Abstract
Immune checkpoint inhibitor (ICI) combinations and tyrosine kinase inhibitor (TKI) use are standard for metastatic renal cell carcinoma (mRCC), leading to improved outcomes. However, due to a lack of predictive biomarkers, the presence or absence of immune-related adverse events (irAE) is currently used as a predictive factor in clinical practice. To elucidate the impact of irAEs on efficacy, a cohort of patients with mRCC who received ICI-based combination therapy as initial treatment was analyzed. Patients were divided into two groups: those who received dual-ICI therapy (ICI-ICI, N = 55) or ICI and TKI therapy (ICI-TKI, N = 55). Subsequent to this initial categorization, each group was further subdivided based on the presence or absence of irAEs. In the ICI-ICI group, patients with irAEs exhibited significantly prolonged overall survival (OS) and progression-free survival [PFS; OS (median): not reached vs. 17.9 months, P = 0.03/PFS (median): 51.4 vs. 5.8 months, P < 0.01]. Conversely, no such correlation was observed between irAEs and OS/PFS in the ICI-TKI group. [OS (median): 26.3 months vs. not reached, P = 0.73/PFS (median): 16.8 months vs. 11.9 months, P = 0.38] Furthermore, treatment discontinuation due to AEs accounted for 65% (N = 32) in the ICI-ICI group and 57% (N = 24) in the ICI-TKI group, with a slightly higher tendency observed in the ICI-ICI group. These findings suggest that the prognostic impact of irAEs may differ depending on the treatment combination, and further basic research is needed to elucidate the underlying mechanisms. SIGNIFICANCE: In patients with mRCC who received ICI-ICI, the occurrence of irAEs was associated with improved survival outcomes, whereas no such association was observed in patients who received ICI-TKI. This suggests that irAEs may reflect the favorable immune response specific to ICI-ICI therapy, whereas differences in the tumor microenvironment, particularly involving neutrophils, in ICI-TKI patients may influence treatment response.