Metastatic Renal Cell Carcinoma Management: From Molecular Mechanism to Clinical Practice

Abstract

The therapeutic sc"enario of metastatic renal cell cancer (mRCC) has noticeably increased, ranging from the most studied molecular target therapies to those most recently introduced, up to immune checkpoint inhibitors (ICIs). The most recent clinical trials with an ICI-based combination of molecular targeted agents and ICI show how, by restoring an efficient immune response against cancer cells and by establishing an immunological memory, it is possible to obtain not only a better radiological response but also a longer progression-free and overall survival. However, the role of tyrosine kinase inhibitors (TKIs) remains of fundamental importance, especially in patients who, for clinical characteristics, tumor burden and comorbidity, could have greater benefit from the use of TKIs in monotherapy rather than in combination with other therapies. However, to use these novel options in the best possible way, knowledge is required not only of the data from the large clinical trials but also of the biological mechanisms, molecular pathways, immunological mechanisms, and methodological issues related to both new response criteria and endpoints. In this complex scenario, we review the latest results of the latest clinical trials and provide guidance for overcoming the barriers to decision-making to offer a practical approach to the management of mRCC in daily clinical practice. Moreover, based on recent literature, we discuss the most innovative combination strategies that would allow us to achieve the best clinical therapeutic results.

Full text

Metastatic Renal Cell Carcinoma
Management: From Molecular
Mechanism to Clinical Practice
Michela Roberto
1,2
*, Andrea Botticelli
1,3
, Martina Panebianco
1,4
, Anna Maria Aschelter
4
,
Alain Gelibter
3
, Chiara Ciccarese
5
, Mauro Minelli
6
, Marianna Nuti
7
, Daniele Santini
8
,
Andrea Laghi
2
, Silverio Tomao
9
and Paolo Marchetti
1,3
1
Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy,
2
Department of Medical-Surgical
Sciences and Translational Medicine, Sapienza University of Rome, Rome, Italy,
3
Medical Oncology Unit, Policlinico Umberto
I, Sapienza University of Rome, Rome, Italy,
4
Medical Oncology Unit, Azienda Ospedaliero Universitaria Sant’Andrea,
Rome, Italy,
5
Department of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy,
6
Department of Medical Oncology, Azienda Ospedaliera San Giovanni Addolorata, Rome, Italy,
7
Department of Experimental
Medicine, University of Rome Sapienza Rome, Rome, Italy,
8
Department of Medical Oncology, University Campus Bio-
Medico, Rome, Italy,
9
Department of Radiological, Oncological and Anatomo-Pathological Sciences, Policlinico Umberto I,
Sapienza University of Rome, Rome, Italy
The therapeutic sc"enario of metastatic renal cell cancer (mRCC) has noticeably
increased, ranging from the most studied molecular target therapies to those most
recently introduced, up to immune checkpoint inhibitors (ICIs). The most recent clinical
trials with an ICI-based combination of molecular targeted agents and ICI show how, by
restoring an efficient immune response against cancer cells and by establishing an
immunological memory, it is possible to obtain not only a better radiological response
but also a longer progression-free and overall survival. However, the role of tyrosine kinase
inhibitors (TKIs) remains of fundamental importance, especially in patients who, for clinical
characteristics, tumor burden and comorbidity, could have greater benefit from the use of
TKIs in monotherapy rather than in combination with other therapies. However, to use
these novel options in the best possible way, knowledge is required not only of the data
from the large clinical trials but also of the biological mechanisms, molecular pathways,
immunological mechanisms, and methodological issues related to both new response
criteria and endpoints. In this complex scenario, we review the latest results of the latest
clinical trials and provide guidance for overcoming the barriers to decision-making to offer
a practical approach to the management of mRCC in daily clinical practice. Moreover,
based on recent literature, we discuss the most innovative combination strategies that
would allow us to achieve the best clinical therapeutic results.
