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Page 6 of 9 Sawhney et al. J Cancer Metastasis Treat 2021;7:48 https://dx.doi.org/10.20517/2394-4722.2021.64

presented a final signal that perhaps a different approach to tackling the problem of recurrence after surgery
is needed.

Immune checkpoint inhibitors
ICIs either alone or in combination with TKIs have been shown to be efficacious in the mRCC setting with
tolerable side-effect profiles. There is great interest, with studies ongoing, in whether this benefit will
translate to the adjuvant setting, especially given the prior failure of TKIs to demonstrate benefit. Indeed,
the biological rationale for enhancing the immune tumor response through programmed cell death protein
1 (PD-1)/programmed death ligand 1 (PDL-1) blockade may represent a more efficacious approach than
antiangiogenic blockade, particularly in clearing circulating tumor cells or micrometastases. Anti-PD-1/PD-
L1 ICIs work by disrupting the expressed tumor surface PD-L1 neoantigen inhibitory response when it
binds to PD-1 T-cells that leads to immune tolerance. Another target for ICIs is cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4), which plays an important role in the regulation of immune activation and
tolerance as it binds to cytotoxic lymphocytes that ligate with B-7 expressed on antigen-presenting cells and
inhibits T-cell proliferation. This combination of anti-PD-1 and anti-CTLA-4 ICIs demonstrated significant
and maintained antitumor efficacy in melanoma and mRCC patients even after their discontinuation [22,23] . A
recent systematic review and meta-analysis, involving 1644 patients across eight studies involving RCC,
demonstrated that tumor PD-L1 expression significantly correlated with OS (HR = 1.98, 95%CI: 1.22-3.22, Z
= 2.77, P = 0.006) and DFS (HR = 3.70, 95%CI: 2.07-6.62, Z = 4.40, P = 0.0001) , suggesting that PD-L1 and
[23]
[24]
PD-1 may be fruitful targets in the adjuvant setting .
One of the several ongoing studies is KEYNOTE-564, a randomized phase 3 trial, evaluating
pembrolizumab vs. placebo for 17 cycles (or one year) of treatment in the setting of intermediate- to high-
risk ccRCC or stage M1 with no evidence of disease (M1 NED), no prior systemic treatment for advanced
RCC, and disease free after complete or partial nephrectomy (and metastectomy in M1 NED). Patients with
M1 disease with a single metastasis that can be completely resected ≤ 1 year from nephrectomy were also
included, and enrolment has completed with 994 patients. At first interim analysis, the primary endpoint of
DFS was met with a HR of 0.68 (95%CI: 0.53-0.87). The estimated DFS rate at 24 months was 77.3% with
pembrolizumab vs. 68.1% with placebo. In addition, this DFS benefit was seen across all subgroups. Median
OS was not reached for both trial cohorts and the P-value did not cross the statistical hypothesis testing
boundary. The AE profile of pembrolizumab was in line with expectations, with no new safety signals. All-
cause AEs of Grades 3-5 occurred in 32.4% and 17.7% of patients receiving pembrolizumab and placebo,
respectively, while Grades 3-5 TRAEs rates were 18.9% and 1.2% in the same respective groups, with no
deaths reported in either trial arm .
[25]

IMmotion010 is an ongoing randomized phase 3 trial evaluating atezolizumab, a PD-L1 inhibitor, vs.
placebo, with treatment three times weekly for 16 cycles or one year, in the setting of high-risk ccRCC or
sarcomatoid (T2 grade 4, T3a grade 3-4, T3b/c any grade, T4 any grade, or TxN+ any grade) after
nephrectomy or complete resection of limited metachronous/synchronous metastasis, and tumor specimens
evaluable for PD-L1. The primary endpoint is independent review-assessed DFS. The study also stratifies
disease stage (T2/T3a vs. T3b/c/T4/N+ vs. metastasectomy) and PD-L1 status on tumor-infiltrating immune
cells (IC; PD-L1 IC expression < 1% vs. ≥ 1%). Secondary endpoints include OS, investigator-assessed DFS,
independent review-assessed and investigator-assessed DFS in patients with ≥ 1% PD-L1 IC, disease-specific
survival, distant metastasis-free survival, and 3-year rates of independent review-assessed and investigator-
assessed DFS. The planned analysis will occur when at least 65% of patients in the two arms have died and
the study has planned to enroll 664 patients .
[26]