Extreme Tumor Mutational Burden Predicts Near‐Curative Outcomes With Checkpoint Immunotherapy in Melanoma: Half the Eligible, Half the Cure

ABSTRACT Tumor‐mutational burden (TMB) is a mechanistic surrogate of neo‐antigen load and thus a plausible biomarker for response to immune checkpoint blockade (ICB). In melanoma, however, the extreme right tail of the mutational spectrum, known as “hypermutation,” remains poorly characterized. This study sought to explore an a priori threshold of hypermutation that would delineate a subgroup with extraordinary benefit from ICB therapy. This study analyzed individual‐patient data from independent cohorts comprising 710 ICB‐treated melanoma patients profiled by whole‐exome sequencing or FDA‐approved targeted panels. Hypermutated tumors displayed a striking enrichment for higher objective response and complete response (CR) rates ( p < 0.0001). Hypermutation independently predicted prolonged progression‐free survival and overall survival. By contrast, the conventional ≥ 10 mut/Mb cut‐off captured many treatment‐eligible patients but conferred markedly lower CR enrichment and weaker survival discrimination. A super‐high TMB threshold of ≥ 25 mut/Mb by MSK‐IMPACT identifies a distinct subset of melanoma patients who achieve truly exceptional benefit, with nearly one in two attaining clinical cure following ICB therapy. These data support prospective validation of “hypermutation” as a clinically actionable biomarker, refine patient counseling, and inform trial stratification in the era of personalized cancer immunotherapy.