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.

Immune Checkpoint Inhibitors in the Treatment of Renal Cancer: Current State and Future Perspective

“…The treatment options for patients with RCC have been expanding in the last few years [9] after the advent of immunotherapeutic agents targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis as a single-agent (Table 1) or combined with anti-CTLA-4 monoclonal antibodies (MoAbs) [10]. More recently, the combination of immunotherapeutic agents with antiangiogenic agents has proven to be a promising therapeutic strategy [11].…”

SOX6 represses tumor growth of clear cell renal cell carcinoma by HMG domain‐dependent regulation of Wnt/β‐catenin signaling

“…Targeted agents that focus on vascular endothelial growth factors or mammalian target of rapamycin signaling and checkpoint inhibitors that target PD‐1 or PD‐L1 have been developed and applied to clinical treatment for advanced ccRCC with a certain degree of efficacy 5‐7 . However, not all patients could benefit from targeted therapy, and some are at risk of serious toxicities and inconsistent response 8,9 . Therefore, further insight into the molecular mechanism underlying the pathogenesis of ccRCC is still needed to identify new promising biomarkers and potentially therapeutic molecular targets.…”

Targeting the Deterministic Evolutionary Trajectories of Clear Cell Renal Cell Carcinoma

“…While checkpoint inhibitor and the antiangiogenic combination is a standard of care for metastatic ccRCC, there is a significant overlap in the toxicity profile of these drugs, with diarrhea, hypertension, and hepatotoxicity being among the most commonly presented [55,61]. These and other adverse effects may all contribute to treatment discontinuation or dose reduction.…”

“…While molecular profiling of multiple specimens is not practical in the setting of clinical practice, the analysis of circulating tumor DNA (ctDNA) obtained from liquid biopsy represents a feasible alternative. Analysis of ctDNA enables identification of both clonal and subclonal tumor-specific mutations with high sensitivity and specificity, with detection rates comparable with those of traditional biopsies [61][62][63][64][65][66]. Furthermore, ctDNA has a relatively short half-life (approximately 2 h), allowing for the evaluation of tumor changes in real-time [67].…”