Case Report: Complete metabolic responses to trastuzumab–deruxtecan in HER2-altered solid tumors: two illustrative cases

Background: Human epidermal growth factor receptor-2 (HER2) alterations, including activating mutations and gene amplification, are emerging therapeutic targets in several solid tumors. Trastuzumab-deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate (ADC), has demonstrated antitumor activity across multiple HER2-altered cancers. However, complete metabolic responses (CMRs) remain uncommon, particularly when assessed by 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography-computed tomography (FDG-PET/CT). Presentation of cases: We report two patients with metastatic HER2-driven malignancies who achieved a CMR under T-DXd. The first case concerns a patient with metastatic non-small cell lung cancer harboring a HER2 exon 20 insertion who progressed on chemoimmunotherapy and HER2-directed antibodies. Third-line T-DXd led to rapid metabolic improvement and complete resolution of all lesions, including a brain metastasis. The second case involves a patient with metastatic micropapillary urothelial carcinoma with HER2 expression, refractory to platinum chemotherapy, avelumab maintenance, and enfortumab vedotin. T-DXd induced an early partial metabolic response (PMR), followed by a confirmed CMR after four cycles. Conclusion: These two observations illustrate the capacity of T-DXd to induce deep and complete metabolic remissions in distinct HER2-altered solid tumors. They support further development of HER2-targeted ADCs beyond traditional indications and highlight the value of FDG-PET/CT for assessing the depth of response to these agents.