Trastuzumab Deruxtecan Induces Complete Pathological Response in Oligometastatic HER2-Mutant NSCLC: Case Report.

Background: HER2 exon 20 insertions are rare oncogenic driver mutations in non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan (T-DXd) has proven efficacy in pretreated metastatic HER2-mutant NSCLC. However, its use as first-line therapy in oligometastatic settings remains undocumented. Case Presentation: A 66-year-old female presented with a right hilar lung mass and a singular symptomatic left frontal brain metastasis. Biopsy confirmed poorly differentiated adenocarcinoma (TTF-1 positive, PD-L1 TPS 0%) with an ERBB2 exon 20 insertion (p.Y772_A775dup). The patient declined standard chemo- and immunotherapy. An individualized treatment plan was developed, initiating off-label first-line T-DXd after resection and consolidating radiotherapy of the affected cerebral region. After four cycles of T-DXd, imaging demonstrated significant tumor reduction. Subsequent surgical resection of the primary tumor revealed a complete pathological response (ypT0N0, R0). Adjuvant T-DXd therapy was continued thereafter. Conclusion: This case illustrates the high efficacy of T-DXd as the sole first-line treatment in oligometastatic HER2-mutant NSCLC. Prospective studies are needed to systematically explore the efficacy and safety of this approach.