Sequencing Novel Medications For HER2+ Metastatic Breast Cancer

Approximately 15-20% of breast cancers overexpress HER2, leading to more aggressive disease and poorer prognosis compared to HER2-negative cancers. 

Historically, patients with HER2-positive metastatic breast cancer (MBC) faced limited treatment options, but the development of HER2-targeted therapies has significantly improved outcomes, including survival.

However, these is still some nuance when it comes to when and how to give these therapies. 

First-Line Therapy: Trastuzumab, Pertuzumab, and Taxanes 

For patients with newly diagnosed HER2-positive MBC, the combination of trastuzumab, pertuzumab, and a taxane (typically docetaxel or paclitaxel) is considered the gold standard in first-line treatment. Dr. Heather McArthur, a clinical director of breast cancer at UT Southwestern in Dallas, Texas, tells SurvivorNet Connect that this regimen is supported by results from the pivotal CLEOPATRA trial, which demonstrated improved overall survival (OS) and progression-free survival (PFS) compared to trastuzumab and chemotherapy alone. 

The trial showed a median OS of 57.1 months with the addition of pertuzumab, compared to 40.8 months without. However, this combination is not without significant toxicity. Common side effects include neutropenia, diarrhea, and febrile neutropenia. Despite these, the survival benefits outweigh the risks for most patients. Paclitaxel is often favored due to better tolerability compared to docetaxel, although both agents are effective. 

Nuances for Hormone Receptor-Positive Patients 

For patients with HER2-positive and hormone receptor-positive disease, endocrine therapy combined with HER2-targeted therapy is a viable option, especially for those with less aggressive disease. The combination of HER2-targeted therapy and endocrine agents like aromatase inhibitors can delay the need for chemotherapy, reducing treatment-related toxicity in this subset of patients. 

Second-Line Therapy: Ado-Trastuzumab Emtansine (T-DM1) and Fam-Trastuzumab Deruxtecan (T-DXd) 

Patients who progress on first-line therapy typically receive an antibody-drug conjugate (ADC). Ado-trastuzumab emtansine (T-DM1) has been a mainstay in second-line treatment for several years, offering a significant survival advantage with a more tolerable side-effect profile than traditional chemotherapy. The EMILIA trial showed that T-DM1 improved OS compared to lapatinib and capecitabine, with fewer high-grade toxicities. Recently, fam-trastuzumab deruxtecan (T-DXd) has emerged as a potent option for patients after progression on trastuzumab and a taxane. The DESTINY-Breast03 trial demonstrated that T-DXd led to superior PFS and OS compared to T-DM1, making it an increasingly favored option in this setting. However, T-DXd carries a notable risk of interstitial lung disease (ILD), which requires close monitoring. 

“The second line was previously T-DM1 based on the Emilia study, but now T-DM1 has been displaced based on the destiny-breast03 study, which looked at T-DM1 going head to head against one of these more novel antibody-drug conjugates Trastuzumab Deruxtecan, which is HER2 targeted antibody that’s linked to a topo isomerase payload,” Dr. McArthur explains.

“There was a significant improvement in progression-free survival and overall survival in favor of the antibody-drug conjugate. So that became for most patients a standard of care in the second line setting,” she says.  

Later-Line Therapies: Tucatinib, Lapatinib, and Neratinib 

For heavily-pretreated patients, multiple HER2-targeted agents remain available, and treatment selection is often guided by factors such as the presence of brain metastases or prior treatment toxicity. Tucatinib, in combination with trastuzumab and capecitabine, has shown remarkable efficacy in patients with brain metastases. 

“In someone with limited burden non CNS disease, I would probably favor the Tucatinib based regimen because of the ease of administration and quality of life for patients. For patients who maybe have large burden disease who are willing to undergo more frequent monitoring, I would consider trastuzumab deruxtecan,” Dr. McArthur explains.

The HER2CLIMB trial reported improved PFS and OS in patients receiving tucatinib versus placebo, including those with central nervous system involvement, making tucatinib a critical agent in this context. Lapatinib and neratinib, both tyrosine kinase inhibitors (TKIs), are other options, though their use has decreased with the rise of newer agents. Neratinib, often combined with capecitabine, offers irreversible HER2 inhibition, but gastrointestinal toxicity, particularly diarrhea, is a common limitation.

Special Considerations and Toxicity Management 

As with any cancer treatment, balancing efficacy and toxicity is critical. For patients experiencing treatment-related cardiotoxicity, especially with trastuzumab-based regimens, regular cardiac monitoring is essential. The incidence of left ventricular dysfunction is low but must be vigilantly managed to prevent irreversible damage. 

Additionally, as HER2-directed agents are often used long-term, managing cumulative toxicity, including fatigue, gastrointestinal issues, and hematologic side effects, is crucial to maintaining patients’ quality of life. For patients intolerant to chemotherapy, dual HER2-targeted therapy with trastuzumab and pertuzumab, without a taxane, may be a reasonable approach. 

Future Directions in HER2-Positive MBC Treatment 

The treatment landscape for HER2-positive MBC continues to evolve. Ongoing trials are investigating novel ADCs, such as trastuzumab duocarmazine, and newer combinations of TKIs and immunotherapies. The role of immune checkpoint inhibitors in HER2-positive disease, though still under investigation, may offer additional therapeutic options, particularly for patients with PD-L1-positive tumors. In the coming years, personalized medicine, guided by molecular profiling, is likely to further refine treatment algorithms, allowing for more tailored therapies based on tumor biology and patient-specific factors. 

The treatment of HER2-positive metastatic breast cancer has advanced significantly with the advent of HER2-targeted therapies. While trastuzumab, pertuzumab, and taxanes remain the cornerstone of first-line treatment, newer agents like T-DXd and tucatinib offer promising results for patients who progress on initial therapy. Despite these advances, challenges remain, particularly in managing treatment-related toxicities and drug resistance. 

Future research will likely bring even more targeted, less toxic treatment options for this aggressive form of breast cancer, offering hope for improved outcomes and quality of life for patients.