progression while on T-DXd treatment?

Sarah L. Sammons, MD:  
For patients currently receiving T-DXd who experience a new brain metastasis or progression of an existing brain metastasis but whose disease is otherwise controlled, it is reasonable to radiate the brain metastases for local control and continue systemic therapy with T-DXd. However, for patients experiencing repetitive CNS events while receiving T-DXd, switching to another systemic regimen like tucatinib/trastuzumab/capecitabine could be considered.

Ian Krop, MD, PhD:
I agree. In fact, there were several T-DM1 and T-DXd trials that allowed patients with isolated CNS progression to receive local radiotherapy and continue the study systemic therapy. The data showed that patients could meaningfully benefit from systemic therapy after isolated progression in the brain. For instance, patients who followed this strategy in the HER2CLIMB trial, experienced a median time to second progression in the body or the brain, or death, of 7.6 months vs 3.1 months in the control arm. So, in my practice and in the ASCO guidelines, it is recommended to perform local therapy and continue systemic therapy.

Your Thoughts
What other complexities do you come across when determining the optimal treatment sequence for your patients with HER2-positive MBC? Does the presence of brain metastases change your treatment approach? Add your comments to the discussion below.

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For your patients with progressive HER2-positive MBC and active brain metastases, which of the following is your preferred systemic treatment?

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