Prognostic impact of immune-related adverse events on combination immune checkpoint/tyrosine kinase inhibition for metastatic renal cancer

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 (irAEs) is currently employed as a predictive factor in clinical practice. To elucidate the impact of irAEs on efficacy, a cohort of mRCC patients 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 irAE. In the ICI-ICI group, patients with irAE 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 months vs 5.8 months, p 0.01). Conversely, no such correlation was observed between irAE 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.