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for these and other predictive biomarkers should be linked to goals of care including novel endpoints
mentioned above such as landmark OS and PFS, TFS and QOL throughout to the TFS period which better
reflect the impact of the immunotherapy component.

FUTURE DIRECTIONS
The role of cytoreductive nephrectomy, which previously provided both symptomatic benefit and improved
overall survival in combination with cytokine therapies, is yet to be defined with current ICI and
ICI/VEGFR TKI combinations [73-76] . The NORDIC-SUN (NCT03977571) and CYTOSHRINK
(NCT04090710) trials are evaluating induction nivolumab/ipilimumab followed by delayed cytoreductive
nephrectomy or interim stereotactic body radiation, respectively followed by nivolumab maintenance [77,78]
[Table 4]. The Phase 2 Cyto-KIK trial (NCT04322955) is evaluating induction nivolumab/cabozantinib with
delayed cytoreductive nephrectomy followed by resumption of systemic therapy . Lastly, the phase 3
[79]
PROBE trial (NCT04510597) includes checkpoint inhibitor-based induction with nivolumab/ipilimumab or
axitinib/pembrolizumab followed by randomization to nephrectomy or continuation of systemic therapy
[80]
for patients with PR/SD and discontinuation of study for patients with CR/PD . Each of these studies will
collect vital clinicopathologic data that have the potential to our understanding of the biologic processes
underlying responses to therapy and guide initial and subsequent treatment choices.

There are several ongoing studies of doublet and triplet regimens for advanced treatment naïve ccRCC. For
patients with intermediate/poor risk disease, the phase 3 trials Checkmate 209-8Y8 (NCT03873402) and
COSMIC 313 (NCT03937219) are investigating nivolumab/ipilimumab compared to nivolumab alone and
nivolumab/ipilimumab/cabozantinib, respectively with primary endpoints of PFS by central review [54,81]
[Table 4]. The PD1GREE (NCT03793166) phase 3 adaptive trial for patients with intermediate/poor risk
treatment naïve ccRCC compares induction nivolumab/ipilimumab followed by either
[82]
nivolumab/cabozantinib or nivolumab alone for patients with PR or SD at 12 weeks . Following induction
nivolumab/ipilimumab, patients with CR continue on nivolumab maintenance, whereas patients with PD
change to cabozantinib monotherapy. However, there remains an unmet need for a clinical trial comparing
first line nivolumab/ipilimumab to anti-PD1/VEGF therapy for all risk disease patients with endpoints of
landmark PFS and OS, complete response rates, treatment free survival, and quality of life. Optimally such a
trial could also validate some of the intriguing biomarker data emerging from some of the recently
published trials. With a widening landscape of treatment combinations, clinical trials investigating
sequences and combinations of therapies must be designed to demonstrate impact on long-term outcomes
such as complete responses, landmark PFS/OS, treatment free survival, and quality of life.

CONCLUSION
The first line treatment paradigm for advanced ccRCC has rapidly evolved with an expanding number of
combination anti-angiogenic/PD1/L1 regimens including axitinib/pembrolizumab, axitinib/avelumab,
cabozantinib/nivolumab and likely lenvatinib/pembrolizumab being added to the existing VEGFR TKI
monotherapy and ICI combination regimens. Figure 1 depicts a current treatment algorithm for frontline
therapy of patients with advanced ccRCC. All of these anti-angiogenic/anti-PD1/L1 combinations have
been (or will be) approved based on benefits relative to sunitinib. These promising early responses must be
contextualized to the long-term benefits of dual immune checkpoint blockade with nivolumab/ipilimumab.
Indeed, the question of whether antiangiogenic and ICI therapies provide synergistic, additive or sub-
additive effects on long-term outcomes, such as cure rate, treatment free survival and landmark PFS and OS
remains under intense scrutiny. Surveillance of long-term toxicities and quality of life measures will also be
important considerations. Prospectively validated biomarkers will be essential with the potential to match
individual patients’ disease biology with checkpoint inhibitors, antiangiogenic TKI, or novel therapies to