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therapy. As these data remain forthcoming, understanding the optimal sequence of these combinations and
other ongoing efforts will be critical to put this data within the context of cabozantinib/nivolumab in the
[34]
first-line setting and increasing data supportive of combination therapy in the post-ICI space . Lastly, in a
similar vein in favor of de-escalation, a discontinuation design study where patients treated with axitinib
and avelumab discontinue axitinib if sustaining a response within the first 36 weeks of therapy also may
provide perspective on these types of adaptive strategies (TIDE-A, NCT04698213).

Towards an individualized designed study using a pre-therapy biomarker for therapy selection, the
[35]
BIONIKK study (NCT02960906) was recently presented . In this innovative clinical trial, tumor tissue
submitted at study entry was analyzed to distinguish participating systemically untreated ccRCC patients
into four molecularly defined groups (ccRCC1-4) based on previously defined transcriptomic features .
[36]
Molecular classification then determined treatment allocation - patients with ccRCC1 (immune-low) and
ccRCC4 (immune-high) were randomized between nivolumab or ipilimumab and nivolumab, and patients
with ccRCC2 (angiogenesis-high) and ccRCC3 (normal-like) tumor signatures were randomized between
ipilimumab and nivolumab or TKI therapy with sunitinib or pazopanib. In these groups, no significant
differences were observed in terms of the primary endpoint of treatment response, but combination
ipilimumab and nivolumab was numerically higher in the ccRCC1 group (immune-low) . While the
[35]
results remain preliminary, this study notably provides a proof of concept that molecular stratification to
target individual tumor biology rationally is feasible and provides initial foundational steps toward precision
medicine approaches integrating angiogenesis targeting, immune therapy, and other novel treatment
approaches.

ESCALATING BEYOND TKI/ICI THERAPY - CAN WE ACHIEVE MORE WITH MORE?
With recent advances having newly yet firmly established doublet combinations as the current standard of
care, multiple ongoing investigations are taking combination therapy one step further and testing triplet
regimens for the first-line treatment of ccRCC [Table 2]. One of the most notable ongoing studies is the
pivotal global phase III COSMIC-313 study (NCT03937219), which randomizes patients with IMDC
intermediate-poor risk disease to receive standard ipilimumab/nivolumab with either cabozantinib or
placebo . After the initial induction phase, patients receive nivolumab (for a maximum of 2 years) and
[37]
cabozantinib or placebo. While encouraging anti-tumor efficacy and tolerability has been reported in phase
I studies , it will be important to note specific and chronic toxicities, particularly in the context of the
[38]
reported cabozantinib/nivolumab therapy data.

Novel agents that have also shown efficacy in the first-line setting are also being positioned in the triplicate
space, with the incorporation of a VEGFR TKI and ICI backbone. For example, belzutifan (MK-6482) is a
potent and selective orally available HIF-2α inhibitor that has received breakthrough designation for the
treatment of VHL associated RCC in patients with non-metastatic tumors. In the phase II setting,
encouraging therapeutic responses have been reported with monotherapy (NCT04195750) and in
combination with cabozantinib (NCT03634540) . In line with this, evaluation in the triplicate setting is
[39]
now being pursued on a global phase III study (NCT04736706). Here, systemically untreated patients are
randomized to receive lenvatinib/pembrolizumab, lenvatinib/pembrolizumab/quavonlimab (an anti-CTLA-
4 antibody), or lenvatinib/pembrolizumab/belzutifan. This study will relevantly shed light on the
combination of VEGF, ICI, and HIF-2α inhibition and will also notably provide data on a competing
triplicate combination given the arm, including lenvatinib with dual ICI approach (similar to COSMIC-
313).