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Sawhney et al. J Cancer Metastasis Treat 2021;7:48 https://dx.doi.org/10.20517/2394-4722.2021.64 Page 7 of 9

Another ongoing ICI-adjuvant trial is the Checkmate-914 phase 3 trial evaluating nivolumab (an anti-PD-1
monoclonal antibody) alone or in combination with ipilimumab (an anti-CTLA4 monoclonal antibody) vs.
placebo for 24 weeks in the setting of high-risk predominantly ccRCC with pT2a (grade 3 or 4),
pT2b/pT3/pT4 (any grade), N0, or any T (any grade) N1 after radical or partial nephrectomy with negative
surgical margins > 4 weeks and ≤ 12 weeks before randomization and no clinical/radiological evidence of
macroscopic residual disease or distant metastases post-nephrectomy and tumor tissue obtained ≤ 3 months
pre-enrollment. The primary endpoint is DFS and some of the key secondary endpoints are OS and DFS for
[27]
nivolumab with ipilimumab vs. nivolumab and safety. The planned enrolment is 1600 patients .
A further trial involving ICIs is RAMPART, which is a randomized, multi-arm and multi-stage phase 3 trial
evaluating durvalumab (an anti-PD-L1 monoclonal antibody), durvalumab plus tremelimumab (an anti
CTLA-4 monoclonal antibody), and active monitoring in the setting of intermediate- to high-risk RCC
post-nephrectomy. The primary endpoints are DFS and OS, and the two of the key secondary endpoints are
[28]
metastasis-free survival and RCC-specific survival time. The planned enrolment is 1750 patients .

With a novel trial design, PROSPER is a randomized unblinded phase 3 trial evaluating nivolumab in the
setting of perioperative stage T2 or greater or node positive M0 RCC of any histology. It is hypothesized
that nephrectomy may remove immune effector cells and cytokines from the tumor site, which may result
in a decreased immune response, and hence the trial participants will be randomized to receive two doses of
neoadjuvant nivolumab pre-nephrectomy with subsequent (adjuvant) nivolumab for 9 months or standard
nephrectomy with subsequent observation. The target enrolment is 766 patients, and the primary endpoint
[29]
is RFS .
Mammalian target of rapamycin inhibitors
Another type of agent that is being investigated in the adjuvant RCC setting is the mammalian target of
rapamycin inhibitor. The EVEREST randomized phase 3 trial is evaluating everolimus in the post radical or
partial nephrectomy setting, and it is estimated to complete enrolment by the end of 2021. The primary
endpoint is RFS, and a key secondary endpoint is OS .
[30]
CONCLUSION
The landscape of adjuvant treatment in RCC is likely to change in the next few years, as ICI trials report
results, despite the initial disappointment with TKIs. The advent of ICIs and newer generation TKIs has led
to a rapid change in the treatment landscape of mRCC, with ICI combinations or ICI-and-TKI
combinations being used more widely after clinical trials have demonstrated their superior efficacy to
sunitinib. This has renewed hope that some of the current adjuvant trials will yield positive results and
become incorporated into the management of non-mRCC patients.

Nevertheless, we are yet to develop a better prognostic tool beyond pathological staging to help select those
[32]
who are more likely to benefit from adjuvant treatment. In a study by George et al. , 10 SNPs (single
nucleotide polymorphisms) in genes associated with RCC tumorigenesis and 3 SNPs (genotype for VEGFR-
1, VEGFR-2, and endothelial nitric oxide synthase) were found to be associated with statistically significant
DFS improvement favoring sunitinib over placebo. In an analysis of sunitinib and placebo groups
combined, they also found a significantly longer OS when there was no CCDC26 rs60315789 insertion as
compared to the heterozygous genotype, pointing to its potential as a post-surgical prognostic
biomarker [31,32] . Similarly, in the ARISER trial, those with higher CA-IX expression were shown to have an
improved DFS that approached statistical significance. Furthermore, as has been demonstrated in other
[9]
solid tumors, those with high PD-L1 expression are more likely to benefit more from ICI treatment .