High tumour mutation burden improves overall survival in solid tumours treated with immune checkpoint inhibitors

This systematic review and meta-analysis examined the relationship between tumour mutation burden and clinical outcomes in patients with solid tumours. The analysis included 5278 patients receiving immune checkpoint inhibitors or chemotherapy. The study evaluated high tumour mutation burden versus low tumour mutation burden cohorts and compared ultra-high tumour mutation burden against a universal 10 mut/Mb cut-off. The primary outcome was overall survival, with progression-free survival as a secondary outcome. The setting of the included studies was not reported in the source data. Methodological variability, cut-off thresholds, sequencing platforms, and cut-off definitions were identified as key limitations. Funding or conflicts of interest were not reported.

In non-small cell lung cancer, high tumour mutation burden was significantly associated with improved overall survival. The hazard ratio was 0.56. For selected gastrointestinal cancers, high tumour mutation burden was significantly associated with improved overall survival. The hazard ratio was 0.36. In advanced or recurrent tumours, high tumour mutation burden was significantly associated with improved overall survival. The hazard ratio was 0.52. For ICI-treated patients receiving combined anti-PD-L1/PD-1 and anti-CTLA-4 therapy, high tumour mutation burden was significantly associated with improved overall survival. The hazard ratio was 0.47. Progression-free survival in these patients with combined therapy also showed improvement. The hazard ratio was 0.50.

In chemotherapy-treated cohorts, high tumour mutation burden was associated with better outcomes, but the association was less consistent. The hazard ratio for overall survival was 0.60. The hazard ratio for progression-free survival was 0.55. When comparing ultra-high tumour mutation burden to a universal 10 mut/Mb cut-off, ultra-high tumour mutation burden had better overall survival. The hazard ratio was 0.44 versus 0.58. Non-beneficial associations were observed in glioma and penile squamous cell carcinoma.

Safety and tolerability findings were not reported in the source data. Adverse events, serious adverse events, discontinuations, and tolerability were not reported. The study did not provide absolute numbers for outcomes or confidence intervals for the effect sizes. The 95% CI was not reported for any primary or secondary outcome. P-values were not reported for the specific comparisons listed.

These results suggest that standardising tumour mutation burden assessment and refining relevant thresholds are essential for optimising its role in precision oncology. The evidence indicates that high tumour mutation burden generally predicts better survival in patients receiving immune checkpoint inhibitors. However, the association was weaker and inconsistent in chemotherapy-treated cohorts. The lack of reported safety data limits the ability to assess the risk-benefit profile of tumour mutation burden stratification. Questions remain regarding the optimal cut-off thresholds for different tumour types and the impact of sequencing platform variability on mutation burden measurement.

The findings highlight the need for caution when interpreting tumour mutation burden as a predictive biomarker across all solid tumour types. The variability in cut-off definitions and sequencing platforms may influence the observed associations. Clinicians should consider the specific tumour type and treatment regimen when evaluating the potential utility of tumour mutation burden testing. The absence of reported adverse events means that safety profiles cannot be directly compared between high and low tumour mutation burden groups. Further research is needed to address these gaps and establish standardized protocols for tumour mutation burden assessment in clinical practice.