The Future of Immunotherapy-Based Combination Therapy in Metastatic Renal Cell Carcinoma

Abstract

In the past two decades, there has been a significant improvement in the understanding of the molecular pathogenesis of Renal Cell Carcinoma (RCC). These insights in the biological pathways have resulted in the development of multiple agents targeting vascular endothelial growth factor (VEGF), as well as inhibitors of the mammalian target of the rapamycin (mTOR) pathway. Most recently, checkpoint inhibitors were shown to have excellent clinical efficacy. Although the patients are living longer, durable complete responses are rarely seen. Historically, high dose interleukin 2 (IL2) therapy has produced durable complete responses in 5% to 8% highly selected patients-albeit with significant toxicity. A durable complete response is a surrogate for a long-term response in the modern era of targeted therapy and checkpoint immunotherapy. Numerous clinical trials are currently exploring the combination of immunotherapy with various targeted therapeutic agents to develop therapies with a higher complete response rate with acceptable toxicity. in this study, we provide a comprehensive review of multiple reported and ongoing clinical trials evaluating the combination of PD-1/PD-L1 inhibitors with either ipilimumab (a cytotoxic T-lymphocyte-associated protein 4, CTLA-4 inhibitor) or with anti-VEGF targeted therapy.

Keywords: VEGF inhibitors; checkpoint inhibitors; mTOR inhibitors; renal cell carcinoma.

Figure 1

Overview of treatment strategy for treatment naïve metastatic RCC, based on IMDC risk-stratification. ccmRCC, clear cell metastatic renal cell carcinoma; non-ccmRCC, non-clear cell metastatic renal cell carcinoma; risk stratification based on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. The International Metastatic RCC Database Consortium (IMDC) prognostic model integrates six adverse factors: Karnofsky performance status (KPS) <80 percent, time from diagnosis to treatment < 1-year, hemoglobin concentration < lower limit of normal, serum calcium > upper limit of normal, neutrophil count > upper limit of normal, platelet count > upper limit of normal. (Favorable risk: no risk factors, intermediate risk: 1 or 2 risk factors, poor risk: 3 or more risk factors).