Ultra-rare TP53 and KRAS variants predict survival in ICI-treated solid tumours.

The prognostic relevance of ultra-rare TP53 and KRAS variants in advanced solid tumours treated with immune-checkpoint inhibitors (ICI) is unclear. We performed a retrospective cohort study using the Memorial Sloan Kettering Cancer Center MSK-IMPACT clinical-genomic dataset (cBioPortal study ID: tmb_mskcc_2018). TP53 and KRAS alterations were stratified by rarity (ultra-rare vs common) and analysed for overall survival (OS). Kaplan-Meier analyses and multivariable Cox proportional hazards models were fitted, adjusting for tumour type, tumour mutational burden (TMB), tumour purity, histology, age and sex. In the overall cohort, 51.4% of tumours harboured TP53 or KRAS mutations. Ultra-rare variants were independently associated with worse OS (HR 1.34, 95% CI 1.14-1.56; p < 0.001), with a median OS of 14.0 months versus 22.0 months in common/wild-type patients. Tumour-specific analyses suggested heterogeneity: non-small-cell lung cancer showed shorter OS for ultra-rare variants (approximately 10-13 months vs 17 months for wild type), whereas melanoma showed improved outcomes (HR 0.59, 95% CI 0.44-0.78; p < 0.001). Ultra-rare TP53 and KRAS variants provide prognostic information in ICI-treated advanced solid tumours, but the direction and magnitude of effect vary by tumour type. These findings support tumour-specific interpretation and motivate mechanistic and therapeutic studies in this underserved molecular subgroup.