Integrated profile of tumor stage and mutational burden predicts disparate clinical responses to immune checkpoint inhibitors: A risk-benefit study

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Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, having demonstrated efficacy and leading to regulatory approvals of ICIs in cancers characterized by high tumor mutation burden (TMB). However, there remains a gap in determining their applicability and risk-benefit profile, across the broad spectrum of patients whose tumors harbor varying TMB levels across distinct tumor stages. By interrogating a large contemporary cohort comprised of 10,233 patients with a diagnosis of cancer across all tumor stages and TMB levels, this study revealed significantly improved overall survival (OS) following ICI therapy (p <0.0001) in patients with a combination of ≥10 mut/Mb and stage IV disease. In contrast, ICI therapy is associated with markedly worse OS in patients with low TMB levels <10 mut/Mb and stages I, II, and III cancer. These findings highlight the critical interplay between TMB, tumor stage, and ICI treatment outcomes, underscoring the importance of integrating clinical and genetic characteristics in weighing the risk-benefit balance of ICI therapy. Although maximizing therapeutic benefits is crucial, it is equally important to identify and manage potential risks that may not be immediately apparent. This may require enrolling patients with less-severe or early-stage disease to enable long-term follow‐up with effective clinical surveillance. By comprehensively evaluating the added benefit of improved treatment efficacy and the potential risk of adverse treatment outcome, a risk-benefit profile can optimize immunotherapy regimens, with profound implications for clinical decision-making and regulatory approvals of ICI.