Cancer treatment reviews · 2026
Distinct outcome patterns according to RAS and BRAF status in MSI-H/dMMR mCRC treated with immune checkpoint inhibitors: A systematic review and meta-analysis.
СтатьяМетаанализСистематический обзорНазвание и аннотация: Перевод пока не подготовлен
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Pretta Andrea, Giampieri Riccardo, Bottelli Andrea, Taravella Ada, Intini Rossana, Ziranu Pina, Liguori Carolina, Manoni Federica, Landi Matteo, Maddalena Giulia, Locci Giorgia, Donisi Clelia, Masiello Mariapaola, Caschili Matteo, Bassetti Anna, Pasquinucci Valentino, Maccioni Antonio, Sperotto Sara, Bergamo Francesca, Berardi Rossana, Pietrantonio Filippo, Cremolini Chiara, Lonardi Sara, Scartozzi Mario
Аннотация
BACKGROUND: Immune checkpoint inhibitors (ICIs) are superior to chemotherapy in metastatic colorectal cancer (mCRC) with MSI-H/dMMR. However, whether oncogenic driver alterations contribute to clinically meaningful heterogeneity in outcomes within this immunotherapy-sensitive population remains unclear. We conducted a systematic review and meta-analysis to evaluate the association between RAS and BRAF mutational status and outcomes in ICI-treated MSI-H/dMMR mCRC.
METHODS: A systematic literature search identified studies reporting outcomes of ICI therapy according to RAS and/or BRAF status in MSI-H/dMMR mCRC. Study-level pooled analyses were conducted using random-effects models to estimate odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS).
RESULTS: Nine studies were included, comprising a total of 13 treatment cohorts and 2564 patients were analysed. ORR did not significantly differ across molecular subgroups. Compared with wild-type tumours, RAS-mutated disease was associated with modestly longer PFS (HR 0.81, 95% CI 0.66-0.99), whereas BRAF-mutated tumours showed shorter PFS (HR 1.37, 95% CI 1.11-1.69). Overall survival was significantly worse in BRAF-mutated disease (HR 1.74, 95% CI 1.17-2.59), while no significant OS differences were observed for RAS-mutated tumours. Exploratory analyses suggested that dual checkpoint blockade may increase response rates particularly in BRAF-mutated and molecularly wild-type subgroups.
CONCLUSIONS: Within MSI-H/dMMR mCRC treated with ICIs, molecular subgroups show distinct survival patterns despite similar response rates. BRAF-mutated tumours retain an adverse prognostic impact, whereas RAS-mutated disease may exhibit more durable disease control. These findings support biological stratification within MSI-H/dMMR mCRC and provide a rationale for prospective biomarker-stratified studies of tailored immunotherapy strategies.
METHODS: A systematic literature search identified studies reporting outcomes of ICI therapy according to RAS and/or BRAF status in MSI-H/dMMR mCRC. Study-level pooled analyses were conducted using random-effects models to estimate odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS).
RESULTS: Nine studies were included, comprising a total of 13 treatment cohorts and 2564 patients were analysed. ORR did not significantly differ across molecular subgroups. Compared with wild-type tumours, RAS-mutated disease was associated with modestly longer PFS (HR 0.81, 95% CI 0.66-0.99), whereas BRAF-mutated tumours showed shorter PFS (HR 1.37, 95% CI 1.11-1.69). Overall survival was significantly worse in BRAF-mutated disease (HR 1.74, 95% CI 1.17-2.59), while no significant OS differences were observed for RAS-mutated tumours. Exploratory analyses suggested that dual checkpoint blockade may increase response rates particularly in BRAF-mutated and molecularly wild-type subgroups.
CONCLUSIONS: Within MSI-H/dMMR mCRC treated with ICIs, molecular subgroups show distinct survival patterns despite similar response rates. BRAF-mutated tumours retain an adverse prognostic impact, whereas RAS-mutated disease may exhibit more durable disease control. These findings support biological stratification within MSI-H/dMMR mCRC and provide a rationale for prospective biomarker-stratified studies of tailored immunotherapy strategies.