P06.11.A TUTOR: A MULTICENTER, PHASE 1 TRIAL OF TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER

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Abstract BACKGROUND Nearly 20-40% of patients with HER2-positive cancer patients develop brain metastases (BMs), where stereotactic radiosurgery (SRS) is standard for care for local disease control. Tucatinib, an oral HER2-selective tyrosine kinase inhibitor (TKI), has been demonstrated to be safe and efficacious in HER2+ breast cancer in combination with capecitabine and trastuzumab. Synergism between these 3 drugs and radiation may enhance DNA damage, causing increased apoptosis. This phase 1 trial aimed to evaluate whether this 3-drug therapy, in combination with SRS, may be safe and provide superior long-term control of intracranial and systemic disease in patients with HER2+ breast cancer BMs (BCBM). MATERIAL AND METHODS TUTOR is a pre-registered (NCT05553522) prospective, single-arm, multicenter, ongoing, phase 1 clinical trial that aims to determine the safety and efficacy of the combination therapy in patients with HER2+ BCBM. Patients with age 18-80 years, ECOG score 0-2, normal organ function, and up to 10 newly-diagnosed BMs are being enrolled at six centers in the US. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases documented by MRI or CSF evaluation, intra-tumoral or peri-tumoral hemorrhage, and BMs within 5 mm of the optic chiasm/nerve. The primary study endpoint is maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg twice daily (BID). Dose level -1 is 250 mg BID, and dose level -2 is 200 mg BID. Up to 40 patients will be enrolled in this study based on a 3 + 3 design. Patients are administered oral tucatinib with SRS as per treating radiation oncologist, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until 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 any non-hematologic toxicity of grade 3 or greater (excluding alopecia). We plan to expand the cohort at MTD to total 40 patients to assess the safety and efficacy. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are being assessed by Hopkins Verbal Learning Test, Controlled Oral Word Association, Trail Making Test Part A and B, and Grooved Pegboard Test. Early and late toxicities are assessed using CTCAE v5.0. Quality of life is assessed by Functional Assessment of Cancer Therapy, including Brain Tumor module (FACT-Br). RESULTS Patient enrollment started in February 2023. CONCLUSION Findings from this trial will demonstrate the safety and efficacy of combination therapy for BCBM.

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