Trastuzumab deruxtecan (T-DXd) was linked with significantly lower incidence of brain metastasis than tucatinib/trastuzumab/capecitabine (TTC) in patients with HER2 positive metastatic breast cancer, according to research presented at the 2026 ASCO Annual Meeting.

Brain metastases are a leading cause of morbidity and mortality in patients with HER2-positive metastatic breast cancer. Two regimens with established central nervous system (CNS) activity, T-DXd and TTC, are used in the second-line setting, but real-world comparative brain metastasis data are limited.

The HER2CLIMB trial established TTC as a standard second-line regimen with CNS activity, including in patients with active brain metastases. The DESTINY-Breast12 trial demonstrated intracranial benefit with T-DXd in patients with stable and active brain metastases. Real-world comparative estimates between the two regimens remain limited.

Researchers used TriNetX, a federated electronic health record network, to identify patients with HER2+ breast cancer previously treated with first-line taxane plus trastuzumab and pertuzumab who were brain metastasis-free at the start of second-line treatment. After 1:1 propensity score matching, 540 patients per arm were included. Median follow-up was 13.4 months.

Incident brain metastases occurred in 12.6% of patients receiving T-DXd vs 20.9% of those receiving TTC, an absolute risk difference of -8.3%.

One-year brain metastasis-free survival was 72.65% with T-DXd vs 67.89% with TTC. Among patients who developed brain metastases, TTC was associated with higher brain metastases-related healthcare burden than T-DXd.

CNS morbidity events were less frequent with T-DXd than TTC, including seizures and cerebral edema.

Overall survival did not differ significantly between T-DXd and TTC.

“In HER2+ [metastatic breast cancer patients] without baseline brain metastases following first-line [taxane plus trastuzumab and pertuzumab], T-DXd was associated with significantly lower incident brain metastases, delayed onset, and reduced CNS morbidity compared with TTC. These findings warrant validation using standardized CNS surveillance and may help inform treatment selection in [patients] at high risk for [brain metastases].”

- Study author Zunairah Shah, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

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References:

https://www.asco.org/abstracts-presentations/261246

https://clinicaltrials.gov/study/NCT02614794

https://clinicaltrials.gov/study/NCT04739761

Disclosures: Some authors declared relevant financial disclosures. See full abstract for details. Pfizer Inc. supported the study.

By Zia Sherrell

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