Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors

• Published in: European journal of cancer (1990) 2023-07, Vol.187, p.15-24
• Main Authors: Manca, Paolo, Corti, Francesca, Intini, Rossana, Mazzoli, Giacomo, Miceli, Rosalba, Germani, Marco Maria, Bergamo, Francesca, Ambrosini, Margherita, Cristarella, Eleonora, Cerantola, Riccardo, Boccaccio, Chiara, Ricagno, Gianmarco, Ghelardi, Filippo, Randon, Giovanni, Leoncini, Giuseppe, Milione, Massimo, Fassan, Matteo, Cremolini, Chiara, Lonardi, Sara, Pietrantonio, Filippo
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - genetics; Colonic Neoplasms - drug therapy; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA Mismatch Repair; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - therapeutic use; Metastatic colorectal cancer; Microsatellite Instability; Mismatch repair deficiency; Mutation; Tumour mutational burden
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2023.03.029

Immune checkpoint inhibitors (ICIs) are the standard treatment in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Tumour mutational burden (TMB) is a promising biomarker for the prediction of treatment outcomes. We screened 203 patients with dMMR/MSI-H mCRC treated with an anti-PD-(L)1 (anti-Programmed-Death-(Ligand)1) plus or minus an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA-4) agent at three Italian Academic Centers. TMB was tested by Foundation One Next Generation Sequencing assay and correlated with clinical outcomes, in the overall population and according to ICI regimen. We included 110 patients with dMMR/MSI-H mCRC. Eighty patients received anti-PD-(L)1 monotherapy and 30 received anti-CTLA-4 combinations. Median TMB was 49 mut/Mb (range: 8–251 mut/Mb). The optimal prognostic cut-off for progression-free survival (PFS) stratification was 23 mut/Mb. Patients with TMB ≤23 mut/Mb had significantly worse PFS (adjusted Hazard Ratio [aHR] = 4.26, 95% confidence interval [CI]:1.85–9.82, p = 0.001) and overall survival (OS) (aHR = 5.14, 95% CI: 1.76–14.98, p = 0.003). Using a cut-off optimised for predicting treatment outcome, anti-CTLA-4 combination was associated with a significant PFS/OS benefit versus anti-PD-(L)1 monotherapy in patients with TMB>40 mut/Mb (2-year PFS: 100.0% versus 70.7%, p = 0.002; 2-year OS: 100.0% versus 76.0%, p = 0.025), but not in those with TMB ≤40 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949). Patients with dMMR/MSI-H mCRC and relatively lower TMB value displayed early disease progression when receiving ICIs, whereas patients with the highest TMB values may obtain the maximal benefit from intensified anti-CTLA-4/PD-1 combination. [Display omitted] •The TMB stratifies the outcomes of dMMR/MSI-H mCRC receiving ICIs.•Patients with a low TMB has poor outcomes regardless of the ICI type.•Patients with the highest TMB have greater benefit from anti-CTLA-4 combos.•TMB could be used to drive future research projects and trials’ design.