Prognostic Impact of Immune-Related Adverse Events on Combination Immune Checkpoint/Tyrosine Kinase Inhibition for Metastatic Renal Cancer

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.