The impact of poorly differentiated histology on immunotherapy in advanced gastrointestinal cancers.

Introduction Checkpoint inhibitors (CPI) have significantly improved survival among patients with various cancer types. Prior studies have shown a correlation between immune cell infiltration and poorly differentiated cancers. This study evaluated the impact of poorly differentiated histology on survival in patients with advanced gastrointestinal cancers treated with immunotherapy. Methods This study was a retrospective, single-center analysis of patients with gastrointestinal cancers treated with checkpoint inhibitors between 2016 and 2021. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to assess the association between tumor and patient characteristics, progression free survival, and overall survival. Results A total of 123 patients were eligible and included in the analysis. Median age was 66 years (23-88 years). Majority had stage IV disease (89%), were white (65.5%), and were male (64.5%). Most common diagnoses were hepatocellular carcinoma (30.5%), gastric adenocarcinoma (16.5%) ,esophageal adenocarcinoma (17%) and colorectal cancer (19.8%). About 32% of the tumors were microsatellite instability-high (MSI-HIGH/DMMR), with BRAF V600E mutation rate of 10%. About 25% of the patients received checkpoint inhibitors as initial treatment while 35.5% had received two or more prior lines of therapy. Compared with well and moderately differentiated histology, patients with poorly differentiated tumors had a shorter median overall survival (mOS) (not reached [NR] vs. NR vs. 9.3 months, p=0.0264). There was no statistically significant difference in median progression free survival between histology types (2.5 vs.4.2 vs. 2 months, p=0.1314). On univariate survival analysis, moderately differentiated tumors correlated with a significantly longer mOS (HR: 0.48, CI: 0.24-0.93, p=0.030) and mPFS (HR: 0.62, 95%CI: 0.38-1.00, p=0.048) compared to poorly differentiated histology. Female patients (HR: 0.55, 95%CI: 0.34-0.90, p=0.018) and Eastern Cooperative Oncology Group (ECOG) of 1 (vs. ≥2) had significantly longer mPFS (HR: 0.58, 95%CI: 0.35-0.97, p=0.036). ECOG of 1 also correlated with longer mOS (HR: 0.47, 95%CI: 0.23-0.94, p=0.034). Microsatellite stable (MSS) tumors had significantly shorter mPFS (HR: 5.74, 95%CI: 2.41-13.63, p<0.001) and mOS (HR: 5.45, 95%CI: 1.64-18.12, p=0.006). The number of prior systemic therapies was also associated with shorter mPFS (HR: 1.19, 95%CI: 1.03-1.39, p=0.022) and mOS (HR: 1.23, 95%CI: 1.01-1.50, p=0.045). On multivariable analyses, ECOG status of 0/1 vs. ≥2 and MSI-HIGH/DMMR vs. MSS remained significantly associated with longer mPFS and mOS. There was no correlation with histologic differentiation status, race or mutations such as BRAF V600E or KRAS.