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Metastatic Renal Cell Carcinoma Database Consortium (IMDC) [17,18] . The earlier MSKCC model was
developed to predict benefit from interferon-α, whereas the IMDC model predicted benefit from VEGFR
TKI. Both models include time from diagnosis to treatment, Karnofsky performance status, and
hemoglobin and calcium concentrations. Additionally, the MSKCC model incorporates lactate
dehydrogenase level, whereas IMDC includes neutrophil and platelet count. In both models, patients with
favorable-risk disease have 0 risk factors, those with intermediate-risk disease have 1-2 factors, and those
with poor-risk disease have greater than 3 factors. The IMDC model has been utilized as a risk stratification
tool for clinical trials of VEGFR TKI and combination regimens; however, its applicability to
immunotherapy is likely limited. We will highlight potential future mostly laboratory biomarkers in
development.

FIRST LINE TREATMENT OPTIONS FOR CCRCC
Targeting angiogenesis and the VEGF pathway
ccRCC is strongly associated with mutations in the VHL tumor suppressor gene, which results in functional
inactivation of VHL proteins and downstream hypoxia-independent upregulation of pro-angiogenic factors
including VEGF. Among all epithelial cancers, ccRCC has the highest expression of VEGFA, providing
[19]
rationale for targeting VEGF and its receptor . VEGF receptor blockade with TKIs in RCC has
demonstrated several physiologic changes including reduction in blood vessel density, decreased tumor
[20]
perfusion, and may lead to infarction of the VEGF-dependent tumor microenvironment . Resistance to
TKI therapy has been demonstrated to occur by angiogenic escape through activation of compensatory
vascular signaling pathways including platelet derived growth factor (PDGFR), MET, AXL, and fibroblast
[21]
growth factor receptor (FGFR) . TKIs to multiple tyrosine kinases in addition to the VEGF receptor,
including PDGFR (pazopanib, sunitinib, lenvatinib), MET/AXL (cabozantinib), FGFR (lenvatinib) were
developed to simultaneously target parallel pathways causing decreased tumor vascularization and growth
and delayed angiogenic escape .
[22]
Sunitinib and pazopanib were the first TKI to improve PFS in the first line setting compared to interferon-
alpha (IFNα) and placebo, respectively [11,12] . Sunitinib was FDA approved for first line therapy of ccRCC in
January 2006 followed by pazopanib in October 2009. These agents were compared in the phase 3
COMPARZ trial with pazopanib demonstrating noninferiority in PFS with similar OS in all IMDC risk
groups . However, there were considerable differences in OS outcomes for each agent across IMDC
[12]
groups: favorable risk 42.5 and 43.6 months, intermediate risk 26.9 and 26.1 months, and poor risk 9.9 and
7.7 months, respectively. Patients required frequent dose reductions (44%-51%) and discontinuation (20%-
24%) due to adverse effects with similar grade 3-4 hypertension (15%). Differences in safety and tolerability
were noted with pazopanib demonstrating higher rates of liver function abnormalities and sunitinib higher
rates of fatigue, palmar-plantar dysesthesia, and cytopenias. The phase 3b PISCES sequential cross-over trial
demonstrated superior patient and provider preference as well as higher health-related quality of life
measures for pazopanib over sunitinib . Pazopanib emerged as a preferred front line VEGFR TKI agent
[23]
based on similar efficacy, less toxicity, and better tolerability.

Although the mTOR inhibitor temsirolimus was approved in the first line setting for patients with
intermediate and poor risk RCC based on its superiority to interferon in the Global ARCC trial, the
RECORD-3 trial subsequently showed that the oral mTOR inhibitor everolimus was inferior to sunitinib
across all IMDC risk groups [24,25] . As a consequence, mTOR inhibitor use has been relegated to second or
later lines of therapy, particularly in patients with tumors showing mutations in the PI3K, MTOR, TSC
pathway or in combination with VEGFR TKI such as lenvatinib .
[26]