Optimization of first-line systemic therapy in patients with advanced clear cell renal cell carcinoma

Although five immune-oncologic-drug-based combination therapies, such as ipilimumab plus nivolumab, avelumab plus axitinib, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, have been approved for advanced renal cell carcinoma (RCC) in Japan, the optimal therapy for advanced RCC has not been determined. Without head-to-head comparison, several network meta-analyses using phase 3 clinical trials presented the highest likelihood of maximal overall survival, progression-free survival, and objective response rate according to several categories such as the International Metastatic Renal Cell Carcinoma Database Consortium risk group, programmed cell death 1-ligand 1 expression, sarcomatoid features, or the safety profile of treatment-related adverse events; however, they did not include the results of additional long-term follow-up data in each clinical trial. In the real world, advanced RCC treatment depends on several factors, such as age, comorbidity, tumor burden, or the presence of symptoms that affect daily life. To relieve tumor-related symptoms, tumor burden reduction is required, which may lead to the use of therapies with high response rates and low risk of disease progression. Moreover, patients with comorbidities, such as uncontrolled diabetes, are required to avoid steroid therapy for adverse events, which may necessitate the use of therapies with a low incidence of adverse events that are needed for high-dose steroids or permanent steroid replacement therapy. Moreover, novel drugs, such as the hypoxia-inducible factor 2a inhibitor (belzutifan) or immunostimulatory interleukin-2 cytokine prodrug (bempegaldesleukin) have been developed, and phase 3 clinical trials of combination therapy using these drugs for treatment-naïve advanced RCC are ongoing. Further development of systemic therapies for advanced RCC is required.