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Sequencing Tx HER2 MBC
Expert Thoughts on Sequencing Therapy for Patients With HER2+ Metastatic Breast Cancer 

Released: January 29, 2025

Expiration: January 28, 2026

Ian Krop
Ian Krop, MD, PhD
Sarah L. Sammons
Sarah L. Sammons, MD
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Key Takeaways
  • Currently, taxane with trastuzumab and pertuzumab (THP) followed by HP maintenance is standard first line therapy for HER2-positive metastatic breast cancer (MBC).
  • Recently reported results from the phase III PATINA trial support the addition of palbociclib to maintenance HP and endocrine therapy following induction therapy in patients with HR-positive/HER2-positive MBC.
  • T-DXd is standard second line therapy for most patients while tucatinib, trastuzumab and capecitabine can be an option for those with predominant central nervous system disease.
  • Later lines of therapy for HER2-positive MBC should be selected considering patient preference and treatment history.

Ian Krop, MD, PhD:
In this commentary, we will take a look at the topic of sequencing therapy for HER2-positive metastatic breast cancer (MBC), which is particularly exciting today because we don't have a true standard of care beyond the second-line setting and therapy options in this space are rapidly evolving. We have multiple treatment options but limited comparative data to say that one is more active or preferred over another. To some extent, we are currently basing our treatment approaches on the specific presentation characteristics of each patient and where they are in their treatment journey. 

First- and Second-Line Standard of Care

Ian Krop, MD, PhD:
For most patients with HER2-positive MBC that we see in our clinics today, first-line therapy remains a taxane plus trastuzumab and pertuzumab (THP) because this combination is both effective and typically well tolerated. Recently reported results from the phase III PATINA trial demonstrated the benefit of adding palbociclib to maintenance HP and endocrine therapy following induction THP in patients with hormone receptor (HR)-positive/HER2-positive MBC, with a more than 15-month improvement in median PFS (see more details below). These results provide strong support to adopting this regimen into the maintenance setting for this patient population. Second-line treatment is most commonly trastuzumab deruxtecan (T-DXd) based on results from the DESTINY-Breast03 trial though there may be some patients with highly active brain metastases who receive tucatinib with capecitabine and trastuzumab. However, recent data from the DESTINY-Breast12 study confirm that T-DXd also has robust and durable activity against HER2+ brain metastases.

Sarah Sammons, MD:
Over the next couple of years, I expect therapy sequencing for HER2-positive MBC will become a lot more complex because T-DXd may move into the first-line setting if the ongoing DESTINY-Breast09 trial shows that T-DXd with or without pertuzumab as initial therapy improves outcomes compared to THP.

Challenges in the Third- and Fourth-Line Settings

Sarah Sammons, MD:
Today, our clinical challenge is determining what to give patients with HER2-positive MBC in the third-line setting and beyond. The reality is that most approved HER2-targeted agents have not been studied in patients who had disease progression after T-DXd, but real-world data tell us that they probably have some efficacy and should be used in this setting. The most commonly used third-line therapy is tucatinib combined with trastuzumab and capecitabine based on results of the HER2CLIMB trial showing clear superiority compared with the combination of capecitabine and trastuzumab alone. The addition of tucatinib improved both progression-free survival (PFS) with a 43% reduction in risk of disease progression or death and overall survival (OS) with a 27% reduction in risk of death. Of importance, the tucatinib regimen is also active in patients with brain metastases, which are unfortunately common in patients with HER2-positive MBC.

Ian Krop, MD, PhD:
After tucatinib/trastuzumab/capecitabine, we often use trastuzumab emtansine (T-DM1) as our fourth-line therapy choice. T-DM1 has been shown to be active in later lines and is a reasonable approach for patients after tucatinib-based therapy or in the third-line setting for patients not considered to be good candidates for tucatinib. Many practitioners prefer to use tucatinib-based therapy in the third-line setting rather than T-DM1 because of the similar mechanism of action of T-DXd and T-DM1 as HER2-targeting antibody–drug conjugates (ADCs). Although these 2 ADCs have different payloads, if disease progression on T-DXd occurs due to resistance through loss or downregulation of HER2, this would affect both agents. Intuitively, it makes more sense to use tucatinib-based therapy, as a completely different class of agent, after T-DXd. Some real-world evidence from the nationwide Flatiron database has shown some activity of tucatinib and other agents after T-DXd, but in the future, it would be useful to have comparative data in the setting of progressive disease following treatment with T-DXd.

