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Novel Management of HER2 Positive MBC
The Changing Landscape of First-line and Maintenance Therapy for HER2-Positive Metastatic Breast Cancer

Released: April 30, 2026

Erika Hamilton
Erika Hamilton, MD, FASCO
Ian Krop
Ian Krop, MD, PhD
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Key Takeaways
  • Trastuzumab deruxtecan combined with pertuzumab represents a potential new first-line option for patients with HER2-positive MBC, significantly improving PFS and complete response rates over THP in the DESTINY-Breast09 trial.
  • In the PATINA trial, the addition of palbociclib to endocrine therapy plus trastuzumab and pertuzumab in the maintenance setting following THP yielded a median PFS of ~44 months among patients with HR-positive/HER2-positive disease.
  • Tucatinib added to maintenance trastuzumab and pertuzumab provided a clinically meaningful PFS benefit in patients with HER2-positive disease that was both HR-positive and negative based on data from the HER2CLIMB-05 study.

The field of first-line therapy and maintenance treatment for patients with HER2-positive metastatic breast cancer (MBC) has recently evolved, with significant clinical trial data potentially shifting established paradigms. In this commentary, Erika Hamilton, MD, FASCO, and Ian Krop, MD, PhD, discuss these data and the possible impact on treatment for patients with HER2-positive metastatic breast cancer.

Historical Treatment Paradigms

Ian Krop, MD, PhD:
When we think about first-line therapy for HER2-positive MBC, it is important to start with the historical foundation established by the CLEOPATRA trial. This study evaluated docetaxel with trastuzumab with or without pertuzumab in patients with newly diagnosed HER2-positive metastatic disease and clearly demonstrated that dual HER2 blockade significantly improved outcomes. Median progression-free survival (PFS) approached 19 months, and overall survival improved by nearly 17 months with the addition of pertuzumab, establishing taxane plus trastuzumab and pertuzumab (THP) as the standard of care for more than a decade.

Key insights from CLEOPATRA were not only the efficacy of dual HER2 targeting but also the concept of an induction-maintenance strategy. Patients received chemotherapy for a finite period, typically 6-8 cycles, after which the taxane was discontinued and patients continued maintenance trastuzumab and pertuzumab until disease progression. This approach significantly improved tolerability while maintaining disease control and has been widely adopted in clinical practice.

Erika Hamilton, MD, FASCO:
The induction–maintenance paradigm has shaped how we think about treatment in this setting. The ability to discontinue cytotoxic chemotherapy while maintaining disease control with HER2-targeted therapy is very appealing for patients. The question more recently has been whether we can further improve upon the maintenance phase by incorporating additional targeted therapies.

Novel Maintenance Therapy Strategies: PATINA and HER2CLIMB-05

Ian Krop, MD, PhD:
One important study addressing this is the phase III PATINA trial, which focused on patients with hormone receptor (HR)–positive/HER2-positive MBC. In this study, patients who had completed induction chemotherapy with trastuzumab with or without pertuzumab and taxane/vinorelbine and achieved at least stable disease were randomized to maintenance endocrine therapy plus trastuzumab and pertuzumab with or without the CDK4/6 inhibitor palbociclib.

The rationale for this approach was based on the known role of CDK4/6 signaling in HR-positive disease, as well as preclinical data suggesting synergy between HER2-targeted therapy and CDK4/6 inhibition. The results were quite compelling. The addition of palbociclib led to a median PFS of approximately 44 months, representing an approximately 15-month improvement over endocrine therapy and HER2-targeted therapy alone.

Erika Hamilton, MD, FASCO:
I think many of us were surprised by the magnitude of benefit seen in PATINA. The PFS of more than 40 months is quite compelling in this setting. In terms of safety, there was increased neutropenia, as expected with CDK4/6 inhibition, and some increase in diarrhea, but overall, the regimen was well tolerated, with relatively low discontinuation rates because of toxicity.

Another strategy to potentially improve maintenance therapy is reflected in the phase III HER2CLIMB-05 trial, which evaluated the addition of tucatinib, a HER2-specific tyrosine kinase inhibitor, to maintenance trastuzumab and pertuzumab after induction chemotherapy. This study included patients with both HR-positive and HR-negative tumors, broadening its applicability. The results of this study were positive across both subgroups. The addition of tucatinib improved PFS by 8.6 months compared with trastuzumab and pertuzumab alone. Of importance, despite concerns about overlapping toxicities, particularly diarrhea with both pertuzumab and tucatinib, the increase in high-grade diarrhea was minimal, only approximately 2% higher than the control arm and discontinuation rates due to diarrhea were only ~1%.

