Background: 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.Patients and methods: 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.Results: 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 523 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 540 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949).Conclusion: 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.(c) 2023 Elsevier Ltd. All rights reserved.
Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors
Germani, Marco Maria;Boccaccio, Chiara;Cremolini, Chiara;
2023-01-01
Abstract
Background: 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.Patients and methods: 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.Results: 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 523 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 540 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949).Conclusion: 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.(c) 2023 Elsevier Ltd. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
