High tumor mutation burden mitigates the negative impact of chemotherapy history on immune checkpoint blockade therapy

Abstract

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for the majority of cases. Immune checkpoint inhibitor (ICI) therapy, particularly with PD-1 inhibitors like nivolumab, has become a critical treatment option for advanced NSCLC. ICI therapy has revolutionized treatment, but prior chemotherapy may diminish ICI treatment efficacy. Tumor mutation burden (TMB) has emerged as a crucial predictor of ICI response, yet its interaction with chemotherapy history in ICI therapy is not fully understood. In this study, I investigate the impact of chemotherapy history on ICI treatment outcomes, focusing on TMB as a potential mitigating factor. Analyzing data from 512 patients with advanced NSCLC treated with PD-1/PD-L1 or CTLA-4 inhibitors, this sudy found that prior chemotherapy significantly reduced objective response rates (ORR) to ICI therapy, particularly in patients with low TMB (<15 mut/Mb). However, in patients with high TMB (≥15 mut/Mb), the negative impact of chemotherapy history on ICI treatment efficacy is minimal, suggesting that high TMB mitigates chemotherapy-induced resistance to ICI therapy. Furthermore, while chemotherapy history is associated with worse overall survival (OS) and progression-free survival (PFS) following ICI therapy in low-TMB patients, no such association is observed in high-TMB patients. These findings highlight the importance of TMB as a predictive biomarker, emphasizing the need for optimal treatment sequencing and personalized therapeutic strategies to overcome chemotherapy-induced immune resistance and maximize ICI treatment efficacy. These results suggest that ICI therapy may be more beneficial as a first-line treatment, particularly for patients with low TMB.

Keywords: Chemotherapy; Immune checkpoint inhibitor; Immunotherapy; Non-small-cell lung cancer.