Early-onset low-grade adverse events as predictive biomarkers in advanced NSCL: A multi-treatment cohort analysis

Purpose: This study aims to assess whether early-onset, grade 1 (G1) and low-grade (LG) treatment-related adverse events (TrAEs) can serve as predictive markers for favorable survival outcomes in advanced non-small cell lung cancer (NSCLC) across different treatment modalities. Methods: We analyzed data from 577 NSCLC patients across 11 cohorts treated at Moffitt Cancer Center: 5 immunotherapies (n=383), 3 targeted therapies (n=88), and 3 chemotherapies (n=106). Data for analysis used AE data derived from Common Terminology Criteria for Adverse Events (CTCAE v4-5), treatment response including comparison of responder (complete response (CR) and partial response (PR)) versus non-responder (stable disease (SD) and progressive disease (PD)) and comparison of disease control (DC: CR/PR/SD) versus PD using Wilcoxon two-sample test, progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier survival curve with log-rank test. Our analytic approach leveraged multiple AE parameters to develop a set of innovative AE biomarkers. Early-onset G1/LG TrAEs were defined as those occurring within 30 days of treatment initiation. Results: Early-onset AE analysis across all treatment types revealed that (a) Immunotherapy had lower frequency of G1 and LG TrAEs compared to chemotherapy and targeted therapy; (b) higher frequency of G1 and LG TrAEs were associated with better treatment response in immunotherapy (responder vs non-responder with p=0.047 (G1) and 0.069 (LG); DC vs PD with p=0.005 (G1) and 0.018 (LG)), but no significant results in chemotherapy and targeted therapy; (c) For patients who did not encounter HG non-treatment related AEs (non-TrAEs), if they frequently experienced G1 and LG TrAEs, their survival outcomes tended to be better compared to the ones with less or no AE experiences in immunotherapy (median PFS: 5.5 vs 3.5 months with p=0.03 for G1 and 5.5 vs 3.3 months with p=0.015 for LG; median OS: 18.2 vs 12.2 months with p=0.008 for G1 and 16.1 vs 12.2 months with p=0.04 for LG). Please note that non-TrAEs represent a strong surrogate for compromised baseline health status. Without proper adjustment, this factor may confound the observed association between early-onset G1 and LG TrAEs and survival outcomes. For in chemotherapy and targeted therapy, both G1 and LG TrAEs did not show significant survival association. Conclusion: G1 and LG TrAEs within 30 days of therapy initiation were associated with better treatment response and improved survival in advanced NSCLC, especially in immunotherapy-treated patients. These findings support the use of early-onset G1/LG TrAE profiles as potential predictive biomarkers.