A multicenter phase 1 trial of tucatinib, trastuzumab, and capecitabine with stereotactic radiosurgery in patients with brain metastases from HER-2–positive breast cancer (TUTOR).

TPS2089 Background: 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), for which stereotactic radiosurgery (SRS) is used for local disease control. Tucatinib, an oral HER-2-selective tyrosine kinase inhibitor (TKI), has been demonstrated to be safe and efficacious in HER-2-positive breast cancer in combination with capecitabine and trastuzumab. The synergism between these three drugs and radiation may potentially enhance DNA damage, causing increased apoptosis. We hypothesize that this 3-drug therapy, in combination with SRS in patients with HER-2 positive breast cancer BM (BCBM), may be safe and provide superior long-term control of intracranial and systemic disease. Methods: This is a prospective, single-arm, multicenter, ongoing, phase 1 clinical trial. Patients aged 18-80 years, ECOG score 0-2, normal organ function, and up to 10 newly-diagnosed BMs is planned to enroll at six centers in the US. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases, evidence of intra-tumoral or peri-tumoral hemorrhage, and BMs within 5 mm of the optic chiasm/nerve. Patients receive oral tucatinib alongside SRS, followed by a two-week dose-limiting toxicity (DLT) period, and subsequently continue the regimen until disease progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and grade 3 non-hematologic toxicity. Primary study endpoint is maximum tolerated dose (MTD) of tucatinib in combinatorial therapy. This de-escalation study starts at 300 mg dose level (DL), with DL-1 250 mg, and DL-2 200 mg, based on a 3 + 3 design. Cohort expansion at MTD is planned to a total of 40 patients. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, overall survival, quality of life as assessed by FACT-Br, toxicity, and neurocognitive function. The trial has been approved by the Institutional Review Board (IRB) and currently is enrolling patients. Clinical trial information: NCT05553522 .