Keywords: renal cancer carcinoma, targeted therapy, tyrosine kinase inhibitor (TKI), immune checkpoints inhibitor,
new biomarkers
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576391
Edited by:
Eugenio Zoni,
University of Bern, Switzerland
Reviewed by:
Eric Jonasch,
University of Texas MD Anderson
Cancer Center, United States
Michael Staehler,
Ludwig Maximilian University of
Munich, Germany
*Correspondence:
Michela Roberto
michela.roberto@uniroma1.it
Specialty section:
This article was submitted to
Genitourinary Oncology,
a section of the journal
Frontiers in Oncology
Received: 23 January 2021
Accepted: 29 March 2021
Published: 22 April 2021
Citation:
Roberto M, Botticelli A, Panebianco M,
Aschelter AM, Gelibter A, Ciccarese C,
Minelli M, Nuti M, Santini D, Laghi A,
Tomao S and Marchetti P (2021)
Metastatic Renal Cell Carcinoma
Management: From Molecular
Mechanism to Clinical Practice.
Front. Oncol. 11:657639.
doi: 10.3389/fonc.2021.657639
REVIEW
published: 22 April 2021
doi: 10.3389/fonc.2021.657639

INTRODUCTION
Renal cancer is the 10th most common cancer in Italy, with
approximately 13,400 new cases per year (1), 70–80% have clear
cell histology, while papillary, medullary, chromophobe, and
other forms classified as non-clear cell histology are rare.
Approximately 25% of patients present with the advanced-stage
disease since their diagnosis, and among those undergoing
nephrectomy, about one-third experience a distant recurrence
during the rest of their lives and are initiated to systemic treatment.
Despite the significant therapeutic improvements, the 5-year
survival rate of patients with metastatic renal cell cancer (mRCC)
remains poor, especially in patients with unfavorable prognostic
factors (2). The two validated prognostic models for the
classification of patients with mRCC within clinical trials are
the Memorial Sloan Kettering Cancer Centre (MSKCC) model
(3) and the International mRCC Database Consortium (IMDC)
that date back to 2005 and 2009, respectively (4). Although more
than 10 years have elapsed, and in the meantime, drug molecules
with new mechanisms of action have been developed, clinical
trials still stratify patients into those with favorable (with 0 poor
prognostic factors), intermediate (with 1–2poorprognostic
factors), or poor risk in the presence of at least three of the
following prognostic factors: less than 1 year from diagnosis to
treatment time, a Karnofsky PS score of <80 at the start of
treatment, anemia, neutrophil or platelet count greater than the
normal upper limit, or hypercalcemia (corrected Ca >10 mg/dl or
>2.5 mmol/L).
The therapeutic scenario of mRCC has undergone incredible
enrichment in recent years, ranging from the most studied
tyrosine kinase inhibitor (TKI)-targeted therapies (anti-
vascular endothelial growth factor (VEGF) and anti-mTOR) to
those most recently introduced (anti-MET, anti-RET, and anti-
FGFR) up to immunotherapy (IO) (anti-PD-1, anti-PD-L1, and
anti-CTLA-4). Literature data on new therapeutic indications
with cabozantinib in both the first and second lines (5,6),
nivolumab after anti-VEGF TKI progression (7), nivolumab
combined with ipilimumab in naive patients with poor
prognostic factors, and pembrolizumab combined with axitinib
in all prognostic subgroups (8), have modified the prognosis of
patients with mRCC. Especially, patients classified as
‘intermediate’risk pass from a historical median survival of
approximately 20 months to 3 years in the front line, which is
almost equal to that of patients with favorable prognosis. On the
one hand, we have seen a considerable improvement in the
therapeutic algorithm of mRCC [clinical guidelines reported
different therapeutic options only in patients with intermediate
prognosis (1)]. On the other hand, the rate of development in the
identification of new prognostic and predictive factors has not
been the same throughout. Therefore, MSKCC/IMDC remains
the standard prognostic classification criteria. However, in light
of the complex mechanisms of action of the new TKI molecules,
such as cabozantinib or combinations of TKIs and IO, or even
more combinations of different immune checkpoint inhibitors
(ICIs), are we sure that these ‘old’criteria are sufficient?
In the era of precision medicine, in which knowledge of the
molecular and genomic aspects of renal cancer has become ever
wider, how can we think that criteria based on obvious clinical
considerations (poor performance status and a short
progression-free interval) and hematochemical parameters are
sufficient to determine a therapeutic choice? To make the best
use of new drugs and associations and to propose new
therapeutic sequences, better knowledge is required not only of
the data derived from the large clinical trials but also of the basic
biology, the complexity of involved molecular pathways, the
immunology of tumours, and methodological problems related
to both new response criteria and new endpoints. In this complex
scenario, this review aims to provide a practical approach to the
management of advanced renal cancer, framing the new results
in daily clinical practice and providing points for reflections to
overcome decision-making barriers based on physician
therapeutic choice.
