Phase I trial of trastuzumab deruxtecan in combination with stereotactic radiosurgery for brain metastases from HER2-positive breast cancer.

Abstract

TPS2093 Background: Brain metastases (BM) develop in nearly 40-50% of patients with HER2-positive breast cancer. Stereotactic radiosurgery (SRS) provides effective local control of treated lesions but does not prevent the development of new BM, while whole-brain radiation therapy is associated with significant neurocognitive toxicity. Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody-drug conjugate (ADC) that has demonstrated significant systemic and intracranial activity in patients with HER2-positive breast cancer. Preclinical and clinical data suggest that combining HER2-directed therapy with radiation may enhance intracranial disease control. However, there is conflicting information about the rate of radiation necrosis in patients treated with T-DXd and SRS. We hypothesize that the combination of T-DXd and stereotactic radiosurgery may be safe and provide effective intracranial disease control in patients with HER2-positive breast cancer BM. Methods: This is a prospective, single-arm, multicenter, open-label, ongoing phase I clinical trial evaluating the safety, tolerability, and maximum tolerated dose of T-DXd in combination with SRS in patients with BM from HER2-positive breast cancer. Eligible participants are adults (≥18 years) with histologically confirmed HER2-positive breast cancer, Eastern Cooperative Oncology Group performance status of 0–2, adequate organ function, and 1–10 newly diagnosed BM who are candidates for SRS. Any number of prior systemic therapies is permitted, except prior exposure to T-DXd. Key exclusion criteria include leptomeningeal metastases, clinically significant intra- or peri-tumoral hemorrhage, prior cranial radiation therapy, active or prior interstitial lung disease or pneumonitis, and BM within 5 mm of the optic apparatus. Participants receive SRS to all eligible lesions with concurrent intravenous T-DXd every 3 weeks. A standard 3+3 dose de-escalation design is used, starting at 5.4 mg/kg with planned de-escalation to 4.4 mg/kg and 3.2 mg/kg. Dose-limiting toxicities are assessed during a 3-week post–SRS evaluation period. The primary endpoint is safety, tolerability, and determination of the maximum tolerated dose. Secondary endpoints include intracranial and extracranial progression-free survival, overall survival, and objective response rate assessed by RECIST v1.1. Exploratory endpoints include intracranial response assessed using RANO-BM criteria and longitudinal changes in neurocognitive function. Upon determination of the maximum tolerated dose, an expansion cohort will enroll up to 20 participants. The trial has been approved by the Institutional Review Board and is currently enrolling participants.