Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1)

Background Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, “primary refractory” ( P ref ), face dismal outcomes. Objective Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of P ref patients. Methods This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan–Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve. Results In our study, the P ref rate was 19%. Nivolumab/ipilimumab showed the highest P ref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non- P ref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for P ref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of P ref . This study presents limitations, mainly because of its retrospective design. Conclusions The ARON-1 study provides valuable insights into P ref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.