THE HETEROGENEITY OF RENAL TUMOR
RCC includes a heterogeneous group of tumors that are
characterized by different clinical and genomic factors and are
increasingly well defined in both syndromic and sporadic
settings (9). These tumor types originate from different cells;
for example, clear cell and papillary carcinomas arise from the
proximal or parietal kidney cells, whereas chromophobe
carcinomas arise from the intercalated cells (10)andare
characterized by different genomic drivers that lead to
tumorigenesis. In more than 90% of clear cell RCC cases,
large-scale genomic sequencing has identified chromothripsis
of chromosome 3p, typically with a concurrent gain of 5q (>67%)
and loss of 15q (45%) (9). In particular, the loss of 3p results in
the inactivation of Von Hippel–Lindau disease tumor suppressor
protein (VHL). Mutations in genes encoding other components
of the VHL complex [such as TCEB1 (also known as ELOC)]
also lead to VHL inactivation (11–13). pVHL is part of a
multiprotein complex with ubiquitin ligase activity. Within this
complex, pVHL is the subunit that recognizes protein substrates,
stimulating their ubiquitination and proteasome-dependent
degradation. The main target of this complex is the
transcription factor hypoxia-inducible factor 1 (HIF-1a),
which plays a key role in the cellular response to hypoxic
conditions. It stimulates the transcription of genes involved in
promoting angiogenesis and invasive growth. In renal cancer
cells, this complex does not function; therefore, HIF-1a
accumulates in cells and activates a cascade of other genes that
encode factors that induce hypoxia, including VEGF or those
involved in alternative pathways to VEGF, such as fibroblast
growth factor receptor (FGFR), platelet-derived growth factor
receptors (PDGFRs), AXL, and c-MET, all of which are involved
in angiogenesis, tumor growth, and survival (14).
Zinc-finger and homeobox protein 2 (ZHX2) is a VHL target.
VHL loss-of-function mutations usually result in an increased
abundance and nuclear localization of ZHX2. Loss of ZHX2
inhibits signaling through the transcription factor NF-kB, and
ZHX2 binds to many NF-kB target genes, revealing that ZHX2 is
a potential therapeutic target for RCC (15).
Roberto et al. Metastatic Renal Cell Carcinoma Management
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576392

VHL inactivation alone is insufficient for RCC tumorigenesis,
and several gene mutations contribute to tumor heterogeneity
that characterizes RCC. Intratumoral heterogeneity, defined as
the presence of genetically different clones in different
subpopulations of the same tumor, is a typical renal tumor
condition (16). Accordingly, phylogenetic studies show how
the tumorigenesis in the RCC follows an evolutionary model,
‘tree-like’: in the trunk lies the main mutation (e.g. the VHL gene
in the clear cell tumor) that paves the way for tumorigenesis, and
from the trunk, different subclonal mutations branch out, which
contribute to tumor growth and progression. Data from the
TRACERx renal study have identified secondary mutations and
chromosomal changes involved in tumor evolution (17).
Excluding hereditary forms, which cover only 4% of cases, for
sporadic forms, The Cancer Genome Atlas (TCGA) has identified 19
genes involved in addition to VHL, including BAP1, PBRM1, SETD2,
KDM5C, KDM6A, mTOR, PTEN, PIK3CA,andp53 (18). The
constitutive activation of the mTOR cascade plays an equally
important role in renal tumorigenesis through the loss of p53
expression or mutation of genes such as PI3K and PTEN. Therefore,
TKI therapies directed against one or more of these factors will always
be a therapeutic weapon of fundamental importance, as these are
precisely targeted against the genetic mechanisms based on
tumorigenesis and proliferation of renal cancer cells (Figure 1).
In addition to proper genetic damage, we must consider the
variations induced by the environment (epigenetics), alterations
in receptor expression, and all the complexity that revolves
around the tumor microenvironment.
Systemic inflammation is frequently observed in advanced
RCC (19). Nevertheless, the functional correlation between
inflammation and RCC metastasis remains unclear. Recent
data have demonstrated that cancer cells can secrete cytokines
and chemokines through a process known as cancer-cell-
intrinsic inflammation, altering the immune landscape (20–22).