We hoped the HER2CLIMB-02 trial, which tested the addition of tucatinib to T-DM1, would simplify the choice of third-line treatment by administering both agents together. However, although this drug combination did improve PFS compared with T-DM1 alone, the benefit was small and was associated with substantially increased toxicities. So, we would recommend treating with tucatinib plus trastuzumab/capecitabine in the third-line setting followed by T-DM1 or vice versa in select cases.

Later Lines of Treatment

Ian Krop, MD, PhD:
Subsequent therapy following third- and fourth-line treatment is where therapeutic sequencing becomes very heterogeneous. All the remaining approved HER2-targeted therapies have been used for many years. For instance, various combinations of trastuzumab with a chemotherapy agent, like eribulin or navelbine, that patients have not yet received, can be active. We also have another approved HER2-targeted antibody called margetuximab, which is similar to trastuzumab, but has been modified to increase antibody-dependent cellular cytotoxicity. The SOPHIA trial showed margetuximab plus chemotherapy had superior PFS compared to trastuzumab plus chemotherapy (5.8 months vs 4.9 months; HR: 0.76; P = .03), although there was no significant difference in OS (21.6 months vs 21.9 months; HR: 0.95; P = .620). Other agents include endocrine therapy in combination with HER2 therapy, such as fulvestrant with trastuzumab and the CDK4/6 inhibitor abemaciclib which improved PFS vs trastuzumab plus chemotherapy.

Lastly, there are other tyrosine kinase inhibitors besides tucatinib that have shown benefit for patients with HER2-positive MBC. Neratinib is a very potent HER2 and other ErbB family kinase inhibitor that benefited patients when combined with capecitabine compared to lapatinib with capecitabine. However, neratinib studies were all in patients who had not been previously treated with tucatinib, so it is unknown whether neratinib is still efficacious after disease progression on tucatinib. It is plausible that neratinib’s mechanism of targeting more kinases than tucatinib could help it have a benefit, but we lack those data.

Due to the variety of options and limited data, after the third- or fourth-line setting, treatment selection should be done in partnership with patients and tailored to their preference of side effects or type of treatment. For instance, different patients may prioritize avoiding hair loss, multiple IV therapies, diarrhea, or neuropathy. Most patients will be treated with many of the available treatment options over the course of their disease, and for now sequencing in later lines will be less data-driven and more based on patient preference.

New Data Impacting the Management of HR-Positive/HER2-Positive MBC

Sarah Sammons, MD:
To end this commentary with an example of the rapid pace of treatment paradigm shifts, the most important recent data for HER2+ advanced breast cancer were the PATINA trial reported at the San Antonio Breast Cancer Symposium in December 2024. This open-label, international, phase III clinical trial enrolled patients with HR-positive and HER2-positive metastatic breast cancer without evidence of disease progression following standard of care induction therapy with trastuzumab with a taxane with or without pertuzumab. These patients were randomized to maintenance therapy with trastuzumab, optional pertuzumab, and endocrine therapy with or without palbociclib. The latest results show a marked improvement in median PFS with palbociclib (44.3 months vs 29.1 months without palbociclib; HR: 0.74; P = .0074). The median PFS of 44.3 months is the longest ever reported in this patient population. The addition of palbociclib was also generally well tolerated with a low discontinuation rate and an adverse event profile consistent with that expected for this drug. We await FDA approval for this regimen, but we expect these data to be paradigm-shifting since we have previously treated HER2-positive disease similarly regardless of HR status. Now, it appears that we may need to optimally target HR in our patients, and we may see more trials exploring this concept in the future.

Your Thoughts
What are your questions regarding treatment sequencing for your patients with HER2-positive MBC? What are your biggest challenges when caring for these patients? Add your questions and comments to the discussion below.

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Other than trastuzumab, which of the following HER2-targeted agents are you currently using in your practice? Please select all that apply.

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