Trastuzumab deruxtecan: An antibody-drug conjugates for non-small cell lung cancer

ObjectivesThis review compiles to provide an overview of non-small cell lung cancer (NSCLC) and the therapeutic rationale for antibody-drug conjugates (ADCs), followed by a summary of current evidence highlighting the efficacy, safety, and adverse event management of trastuzumab deruxtecan (T-DXd) in HER2-mutant metastatic NSCLC.Data SourcePUBMED, ClinicalTrials.gov, and Google Scholar were searched to retrieve relevant clinical studies including randomized controlled trials, non-randomized studies, observational studies, and real-world evidence from its approval to July, 2025 for the treatment of patients with HER2-mutant metastatic NSCLC received prior systemic therapy. The search strategy was guided by the target therapeutic area, intervention type, and population studied.Data SummaryT-DXd, a HER2-targeted ADC and second line treatment, has shown significant clinical benefit in HER2-mutant metastatic NSCLC, as evidenced by key clinical trials (NCT04644237 and NCT04644237) demonstrating high objective response rates (ORRs) and disease control rates (DCRs). Although it exhibits a manageable safety profile, interstitial lung disease (ILD) remains a notable adverse event (AE), with improved tolerability observed at the lower dose of 5.4 mg/kg. Moreover, multidisciplinary Strategies are also used to manage T-DXd associated AEs. Additionally, ongoing trials are evaluating the combination of T-DXd with immunotherapy and targeted agents to optimize safety outcomes and efficacy in high-risk NSCLC populations.ConclusionsT-DXd at 5.4 mg/kg offers substantial efficacy with better tolerability than 6.4 mg/kg. Incorporating AE mitigation, real-world insights, and combination trial data may further optimize its safety and clinical benefit in this biomarker-defined population.