Cancer-cell-intrinsic inflammation contributes to cancer
metastasis and the initial progression of cancers. The driver
gene mutations responsible for the inflammation in different
tumors are TP53 and KRAS mutations (23–26). These mutations
lead to increased cytokine release, which recruits myeloid cells in
the primary tumor microenvironment or (pre-) metastatic sites.
It has been demonstrated that epigenetic remodeling
determines the massive expression of inflammation-related
genes in RCC. Synchronous inhibition of the bromodomain
and extra-terminal motif suppressed C-X-C-type chemokines
in clear cell RCC cells and decreased neutrophil-dependent lung
metastasis, suggesting a potential therapeutic strategy (27).
The cells of the immune system (T cells, B cells, and natural
killer cells), which represent the targets of known ICIs, such as
anti-CTLA4, anti-PD-1, or anti-PD-L1, are found within the
tumor microenvironment. In addition to playing a key role in the
carcinogenesis process, some parameters such as the expression
of PD-L1 have been associated with a worse prognosis (28)as
well as a higher degree of tumor aggressiveness (29). Thus, the
use of ICIs that block PD-1/PD-L1 binding or amplify the overall
immune response findsinthisbiologicalrationaleitshigh
activity in patients with mRCC (Figure 1).
It remains evident that the intratumoral heterogeneity
problem is responsible for the difficulty in identifying a single
driver mutation and for overcoming mechanisms of clonal
selection during targeted treatment (30). To make things
FIGURE 1 | Representation of the main pathways involved in the mechanisms of tumorigenesis and proliferation of renal cancer cells and their targeted agents.
PD1, programmed cell death-1 receptor; PD-L1, programmed death-ligand 1; CTLA4, cytotoxic T-lymphocyte-associated protein 4; CD80, cluster of differentiation
80; CD86, cluster of differentiation 86; MHC, major histocompatibility complex; PI3K, phosphatidylinositol-3-kinase; AKT, serine/threonine kinase 1; mTOR,
mechanistic target of rapamycin; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; cMET, mesenchymal
epithelial transition factor; AXL, AXL receptor tyrosine kinase; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; VEGFR,
vascular endothelial growth factor receptor.
Roberto et al. Metastatic Renal Cell Carcinoma Management
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576393

worse, a microenvironment response exists: tumors treated with
anti-angiogenic agents present an inflammatory infiltrate consisting
mainly of regulatory T cells (CD4
+
FOXP3
+
) and express high levels
of PD-L1, thus demonstrating the conditions associated with a worse
prognosis (31). These findings suggest that the immunosuppressive
phenotype found in metastatic sites, for example, is the result of close
communication between the occurrence of anti-angiogenic
treatment-resistant subclones and the enrichment of inflammatory
infiltration with Treg cells to evade the anti-tumor immune response.
Given the above-mentioned data, the rationale for combining TKIs
with ICIs has become increasingly clear.
THE LATEST APPROVED THERAPEUTIC
STRATEGIES IN MRCC
Cabozantinib
Cabozantinib is a multi-targeting TKI directed against the
receptors of factors involved in tumor growth, angiogenesis,
pathological bone remodeling, chemoresistance, and metastatic
progression of cancer, such as VEGF, MET, GAS6(AXL), RET,
ROS1, TYRO3, MER, KIT (stem cell factor), TRKB, Fms-like
tyrosine kinase-3 (FLT3), and TIE-2 (32). Based on its broad
mechanism of action, it is believed to overcome resistance to
anti-VEGF agents, such as sunitinib and pazopanib; thus, it was
first tested as a second-line therapy in patients previously treated
with anti-VEGF therapy (5)andsubsequentlyasfirst-line
therapy in patients with intermediate–poor-risk prognosis (6).
In the phase III METEOR trial, 658 patients with mRCC, who
had previously been treated with at least one VEGF tyrosine
kinase receptor inhibitor (VEGFR-TKI), were randomized 1:1 to
receive cabozantinib (n = 330) or everolimus (n = 328), including
those who may have previously been treated with other therapies,
including cytokines and antibodies directed against VEGF, the
PD-1 receptor, or other ligands. Additionally, patients with
treated brain metastases were included. The primary endpoint
of the study was progression-free survival (PFS). Secondary
endpoints were objective response rate (ORR) and overall
survival (OS). Most patients were males (75%), with a median
age of 62 years. Seventy-one percent of patients had previously
been treated with only one VEGFR-TKI. In 41% of patients,
sunitinib was the single VEGFR-TKI previously received.
