Cumulative toxicity assessed by area-under-the-curve (AUC) in targeted therapy versus chemotherapy for advanced EGFR -mutant NSCLC.

12141 Background: Current adverse event (AE) reporting standards emphasize peak toxicity, which may inadequately capture the cumulative burden of persistent low-grade AEs characteristic of targeted therapies. We conducted a post-hoc analysis of the LUX-Lung 3 trial to compare longitudinal toxicity patterns of targeted therapy and chemotherapy over time. Methods: This post-hoc analysis used individual, de-identified patient-level data from the phase III LUX-Lung3 clinical trial comparing afatinib with platinum-based chemotherapy as first-line treatment for advanced EGFR-mutant NSCLC, accessed through Vivli. Select treatment-related AEs were evaluated longitudinally by grade. Cumulative toxicity burden was quantified using the area-under-the-curve (AUC) of AE grade prevalence over time. Pearson correlation was used to assess temporal trends in AUC. Results: A total of 340 patients had evaluable AE data, including 229 (67%) treated with afatinib and 111 (33%) treated with chemotherapy. The median onset of grade 1-2 AEs generally occurred earlier with chemotherapy than afatinib. The median onset of chemotherapy-related fatigue was 4 days and nausea 2 days, whereas median onset of afatinib-related diarrhea was 4 days, rash 8 days, and paronychia 37 days. Longitudinal AUC analysis (Table 1) demonstrated a significant improvement in grade 1-2 chemotherapy-related nausea (p=0.003) and stomatitis (p=0.05), and a trend towards improvement in fatigue (p=0.2) by 12-months. In contrast, grade 1-2 afatinib-related rash (p=0.4) and diarrhea (p=0.99), remained stable, while paronychia increased over time (p=0.004). For grade 3+ AEs, the AUC improved over time for both the chemotherapy (p=0.04) and afatinib (p=0.02) groups. Conclusions: Assessment of time to onset and longitudinal AUC reveal distinct temporal AE patterns for targeted therapy and chemotherapy. Longitudinal toxicity reporting is feasible and highlights the sustained burden of chronic AEs associated with targeted therapies that are clinically meaningful yet underrepresented by conventional peak toxicity reporting. Cumulative toxicity of afatinib and chemotherapy was quantified using the area under the curve of grade 1-2 adverse events prevalence at landmark time points.* Adverse event Month 1 Month 3 Month 6 Month 12 Pearson’s coefficient p-value Afatinib (%) Rash 0.24 0.39 0.44 0.45 0.24 0.4 Diarrhea 0.30 0.44 0.47 0.45 -0.002 0.99 Paronychia 0.02 0.20 0.32 0.39 0.74 0.004 Chemotherapy (%) Fatigue 0.05 0.09 0.09 0.07 -0.36 0.2 Nausea 0.07 0.17 0.17 0.10 -0.60 0.03 Stomatitis 0.02 0.02 0.02 0.01 -0.56 0.05 *Trends were assessed using Pearson’s correlation coefficient and corresponding p-value.