Trastuzumab Deruxtecan + Stereotactic Radiosurgery (SRS) in HER2+ Breast Cancer Brain Metastases

Incidence of dose-limiting toxicities (DLTs)

DLTs will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) v5.0 starting from the first dose of T-DXd through 3 weeks after SRS. DLT is defined as the appearance of side effects during treatment that are severe enough to prevent continuation of treatment at a participant's assigned dose. Any of the following events will be considered a DLT if treatment-related: * ≥ Grade 4 non-hematologic toxicity except nausea and vomiting (if manageable with supportive care measures), alopecia, drug-related fever, and toxicities secondary to neutropenia and sepsis * ≥ Grade 3 neurologic toxicity (sensory or autonomic) * Grade 4 platelet count (\<25,000/mm³) 50 days beyond the start of the most recent chemotherapy (not related to recurrent leukemia) * Grade 4 neutropenia 50 days beyond the start of the most recent chemotherapy (not related to recurrent leukemia) * Grade 3 non-hematologic toxicity (excluding alopecia or toxicities secondary to neutropenia

Determination of the maximum tolerated dose (MTD) of T-DXd in combination with SRS

The MTD will be determined using a standard 3+3 dose de-escalation design across predefined dose levels of T-DXd (5.4 mg/kg, 4.4 mg/kg, and 3.2 mg/kg IV every 21 days), based on the number of participants who experience a DLT at each dose level.

Intracranial Progression-free survival (PFS) at 6 months (PFS-6)

Intracranial PFS-6 will be defined as the time from first dose of study drug until intracranial disease progression (i.e., progression within the skull) or death from any cause using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at 6 months post-treatment. Progression is defined as at least 20% increase in the sum of the longest diameters of the target lesions, appearance of any new lesions, or unequivocable progression of any non-target lesions. For participants whose disease has not progressed at the time of the analysis, censoring will be performed using the date of the last valid disease assessment.

Extracranial PFS-6

Extracranial PFS-6 will be defined as the time from first dose of study drug until extracranial disease progression (i.e., progression outside of the skull) or death from any cause using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at 6 months post-treatment. Progression is defined as at least 20% increase in the sum of the longest diameters (LD) of the target lesions compared to the smallest recorded LD since treatment started, appearance of any new lesions, or unequivocable progression of any non-target lesions. For participants whose disease has not progressed at the time of the analysis, censoring will be performed using the date of the last valid disease assessment.

Overall survival (OS)

Median OS will be defined as the time from the beginning of study drug treatment until death due to any cause at the end of the study (\~2 years). For participants who have not died at the time of the analysis, censoring will be performed using the date the participant was last known to be alive.

Objective response rate (ORR)

ORR will be defined as the proportion of participants achieving a complete response (CR) or partial response (PR) using RECIST v1.1 as their best overall response by the end of the study (\~2 years). Participants with CR or PR will be counted as successes and all other participants (including those with missing response information) will be counted as failures. CR is defined as disappearance of all target and non-target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. All lymph nodes must be non-pathological in size (\<10 mm short axis). PR is defined as at least 30% decrease in the sum of the LD of target lesions compared to baseline. There can be no appearance of new lesions.