According to the MSCKK criteria for the prognostic risk
category, in 46% of patients, the prognosis was favorable; in
42%, it was intermediate (one risk factor); and in 13%, it was
poor (two or three risk factors). In 54% of patients, three or more
organs, including the lungs (63%), lymph nodes (62%), liver
(29%), and bones (22%), had metastatic disease. The median
duration of treatment was 7.6 months (range 0.3–20.5) for
patients who received cabozantinib and 4.4 months (range 0.2–
18.9) for patients who received everolimus. A statistically
significant improvement has been demonstrated in PFS for
cabozantinib compared to everolimus (7.4 months compared
to 3.9 months, hazard ratio [HR] = 0.51 [0.41–0.62], p = 0.0001).
In a subsequent interim analysis, a statistically significant
improvement was also demonstrated in terms of OS [320
events, median value of 21.4 months compared to 16.5
months; HR = 0.66 (0.53, 0.83), p = 0.0003]. Comparable OS
results were observed with a follow-up analysis (descriptive) at
430 events. Exploratory analyses of PFS and OS in the intent-to-
treat population also showed consistent results in favor of
cabozantinib compared to everolimus in different subgroups
defined by age (<65 years compared to ≥65 years), sex, risk
group, ECOG status (0 compared to 1), time from diagnosis to
randomisation (<1 year compared to ≥1 year), tumor expression
of MET (high compared to low compared to unknown), bone
metastasis, visceral metastasis, number of VEGFR-TKIs
previously received (one vs two), and duration of first
treatment with VEGFR-TKI (≤6 months vs >6 months). Dose
reductions were more frequent with cabozantinib than with
everolimus, but no statistically significant difference in terms of
discontinuation of severe adverse events was reported (5,33).
The safety and efficacy of the first-line cabozantinib were
evaluated in the CABOSUN study, a randomized, open-label,
controlled vs sunitinib phase II study, which enrolled 157 mRCC
patients, classified as intermediate or poor risk according to
IMDC criteria. The patients (n = 157) were randomized 1:1 to
receive cabozantinib (n = 79) or sunitinib with a schedule of 4
weeks on/2 weeks off (n = 78). The patients were stratified
according to the IMDC risk category (81% intermediate and
19% poor) and the presence or absence of bone metastases.
Approximately 75% of patients underwent nephrectomy before
the start of treatment. The primary endpoint was the PFS, and
the secondary endpoints were ORR and OS. Most patients were
males (78%) with a median age of 62 years. Most patients (87%)
had an ECOG performance status of 0 or 1; 13% had an ECOG
performance status of 2. Thirty-six percent of the patients had
bone metastases. The study has reached the primary endpoint of
statistically significant improvement of the PFS for cabozantinib
compared to sunitinib [8.6 months regarding 5.3 months; HR =
0.48 (0.32–0.73), p = 0.0005]. Patients showed a favorable effect
with cabozantinib compared to sunitinib irrespective of MET
status (positive or negative); however, cabozantinib demonstrated
greater activity in patients with positive MET status than that in
patients with negative MET status [HR = 0.32 (0.16 and 0.63) vs
0.67 (0.37 and 1.23)]. In addition, compared to the treatment with
sunitinib, treatment with cabozantinib has been associated with a
trend of longer OS (30.3 months compared to 21.0 months; HR
0.74 [0.47–1.14]) (6).
In the two aforementioned studies, the most frequently
reported serious adverse events with cabozantinib were
hypocalcemia, hypokalemia, thrombocytopenia, hypertension,
palm-plantar erythrodysesthesia syndrome, proteinuria, and
gastrointestinal events (abdominal pain, inflammation of the
mucous membranes, constipation, diarrhea, and vomiting) and
were generally found during the first 8 weeks of treatment. In the
METEOR study, dosing reductions and dosing interruptions of
59.8 and 70%, respectively, occurred in relation to an adverse
event caused by cabozantinib. In CABOSUN, where patients
were naïve to treatment, the percentages of reduction and
Roberto et al. Metastatic Renal Cell Carcinoma Management
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576394

treatment interruption were quite similar (46 and 73% of
patients, respectively). Therefore, it does not seem to be a
condition of drug toxicity. However, hypertension has been
observed more frequently in the population of naïve patients
(67%) than in patients included in the METEOR trial who had
been previously treated with anti-VEGF targets (37%).
