Evaluating post-T-DXd treatment strategies in HER2-positive metastatic breast cancer

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PURPOSE: Trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer (MBC). Despite its efficacy, eventual resistance and disease progression are common, and no prospective studies exist to guide therapy in T-DXd-resistant HER2-positive MBC. METHODS: This retrospective study analyzed patients with HER2-positive MBC who received cancer-directed therapies following treatment with T-DXd at Memorial Sloan Kettering Cancer Center. RESULTS: Eighty-one eligible patients were identified, who received 199 lines of therapy collectively. Post-T-DXd therapies included other ADCs, chemotherapy, HER2-targeted antibodies, hormone-based therapy, tyrosine kinase inhibitors (TKIs), and clinical trials. The median overall survival (OS) after stopping T-DXd treatment was 19 months, with a median progression-free survival (mPFS) of 3.7 months per subsequent treatment line. Chemotherapy was the most common treatment (42% of treatment lines; mPFS 3.4 months). No single therapeutic approach was clearly superior, although subsets of patients appeared to benefit from hormone therapy or TKIs. In a multivariate analysis including treatment type, treatment line, hormone receptor (HR) status, presence of brain metastases, and reason for T-DXd cessation, patients who discontinued T-DXd due to toxicity, rather than disease progression, had significantly better outcomes on subsequent therapy lines (HR 0.35; p < 0.001). CONCLUSION: Our study indicates that patients emerge from T-DXd treatment with highly refractory disease. These findings highlight the urgent need for optimized treatment strategies and novel therapeutic options for this patient population.

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