Primary resistance to nivolumab plus ipilimumab therapy affects second‐line treatment outcomes in patients with metastatic renal cell carcinoma

Abstract

Nivolumab plus ipilimumab (NIVO+IPI) has a long‐term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second‐line treatment in patients with mRCC. The data used in this multi‐institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor‐tyrosine kinase inhibitor. Associations between PRD and progression‐free survival of second‐line treatment (PFS), progression‐free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male‐dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176–2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649–6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040–5.437; p < 0.001). Before starting second‐line therapy, patients with PRD tended to have a poor performance status compared with non‐PRD patients and a higher IMDC risk. Second‐line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first‐line treatment was associated with poor clinical course, even with second‐line therapy.