Prognostic Factors and Treatment Effect Modifier Candidates in Advanced HER2-Mutant NSCLC: A Targeted Literature Review

Background: The expanding availability of targeted therapies for HER2-mutant non-small-cell lung cancer (NSCLC) has led to increased interest in understanding the baseline characteristics of patients that may impact clinical outcomes. This literature review evaluates prognostic factors and treatment effect modifiers in HER2-mutant NSCLC to inform indirect treatment comparison (ITC). Methods: A targeted literature review (TLR) was conducted and reported in accordance with an adapted PRISMA framework. The review included observational studies and clinical trials assessing survival outcomes among adults with advanced HER2-mutant NSCLC, irrespective of prior systemic therapy. Subgroups of interest included age, sex, smoking status, Eastern Cooperative Oncology Group performance status (ECOG PS), metastatic status, prior treatment history, HER2-mutation subtype, and other clinically relevant baseline characteristics. Searches were conducted in Embase and MEDLINE to identify English-language publications from January 2019 to 20 December 2025. Results: Based on data from 33 included publications (19 observational studies and 14 publications reporting results from 11 clinical trials), most demographic factors, including age, sex, and smoking status, were not found to be of consistent prognostic or predictive value in HER2-mutant NSCLC patients. However, ECOG PS and metastatic burden showed the most consistent prognostic associations with clinical outcomes, whereas associations for HER2-mutation subtype (especially the YVMA/Y772_A775dup variant) were heterogeneous, appeared to differ by treatment and were largely exploratory. TP53 co-mutations were associated with poorer outcomes in all TKI-treated cohorts reporting them; no evidence is available for other treatment classes. Conclusions: These findings provide a structured evidence base for variable selection and sensitivity analyses in ITCs, while underscoring the need for prospective controlled studies capable of formally evaluating treatment heterogeneity in this molecularly distinct population.