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transformed significantly, and the serial introduction of novel classes of therapeutic agents has notably
improved clinical outcomes over time. Earlier versions of immunotherapy in the form of recombinant
cytokines constituted a standard in the 1990s, but their use was limited by poor tolerance, and only modest
[1]
activity with sustained clinical benefit was achieved in a minority of patients . Molecular targeting agents,
including multi-tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor (VEGF) receptor
and mTOR pathway blockers, subsequently took their place as the standard of care for patients in the first-
line setting and were typically given as single agents . The introduction of contemporary immunotherapy
[2]
in the form of immune checkpoint inhibitors (ICIs) initially occurred in pre-treated patients treated with
PD-1 directed monotherapy , but this quickly moved into the frontline setting where combination therapy
[3]
pairing agents targeting PD-1 and CTLA-4 were shown to improve patient survival, freedom from
progression and quality of life compared to the prior gold standard, single-agent TKI therapy . Soon after,
[4]
the introduction of combinations pairing the old with the new, TKI plus ICI therapy again demonstrated
superior patient response and survival outcomes when compared to TKI alone. The advent of several new
regimens approved over 2018-2021 has now ushered in a new treatment era, with combination therapy as
the frontline standard for all eligible advanced ccRCC patients . As all these novel regimens have
[5-8]
demonstrated superiority over TKI alone, but none have been compared to one another, selection of a
preferred contemporary standard for clinical practice or as the comparator on new prospective trials
remains complex. Lastly, while SURTIME and CARMENA investigated the role of cytoreductive
[10]
[9]
nephrectomy with sunitinib, these studies provide complementary data and inform that many patients will
start with immediate upfront systemic therapy with subsequent consideration of cytoreduction if clinical
circumstances permit. Here, we review currently approved treatment regimens and overall treatment
strategies for patients systemically treatment-naïve ccRCC.

COMBINATION THERAPY IS THE FRONTLINE STANDARD FOR ADVANCED CCRCC
For many years the routine assessment of patients with metastatic ccRCC initiating first-line systemic
therapy integrated clinical prognostic tools like the Memorial Sloan Kettering Cancer Center (MSKCC) and
the International Metastatic RCC Database Consortium (IMDC) risk classification system [11,12] . Developed
during the cytokine and targeted therapy eras, respectively, these programs integrate clinical and laboratory
data to group patients into favorable, intermediate, and poor-risk strata. However, for years, these tools
were merely appreciated (and serially validated) for their usefulness in informing disease prognosis, and
registration strategies in the metastatic setting rarely focused on specific risk categories [13,14] . More recent
data highlight that these risk classifiers serve as clinical surrogates for underlying tumor biology, with RCC
tumors characterized across different disease phenotypes, including enrichment of upregulation of tumor
angiogenesis in favorable risk patients vs. proliferative/inflammatory profiles in patients with
intermediate/poor-risk disease [15-17] . This has enabled a more nuanced understanding of how risk status (and
underlying biology) may be informative for choice of therapy in previously systemically untreated ccRCC
patients.

COMBINATION IMMUNE CHECKPOINT BLOCKADE THERAPY
The first modern combination therapy proven to be superior to TKI monotherapy was ipilimumab plus
[4]
nivolumab on the CheckMate-214 trial . Extended follow-up analyses of this global phase 3 study with a
dedicated focus on IMDC intermediate/poor-risk patients confirm superior clinical outcomes over single-
agent sunitinib for the three co-primary endpoints: overall response rate (ORR), progression-free survival
(PFS, HR = 0.73), and overall survival (OS, HR = 0.68) (see Table 1) [18,19] . In the updated 4-year and recently
presented 5-year survival analyses, there is also a better appreciation for the long-term clinical benefit from
therapy in those patients who achieve radiographic response to therapy. For instance, of those patients who
achieved a complete response (CR), 32% of patients continue to remain on systemic therapy, and 46% of