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Atmaja et al. J Cancer Metastasis Treat 2021;7:xx https://dx.doi.org/10.20517/2394-4722.2021.66 Page 7 of 14

[58]
(Atezolizumab) . The significant efficacy of these new immunotherapy agents in other malignancies, such
as melanoma and lung cancer, ignited a burgeoning interest in using immune therapies in mRCC [59,60] . The
treatment landscape for mRCC was revolutionized after the FDA approval of Nivolumab and Ipilimumab in
[26]
April 2018 . Since then, three additional combination therapies, Pembrolizumab plus Axitinib, Avelumab
plus Axitinib, Nivolumab plus Cabozantinib, have also shown remarkable results, leading to their FDA
approvals in April 2019, May 2019, and January 2021 respectively [61-63] .

Favorable-risk disease
Sunitinib has been, for many years, the preferred first-line treatment for patients identified as having
favorable risk . A large, randomized, phase III trial of treatment-naïve patients demonstrated that the
[64]
median PFS, ORR and median OS with Sunitinib was 9.5 months, 25% and 29.3 months respectively . A
[64]
sub-analysis within a network meta-analysis of 15 randomized control trials showed that Sunitinib resulted
in a significant PFS benefit compared with Everolimus . This was likely attributable to the difference in the
[22]
mechanism of action between the TKI and mTOR inhibitors. Sunitinib blocks VEGFR 1, 2 and 3, as well as
[17]
PDGFR . Whilst the VEGFRs may be the more pertinent targets, PDGF plays a major role in pericyte
[65]
recruitment on developing tumor vessels . Resistance against antiangiogenic drugs has been associated
with the presence of pericyte-covered vessels . As stated above, Everolimus and Temsirolimus only block
[65]
the mTORC1 activation pathway, leaving mTORC2 signaling unopposed [23,24] . It has been suggested that
there may be a potentially synergistic benefit from using combinations of targeted agents that inhibit
separate pathways. However, a combination of Temsirolimus plus Bevacizumab, or Bevacizumab plus
Interferon-alpha, only provides little survival benefit compared to Sunitinib alone, while the combination of
[22]
ICI and VEGFR inhibitors as frontline therapy could provide enhanced efficacy in mRCC .

In the favorable-risk group, patients treated with Ipilimumab and Nivolumab in CheckMate 214 had ORR
and PFS lower than those achieved with Sunitinib {29% vs. 52% and 15.3 months vs. 25.1 months [Hazard
[26]
Ratio (HR) = 2.18; P < 0.001]} . In ICI and VEGFR studies, a recent meta-analysis showed that Avelumab
plus Axitinib is associated with a significant improvement in PFS when compared with Sunitinib [22,62] .
However, additional follow-up is required in the JAVELIN Renal 101 trial to prove that this combination of
results is a real OS benefit . Another study, CheckMate 9ER, with Nivolumab plus Cabozantinib vs.
[62]
Sunitinib, has shown benefit across all IMDC risk and PD-L1 subgroups at 18.1-month follow-up, although
a longer follow-up is required to assess whether the responses are durable .
[63]
[66]
The Favorable-risk disease tends to be associated with increased angiogenesis . PBRM1 is the second most
commonly mutated gene in ccRCC, and it plays a role in suppressing hypoxic transcriptional signatures. Its
loss in the metastatic setting confers a favorable effect, potentially through the upregulation of VEGF
therapy targets, such as HIF .
[67]

Intermediate/poor risk disease
For patients with IMDC-identified intermediate or poor-risk disease, several different frontline regimes can
be considered. The combination of ICIs with VEGFR-TKIs has emerged to be the optimal first-line therapy
of choice. In this patient cohort, the CheckMate 214 trial demonstrated the superiority of Ipilimumab plus
Nivolumab over Sunitinib [ORR of 42% vs. 27% (P < 0.0001), PFS of 11.6 months vs. 8.4 months (HR = 0.82;
[26]
99%CI: 0.64-1.05; P = 0.03), median OS not reached vs. 26 months] . The advantage of using Avelumab
plus Axitinib, over Sunitinib, in mRCC patients of all IMDC risk subgroups was demonstrated in the
JAVELIN 101 trial, with an ORR of 55.2% vs. 25.7% and a median PFS of 13.8 months vs. 8.4 months (HR =
0.69; 95%CI: 0.56-0.84; P = 0.0001) . The KEYNOTE-426 trial showed an OS benefit in favor of the
[62]
Pembrolizumab plus Axitinib combination vs. Sunitinib at 18 months (82.3% vs. 72.1%, P < 0.0001) . It also
[61]
demonstrated an improvement in ORR and median PFS with combination therapy compared with