Risk of autoimmune hepatitis, non-infectious gastroenteritis, and colitis among patients with metastatic clear cell renal cell carcinoma (ccRCC) treated with pembrolizumab/axitinib vs nivolumab/ipilimumab.

e16530 Background: The treatment landscape for RCC has advanced with targeted therapies and ICIs enabling personalized approaches based on patient characteristics and disease progression. The European Society for Medical Oncology guidelines recommend combination therapies, such as pembrolizumab plus axitinib or nivolumab plus ipilimumab, as first-line options for metastatic RCC in intermediate- or poor-risk patients. We evaluated the risk of autoimmune hepatitis, non-infectious gastroenteritis, and colitis in patients with metastatic ccRCC treated with pembrolizumab/axitinib or nivolumab/ipilimumab. Methods: We conducted a retrospective cohort study utilizing de-identified patient data from the TriNetX platform, a comprehensive electronic health records system consisting of 143 healthcare systems from 18 participating countries and more than 163 million patients' clinical records globally. The risk of autoimmune hepatitis, non-infectious gastroenteritis, and colitis within the first six months of combination therapy among patients with metastatic ccRCC treated with either pembrolizumab/ axitinib (Cohort A) or Nivolumab/Ipilimumab (Cohort B) was assessed. Propensity score matching was utilized to balance baseline characteristics between the cohorts, including age, sex, ethnicity, and comorbidities. Results: For Cohort A, the risk of autoimmune hepatitis within the first six months of therapy was 0.841% (N = 1,783, patients with the outcome = 15) while the risk for Cohort B was 1.618% (N = 1,792, patients with the outcome = 29), p-value 0.0351, Odds Ratio 1.939, 95% CI (1.036,3.629). The risk of non-infectious gastroenteritis and colitis for Cohort A was 6.53% (N = 1,608, patients with the outcome = 105) while the risk for Cohort B was 10.136% (N = 1,618, patients with the outcome = 164), p-value 0.0002, Odds Ratio 1.615, 95% CI (1.227,1.964). Conclusions: Nivolumab and pembrolizumab, both PD-1 inhibitors, differ in their propensity to induce immune-related adverse events (irAEs), such as colitis. Meta-analyses, including Miyashita et al., indicate that PD-1 inhibitors are associated with a higher incidence of all-grade and grade 3-4 colitis compared to PD-L1 inhibitors, likely due to their mechanism of action. Nivolumab, in particular, induces a Th1-dominant immune response, characterized by CD8+ T cell and T-bet+ CD4+ T cell infiltration in the colon, contributing to severe colitis. FDA data further support this, reporting immune-mediated colitis in 2.9% of patients receiving nivolumab monotherapy (1.7% grade 3), compared to 1.7% (1.1% grade 3) with pembrolizumab. Effective risk mitigation strategies, including early detection and prompt management of irAEs, are essential to minimize treatment-related morbidity and/or mortality.