Impact on survival of severe immuno-related adverse events in deficient mismatch repair/microsatellite instable-high digestive cancers treated with immunotherapy

BACKGROUND: Deficient DNA mismatch repair/microsatellite instability-high (dMMR/MSI-H) cancers are very sensitive to immune checkpoint inhibitors (ICIs), yet their use is frequently complicated by immune-related adverse events (irAEs). Our study analyzed the impact of grade ≥3 irAEs (immune-related severe adverse events (irSAEs)) on survival in patients with dMMR/MSI-H digestive cancers treated with ICIs. METHODS: We conducted an international, multicenter, ambispective study involving 1,175 patients from 34 centers. The primary endpoint was the correlation between the occurrence of irSAEs and progression-free survival (PFS). Secondary endpoints included factors associated with irSAEs, correlation between irSAEs and overall response rate (ORR) and overall survival (OS). Prespecified landmark and time-dependent survival models were used to account for the time to irSAE occurrence. RESULTS: Among 1,175 patients treated with ICIs for digestive cancers, 49.1% were female, median age was 66.9 years (IQR 53.7-77.3) and 82.9% had colorectal cancer. Overall, 382 patients (32.5%) had an irAE, including 117 (10.0%) irSAEs. Median time to irSAEs occurrence was 3.78 months (IQR 1.97-7.62). The most frequent irSAEs were gastrointestinal (3.4%), hepatic (1.8%) and dermatologic (1.0%). The only factor associated with irSAEs was the use of an ICI combination versus monotherapy (20.0% vs 11.4%, p=0.03). Among patients with irSAEs, 71.5% received oral and 29.8% intravenous corticosteroids, and 15.7% immunosuppressive agents. Overall, in 26.9% of patients, ICIs were resumed following irSAEs, with an irAE recurrence rate of 57.1%. irSAE was associated with a better ORR (48.6% vs 34.6%, p<0.0001). The multivariable Cox model revealed that irSAE as a time-dependent variable was not associated with better PFS (HR=1.280 (95% CI 0.898 to 1.824), p=0.172) or OS (HR=1.043 (95% CI 0.712 to 1.528), p=0.828). Likewise, landmark analysis at 3 months and 6 months also showed that irSAEs were not associated with better PFS or OS. CONCLUSIONS: The occurrence of irSAE was not independently associated with better survival in patients with dMMR/MSI-H digestive cancers treated with ICIs.