In the past 10 years, much has changed in the management of advanced renal cell carcinoma (RCC; Figure 1). The treatment of early-stage disease has become less morbid, with the widespread adoption of robotic surgical techniques and the increased utility of thermal ablative techniques. For advanced disease, we have seen FDA approval of 7 new agents.1–7 Progress in sequencing technology and copy number analysis has resulted in the discovery of genes8,9 and chromosomal regions10,11 that may be responsible for disease development or progression. The lives of individuals with RCC are clearly better than they were at the beginning of the last decade. On the other hand, we still have much work to do. Unmet needs are found in the diagnosis and characterization of disease, in the choice of frontline systemic therapy, and in the decisions made at resistance. Much of the information obtained for RCC is focused on clear cell histology, and little is known about optimal treatment for variant histologies. In the next 10 years, we must better match therapy to patients and move from a histologically based to a molecularly based classification of disease.
With identification of the von Hippel-Lindau (VHL) gene12 and recognition that sporadic mutations of VHL are key drivers of clear cell RCC biology, an entirely new class of agents was developed to block the downstream consequences of hypoxia inducible factor upregulation and resultant vascular endothelial growth factor (VEGF) overproduction. Inhibitors of the VEGF ligand or VEGF receptor entered into clinical trials in the early 2000s. In December 2005, sorafenib became the first agent in this class to be FDA-approved for advanced RCC.6 A month later, sunitinib was also approved for the same indication.2 In the next 5 years, bevacizumab plus interferon (IFN) α,7 pazopanib,4 and axitinib5 were also approved.
Although individual studies have, for the most part, not shown a significant intra-study increase in overall survival (OS) for patients treated with antiangiogenic agents as frontline therapy, review of the 40% of patients in the upfront sunitinib versus IFN study who received no subsequent therapy shows a 28- versus 14-month OS, respectively.13 Additionally, large retrospective reviews of patient outcome after antiangiogenic therapy show a significant upward shift in OS for good- and intermediate-risk patient subgroups when compared with historical data from patients treated with immunotherapy.14
In the second-line setting, 2 agents are now FDA-approved. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, showed a 4.9-month progression-free survival versus 1.9-months for placebo in patients who experienced progression on sorafenib, sunitinib, or both.1 More recently, axitinib, a highly selective VEGF receptor inhibitor, showed a 6.7-month progression-free survival in a mix of patients who had been treated with immunotherapy or VEGF receptor inhibitor, compared with 4.7 months for patients treated with sorafenib.5
Treatment of individuals with poor-risk features has also advanced in the past 10 years. A randomized phase III study comparing the mTOR inhibitor temsirolimus versus IFN showed a significant prolongation of OS in patients who received upfront temsirolimus.3 Although this improvement is modest, it speaks to an incremental and clinically important advancement in our ability to impact the natural history of advanced RCC, regardless of the initial presenting features.
Patients with advanced RCC clearly have more treatment options today than 10 years ago, and the literature includes statements about the current “embarrassment of riches” in the RCC therapeutic arena. Unfortunately, however, we have not won the battle. Resistance to existing therapies is an almost universal phenomenon, and we do not yet understand the mechanism behind its development. Despite advances in treatment, most patients with advanced disease still face a dramatically shorted life expectancy. An objective look at the therapeutic landscape shows development of only 2 classes of agents after an expenditure of billions of dollars and involvement of thousands of patients in clinical trials, with little to no effort expended on obtaining tissue and blood samples to understand the determinants of response and resistance.
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