Case Report: Successful trastuzumab deruxtecan rechallenge after disease progression in a pretreated

Introduction: Trastuzumab deruxtecan (T-DXd; DS-8201) has emerged as a standard later-line therapy for patients with HER2-mutant non-small cell lung cancer (NSCLC), but the optimal treatment strategy after disease progression using T-DXd remains unclear. Case presentation: We report the clinical course of a female lung adenocarcinoma patient with a HER2 exon 20 mutation who achieved long-term disease control with T-DXd despite multiple lines of chemotherapy, until interstitial pneumonia occurred when combined with a PD-1 inhibitor. After a two-month treatment break, the patient fully recovered from interstitial pneumonia using corticosteroid therapy. After recovery, two additional lines of chemotherapy were administered but produced limited benefit. Thus, T-DXd was reintroduced to control the worsening disease. Notably, T-DXd rechallenge, administered systemically along with local embolization, again provided clinical benefit despite prior radiographic progression on T-DXd and intervening systemic therapies. Overall, the patient achieved prolonged disease control during rechallenge (progression-free survival >14 months) without recurrence of interstitial lung disease (ILD) despite the extensive prior treatment exposure. Conclusion: This case differs from previously reported rechallenge experiences that mainly describe re-exposure after toxicity-related interruption as the rechallenge reported here followed documented disease progression and multiple intervening regimens, suggesting that, in carefully selected patients with HER2-mutant NSCLC who previously responded to T-DXd, rechallenge after progression could be explored as an option when therapeutic alternatives are limited. However, caution is advised and evidence from prospective and real-world cohorts is needed.