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salvage nivolumab/ipilimumab (Part B); however, 28 did not enroll due to symptomatic progression of
disease (17), grade 3-4 toxicity on nivolumab (8), or other (3). Of the patients who received salvage therapy,
best response was PR (13%), SD (30%), and PD (59%). Grade 3-5 treatment-related adverse effects were seen
in 28% on nivolumab monotherapy and 33% on nivolumab/ipilimumab. These results suggest a potential
role for anti-PD-1 monotherapy in patients who have contraindications or an aversion to either an
ipilimumab or VEGFR TKI containing combination regimen, particularly those with favorable risk disease.
However, anti-PD-1 monotherapy is likely inferior to nivolumab/ipilimumab in patients with
intermediate/poor risk disease - a question that is being formally addressed in the Checkmate 8Y8
(NCT03873402) protocol which is currently ongoing, or those whose tumors express sarcomatoid
[48]
features .

Combination VEGF TKI and PD-1 therapy
Angiogenic agents targeting VEGF and ICI therapies have improved survival for patients with advanced
ccRCC and are standard therapies in the management of this disease. Combinations of antiangiogenic and
ICI therapies have the potential to target distinct and complementary pathways, providing synergistic
benefit with concurrent therapy compared with additive effects of sequential therapy. Recent preclinical
studies have demonstrated that VEGFR TKI therapy alleviates immunosuppression in the tumor
microenvironment through targeting regulatory T-cells and MDSC, promoting T-cell infiltration, and
enhancing T-cell mediated cytotoxicity [49-52] . In vivo evidence from animal models has further shown that
combination of sunitinib or cabozantinib with chimeric antigen receptor-modified T cells can increase anti-
tumor efficacy and prolong survival compared to immunotherapy alone . However, there is also
[53]
preclinical evidence suggesting that anti-angiogenic therapy may have an antagonistic effect on the immune
response, particularly in ccRCC, by increasing hypoxia in the TME thereby diminishing anti-tumor
immunity and by upregulating CXCR4 expression leading to the influx of tumor-infiltrating regulatory T
cells and MDSC [54-56] .

Early phase I evaluation of combination sunitinib or pazopanib with nivolumab or pembrolizumab for
advanced RCC showed high rates of response; however, high-grade toxicities limited further
investigation . More recently, several trials have investigated various antiangiogenic agents combined with
[57]
anti-PD1/PD-L1 therapies compared to sunitinib alone. The IMmotion 151 phase 3 trial of first line
combination atezolizumab (anti-PD-L1) and bevacizumab (monoclonal antibody against VEGF) was
[58]
compared to sunitinib with co-primary endpoints PFS in PD-L1+ tumors and OS in overall population .
In patients with PD-L1+ tumors, the combination demonstrated significantly improved PFS (investigator
assessed) compared to sunitinib alone (HR PFS = 0.74; 0.57-0.96; P = 0.0217) [Table 1]. In the overall
population, there was no significant difference in PFS or OS between atezolizumab plus bevacizumab and
sunitinib. On further examination by an IRC, patients with PD-L1+ tumors demonstrated similar PFS
between the combination and sunitinib (HS PFS = 0.93; 0.72-1.21). Interestingly, the IRC analysis of patients
with PD-L1 negative tumors demonstrated a trend towards longer PFS in the atezolizumab plus
bevacizumab groups compared to sunitinib; suggesting that either PD-L1 status is a poor predictive
biomarker for response to the combination or that the Ventana SP142 assay scoring immune cell PD-L1
positivity may be a suboptimal assay. Atezolizumab and bevacizumab was well tolerated compared to
sunitinib with lower rates of grade 3-4 treatment-emergent adverse events (40% vs. 54%) with 16% patients
on atezolizumab and bevacizumab requiring corticosteroids for IRAE [Table 2]. Due to discordant PFS
between investigator and IRC assessments and the absence of OS benefit, the combination of atezolizumab
and bevacizumab was not approved for first line use.