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doubled the median survival (~30 months). Given the highly vascular nature of ccRCC, tyrosine kinase
inhibitors targeting the VEGF signaling pathway provided considerable benefit over the interleukin-2 (IL-2)
and interferon treatments. Seven anti-angiogenic drugs have been approved for first-line and second-line
treatment of metastatic RCC since 2005, including sorafenib, sunitinib, pazopanib, axitinib, bevacizumab,
[61]
cabozantinib, and lenvatinib [59-64] . With the exception of lenvatinib in combination with everolimus and
[65]
bevacizumab use with interferon-α , all approvals for VEGF-targeted therapies have been for single agents.
The development of mTOR inhibitors, temsirolimus and everolimus, have provided additional therapeutic
benefit as second-line single agents or in the first-line setting in patients with poor risk status [66,67] . Despite
these therapeutic advances, the average duration of disease control with these drugs remains only 8-9
[1]
months for first line treatment and 5-6 months in the second line setting . Additional target therapies under
investigation also include PT2385, a first-in-class HIF-2α antagonist, which has shown a favorable safety
[9]
profile and activity in a phase I dose escalation trial .

The new generation of immunotherapies has also shown promise for the treatment of metastatic ccRCC
[Figure 2]. Immunotherapy has long been utilized to treat RCC with the use of interferon-α and high-dose
[68]
IL-2 , but these cytokine therapies were associated with significant toxicity and low response rates. Thus,
the development of T-cell immune checkpoint inhibitors may similarly exploit intrinsic antitumor immune
activity with fewer adverse effects and improved quality of life. Nivolumab, a monoclonal antibody against
programmed cell death protein 1, was approved following the CheckMate 025 randomized control trial,
which demonstrated an overall survival benefit of nivolumab over everolimus in patients who failed prior
[69]
sunitinib or pazopanib therapy . The results of CheckMate 214, a randomized clinical trial investigating
nivolumab in combination with ipilimumab, an inhibitor of checkpoint cytotoxic T lymphocyte-associated
protein 4 (CTLA4), vs. sunitinib in patients with previously untreated advanced ccRCC, were recently
[70]
reported . Overall survival and objective response rates of nivolumab plus ipilimumab were significantly
higher than sunitinib among intermediate- and poor-risk patients. Thus, this combination has been granted
by the FDA as a first-line therapy. Phase III clinical trials of additional combinations of checkpoint inhibitors
with VEGF-targeted therapies are under investigation, which probably will again revolutionize the way we
[1]
treat metastatic kidney cancer .

CONCLUSION
The fields of kidney cancer biology and therapy have undergone transformative changes over the past two
decades. However, we are just at the beginning of contemplating how to best integrate these two seems
distinct yet highly inter-informative disciplines. The exceptional clinical benefits derived from modern
cancer therapy including targeted and immunotherapies have been associated with an astronomical
socioeconomic burden to the society. In the authors’ opinion, the principal way for the medical society
to further improve treatment efficacy and reduce the cost is the thoroughly integrate multi-omics based
predictive biomarkers into standard practice for the selection of the most effective front-line/second line
therapeutics with a curative intent. It is a tall but achievable order thus challenge awaiting to be conquered,
exemplified are the shown transition of therapeutic eras in metastatic kidney cancer from the “Dark Age”
(~2005, 2 drugs, median survival at ~15 moths) through the “Modern Age” (~2015, 9 drugs, median survival
at ~30 months) to the “Golden Age” (2015~, 13 drugs and counting, 30 months and counting with significant
number of patients expected to be cured). Nevertheless, much needs to be done if we wish to reach Diamond
Age by 2025 when most kidney cancer patients could be rendered free of recurrence, progression, and
[1]
thereby mortality from RCC .

DECLARATIONS
Authors’ contributions
Conception, design of the study, and interpretation: Le VH, Hsieh JJ