Js06.5.a tucatinib, trastuzumab, and capecitabine with stereotactic radiosurgery in patients with brain metastases from her-2 positive breast cancer (tutor): a multicenter phase 1 clinical trial

Abstract 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 that aims to determine the safety of the combination therapy in patients with HER-2 positive BCBM. Patients aged 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, evidence of 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. We plan to expand the cohort at MTD to total of 40 patients to assess the safety and efficacy of drug combination. 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. Acute and late toxicity is assessed using CTCAE v5.0. Quality of life is assessed by Functional Assessment of Cancer Therapy, including Brain Tumor module (FACT-Br). Patients are administered oral tucatinib with SRS as per the 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). RESULTS Patient enrollment started in February 2023. CONCLUSION Findings from this trial will demonstrate the safety and efficacy of this combination treatment in BCBM (Clinical Trial Information: NCT05553522).