172 Background: Lynch syndrome is the most common hereditary syndrome associated with colorectal cancer (CRC). Lynch syndrome-associated CRC is typically characterized by microsatellite instability-high tumors which exhibit favorable response to PD-1 immune checkpoint inhibitors (ICIs). Our aim was to identify clinical and demographic factors that influence overall survival (OS) in Lynch syndrome-associated CRC patients treated with pembrolizumab, a PD-1 ICI. Methods: We designed a multicenter retrospective study using TriNetX, a global database of de-identified electronic health records, to evaluate the impact of multiple covariates on OS in patients with Lynch syndrome and stage IV CRC treated with pembrolizumab. Patients who underwent colectomy were excluded. Using the Cox proportional hazards model, we explored the effect of sex, age at index, marital status, obesity, type 2 diabetes mellitus, chronic kidney disease, nicotine dependence, alcohol use, depression, and metastasis to lung, liver, bone, brain, peritoneum or retroperitoneum. Results: Of the 394 patients diagnosed with both Lynch syndrome and stage IV CRC receiving pembrolizumab, 44.7% were males. Increased mortality risk was observed in males compared to females HR 1.558, 95% CI 1.085-2.235; p=0.016. Additionally, peritoneal and retroperitoneal metastases were significantly associated with worse OS HR 1.822, 95% CI 1.151-2.882; p=0.010. Age at index, marital status, obesity, type 2 diabetes mellitus, chronic kidney disease, nicotine dependence, alcohol use, depression, and lung, liver, bone or brain metastases were not significantly associated with worse OS. Conclusions: Male sex and presence of peritoneal or retroperitoneal metastases are poor outcome predictors in Lynch-associated stage IV CRC treated with pembrolizumab. The latter adverse prognostic indicators emphasize the need for careful risk stratification when treating Lynch-associated stage IV CRC patients with pembrolizumab and further guide treatment decisions. Effect of several covariates on overall survival (OS) in patients with Lynch syndrome and stage IV colorectal cancer treated with pembrolizumab. Covariate Hazard Ratio Coefficient Standard Error z P > |z| 95% Confidence Interval Male 1.558 0.443 0.184 2.405 0.016 (1.085, 2.235) Age at Index 1.013 0.013 0.007 1.913 0.056 (1.000, 1.027) Overweight and obesity 0.728 -0.317 0.214 -1.479 0.139 (0.478, 1.109) Nicotine dependence 1.476 0.389 0.219 1.772 0.076 (0.960, 2.269) Alcohol use 0.000 -15.887 2330.127 -0.007 0.995 -- Married 0.980 -0.020 0.185 -0.111 0.912 (0.682, 1.407) Type 2 diabetes mellitus 1.444 0.368 0.205 1.789 0.074 (0.966, 2.160) Depression 0.974 -0.026 0.232 -0.113 0.910 (0.618, 1.536) Chronic kidney disease (CKD) 1.291 0.256 0.227 1.125 0.261 (0.827, 2.016) Secondary malignancy of retroperitoneum and peritoneum <jats:td colspan="1" ro
Naji et al. (Sat,) studied this question.