We also saw that the magnitude of benefit differed somewhat by HR status, with a greater benefit observed in HR-negative disease: more than 12 months compared with just less than 7 months in HR-positive patients, although both groups derived statistically significant benefit.

Ian Krop, MD, PhD:
Taken together, these data reinforce the concept that targeted maintenance therapy is not only feasible but can be highly effective in HER2-positive MBC. We have been using maintenance trastuzumab and pertuzumab for many years, and now we are seeing that adding agents such as palbociclib or tucatinib can further extend disease control, in some cases to several years.

Erika Hamilton, MD, FASCO:
I think the key clinical question now is how to select among these maintenance strategies. HR status is clearly one factor, with CDK4/6 inhibition being particularly relevant for HR-positive disease. However, other clinical features may also influence decision-making.

Ian Krop, MD, PhD:
One important consideration is the presence of central nervous system (CNS) metastases. Tucatinib has demonstrated the ability to penetrate the blood–brain barrier and improve outcomes in patients with brain metastases. Although data in the first-line maintenance setting are limited, HER2CLIMB-05 did include some patients with baseline CNS disease and suggested improved CNS PFS with tucatinib.

Erika Hamilton, MD, FASCO:
I agree. Although the number of patients with brain metastases in HER2CLIMB-05 was relatively small, there was a signal that CNS outcomes were improved, which would make tucatinib an attractive option in that setting.

Novel Approaches to First-line Therapy: DESTINY-Breast09

Erika Hamilton, MD, FASCO:
Recently, we have also seen data from the phase III DESTINY-Breast09 trial, which challenges the traditional first-line paradigm. This study evaluated trastuzumab deruxtecan (T-DXd) in combination with pertuzumab compared with standard THP as first-line therapy for patients with HER2-positive MBC. A significant improvement in PFS was observed with T-DXd plus pertuzumab, with a median of 40.7 months compared with 26.9 months for THP.

This is a substantial improvement, and it raises important questions about how we incorporate this regimen into practice. Of note, DESTINY-Breast09 did not include a predefined maintenance phase. Patients were treated until progression, which differs from the CLEOPATRA paradigm. In addition, we saw higher complete response rates with T-DXd plus pertuzumab, approximately 15% compared with 8.5% with THP, which is clinically meaningful, particularly given the potential for long-term disease control in some patients.

Ian Krop, MD, PhD:
That creates some uncertainty about how to approach maintenance in the context of T-DXd–based therapy. Although the trial did not formally include a maintenance strategy, some patients effectively transitioned to maintenance by discontinuing T-DXd after a median of approximately 20 months because of toxicity while continuing HER2-directed antibodies. In practice, treatment decisions are individualized, as there are no data to guide planned de-escalation. Healthcare professionals should monitor tolerability closely and may reasonably discontinue T-DXd and continue antibody therapy alone if toxicity affects quality of life, despite the absence of a predefined maintenance strategy.

Erika Hamilton, MD, FASCO:
What probably would not be wise is to adapt the CLEOPATRA design and simply stop T-DXd at 6-8 cycles and transition to maintenance therapy. I would want to ensure that patients receive sufficient therapy to achieve maximal response before considering de-escalation.

Ian Krop, MD, PhD:
I agree. Unlike docetaxel, which is typically limited to 6-8 cycles because of tolerability, T-DXd may require a longer duration of therapy to achieve maximal benefit. Therefore, decisions about transitioning to maintenance therapy will likely need to be individualized, balancing efficacy and toxicity.

Erika Hamilton, MD, FASCO:
Overall, we are seeing an evolution in both first-line and maintenance strategies for patients with HER2-positive MBC.

Ian Krop, MD, PhD:
I agree. The field is evolving rapidly, and although we have more effective options than ever before, we also have more complexity in decision-making. Ongoing studies and longer follow-up will be critical to help define optimal sequencing, duration of therapy, and patient selection for these different approaches.

Your Thoughts
Have you employed novel first-line or maintenance therapy in your practice for patients with HER2-positive MBC. If so, what was your experience? Join the conversation by adding a comment and answering the polling question.

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A patient with HR-positive/HER2-positive MBC with no brain metastases has completed 6 cycles of THP with a partial response and manageable grade 1 neuropathy and grade 2 alopecia.

In your current practice, what would you recommend for this patient?

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