Trastuzumab Rezetecan Yields High Intracranial Remission Rates in HER2-Positive BC With Brain Metastases

Trastuzumab rezetecan (SHR-A1811) as a 6.4 mg/kg dose alone or 4.8 mg/kg dose combined with bevacizumab both yield high intracranial remission rates in patients with HER2-positive breast cancer (BC) with brain metastases (BM); however, the lower-dose combination regimen appears to have a better safety profile, according to updated results from the REIN trial presented as an abstract at the 2025 American Society for Clinical Oncology Annual Meeting.

The REIN trial is a prospective, non-randomized, phase 2 trial (ClinicalTrials.gov ID: NCT05769010) assessing the feasibility of the novel HER2-directed antibody-drug conjugate trastuzumab rezetecan with or without other anti-tumor agents in HER2-positive BCBM.

The investigators reported efficacy and safety data of trastuzumab rezetecan combined with bevacizumab and updated results of trastuzumab rezetecan alone in HER2-positive BCBM.

The study enrolled patients with HER2-positive or -low BC with at least one radiotherapy-naïve measurable intracranial lesion. In the trastuzumab rezetecan alone arm, patients received trastuzumab rezetecan 6.4 mg/kg every 3 weeks. In the trastuzumab rezetecan-bevacizumab combination arm, patients received trastuzumab rezetecan 4.8 mg/kg and bevacizumab 15 mg/kg every 3 weeks, until disease progression, unacceptable toxicity, or no further benefit. The primary endpoint was intracranial overall response rate (ORR-IC) per RANO-BM.

As of June 3, 2024, the study has enrolled 58 patients, 33 in the trastuzumab rezetecan alone arm and 25 in the trastuzumab rezetecan-bevacizumab combination arm. Most patients (96.6%) previously received anti-HER2 therapy, and the median number of prior systemic therapies in the advanced setting was 2 (range, 0-9).

Among 54 patients who received one or more efficacy assessments, the confirmed ORR-IC was 84.4% (27/32) in the trastuzumab rezetecan alone arm and 72.7% (16/22) in the trastuzumab rezetecan-bevacizumab combination arm. The investigators reported that all patients achieved intracranial disease control.

Treatment-related adverse events (TRAEs) of grade 3 or 4 occurred in 78.8% (Grade 4, 36.4%) of patients in the trastuzumab rezetecan alone arm and 48.0% (Grade 4, 4%) in the trastuzumab rezetecan-bevacizumab combination arm. Grade 3 or 4 TRAEs that occurred in 1 or more patients included decreased neutrophil counts (alone/combination arms: 69.7% / 36.0%), reduced leucocyte counts (51.5% / 16.0%), decreased platelet counts (30.3% / 0%), anemia (21.2% / 8.0%), reduced lymphocyte counts (21.2% / 0%), and nausea (6.1% / 0%).

“Our findings showed that SHR-A1811 6.4 mg/kg solely or SHR-A1811 4.8 mg/kg combined with bevacizumab both can attain high intracranial remission rates, while the lower-dose combination regimen might exhibit a better safety profile. The long-term outcomes will continue to be followed up,” concluded the investigators.