A Promising Combination for HER2-Positive Breast Cancer with Brain Metastases

At the 2023 San Antonio Breast Cancer Symposium (SABCS), results from the phase III HER2CLIMB-02 study showed that, in previously treated patients with locally advanced unresectable or metastatic HER2-positive breast cancer, tucatinib (Tukysa, Seagen) combined with trastuzumab emtansine (Kadcyla, T-DM1, Genentech), compared with T-DM1 alone, improved progression-free survival (PFS) . A subgroup analysis of patients with brain metastases at baseline also showed beneficial treatment effects in this group.

Accounting for about one-fifth of breast cancers, HER2-positive breast cancer has too much of the protein called human epidermal growth factor receptor 2 (HER2), which promotes human cell growth. More than 25% of women with metastatic HER2-positive breast cancer will develop brain metastases . These are common in HER2-positive breast cancer and are associated with poor outcomes. Few treatment options are available for this group.

Tukysa is a small-molecule medicine taken orally as a tablet in the tyrosine kinase inhibitor class. It blocks a type of enzyme (a kinase) and helps prevent cancer cell growth (see the figure below).

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The earlier HER2CLIMB study showed better outcomes with tucatinib plus trastuzumab and capecitabine in patients who had received multiple systemic treatments, including those with brain metastases. In 2020, the FDA approved this combination for advanced, unresectable or metastatic HER2-positive breast cancer, including cases with brain metastases.

Details of HER2CLIMB-2

Adding tucatinib to TDM-1 significantly improved progression-free survival (PFS) in previously treated HER2+ advanced breast cancer. This was the second randomized study to include patients with brain metastases and show that tucatinib-based treatment delays disease progression in this setting.

Tucatinib is a small-molecule HER2 inhibitor shown to be effective against disease progression in the central nervous system.

Results

In HER2CLIMB-2, researchers randomly assigned 463 patients to tucatinib plus T-DM1 or placebo plus T-DM1. Almost half (44.1%) had brain metastases at baseline.

• At a median follow-up of 24.4 months, tucatinib plus T-DM1 reduced the risk of progression or death by 24% (hazard ratio [HR], 0.76; P = 0.0163). Median progression-free survival was 9.5 months with the combination versus 7.4 months with placebo.
• In HER2CLIMB-2, tucatinib plus T-DM1 benefited progression-free survival (PFS) among patients with brain metastases at baseline (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.46-0.89). Overall survival (OS) could not yet be determined because too few survival events had occurred at the time of presentation.

No statistically significant difference in overall response rate was observed in the intervention arm receiving tucatinib and T-DM1.

Treatment-related adverse effects were more common with tucatinib. They included nausea (65.4% versus 49.4%), diarrhea (56.7% versus 26.6%) and fatigue (48.9% versus 37.3%). Among grade 3 or higher events, increased alanine and aspartate aminotransferase levels stood out, each occurring in 16.5% in the tucatinib arm versus 2.6% for each in controls. Adverse effects causing treatment interruption occurred in 22.1% versus 11.6%. Treatment-related deaths occurred in 1.3% of the tucatinib group versus 0.9% of controls.

Commentary

These results may suggest that tucatinib should continue to be used as second-line treatment in patients with brain metastases. Based on DESTINY-Breast03, trastuzumab deruxtecan is likely to remain the preferred standard for patients without brain metastases.

Brain metastases, however, substantially worsen the course of breast cancer, and effective treatments are urgently needed for these patients. Approaches developed for this group should therefore be evaluated earlier in treatment. Clinical trials including these patients are particularly important because they may offer effective solutions for this challenging aspect of the disease. This highlights the need for a specific focus on this group in research and development.

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