Nivolumab: Monotherapy and ICI
Combination Therapy
Nivolumab was the first anti-PD-1 ICI approved for the
treatment of mRCC, first as monotherapy in patients
previously exposed to a VEGFR-TKI and then in combination
with ipilimumab as the first-line treatment in patients with
intermediate- and poor-risk prognosis. According to data from
the Phase III Checkmate 025, patients who progressed during or
after 1–2 previous anti-angiogenic regimens were eligible for
treatment with nivolumab monotherapy (34). This study
included patients regardless of tumor PD-L1 status and with a
70% Karnofsky performance status (KPS). Patients with a history
of brain metastasis or concomitant brain metastasis, previously
treated with an mTOR inhibitor, affected with an autoimmune
disease in the active phase, or with medical conditions requiring
systemic immunosuppression were excluded from the study. A
total of 821 patients were randomized to receive nivolumab (n =
410) or everolimus (n = 411). The study reached the primary
endpoint of efficacy (median OS equal to 25 months with
nivolumab compared to 19.6 months with everolimus, HR =
0.73 [0.7–0.93], p = 0.0018). Secondary endpoints included ORR
and PFS, as evaluated by the investigator. In this study,
nivolumab was shown to be better than everolimus in pre-
treated patients in terms of ORR (25 vs 5%, p < 0.001, HR for
OS = 0.73; 95% confidence interval (CI) = 0.57–0.93). However,
no significant advantages in terms of PFS have been reported.
Nivolumab in combination with ipilimumab proved to be
superior to sunitinib as the first-line therapy in the Phase III
study Checkmate 214 (8). The study included patients with
mRCC, with clear cell components that were not previously
treated. The primary efficacy population included patients at
intermediate/poor-risk according to the IMDC criteria. A total of
1,096 patients were enrolled, of which 847 at intermediate/poor-
risk were randomized to nivolumab in combination with
ipilimumab (n = 425) for four cycles followed by nivolumab
monotherapy or sunitinib (n = 422). The primary endpoints
were the OS, ORR, and PFS. Patients with mRCC with
intermediate/poor prognosis according to IMDC reported a
statistically significant benefit in terms of both OS and ORR
(HR for OS = 0.63, 95% CI = 0.44–0.89; ORR 42 vs 27%, p <
0.001), regardless of the expression level of PD-L1, although in
the PD-L1 >1% group, the advantage was even more significant
(HR = 0.52; 95% CI = 0.34–0.78). The PFS was not significantly
different between the two groups (HR = 0.82; 95% CI = 0.64–
1.05). In addition, in the 249 patients at favorable risk,
nivolumab plus ipilimumab was detrimental in terms of OS
compared to sunitinib (HR = 1.13 [0.64–1.99] p = 0.6710). In
terms of tolerability, the combination of ipilimumab and
nivolumab was burdened with a higher toxicity than sunitinib
(22 vs 12% of patients, respectively, discontinued treatment for
toxicity) (8) and compared to IO with a single agent, resulting in
a more severe immune-related toxicity percentage (35).
However, a more recent report on the Checkmate 214 study
demonstrated that patient-reported outcomes were more
favorable with nivolumab plus ipilimumab than sunitinib in
patients at intermediate or poor risk, leading to fewer symptoms
and better health-related quality of life (36). Moreover, to better
characterize the association between outcomes and IMDC risk in
CheckMate 214, a post-hoc analysis (n = 1051) of efficacy by the
number of IMDC risk factors was completed. ORR with
nivolumab plus ipilimumab was consistent across zero to six
IMDC risk factors, whereas with sunitinib, it decreased with an
increasing number of risk factors. The benefits of nivolumab plus
ipilimumab over sunitinib in terms of ORR (40–44% vs 16–38%),
OS (HR = 0.50–0.72), and PFS (HR = 0.44–0.86) were
consistently observed in subgroups with one, two, three, or
four to six IMDC risk factors. These results demonstrate the
benefitoffirst-line nivolumab plus ipilimumab over sunitinib
across all intermediate- and poor-risk groups, regardless of the
number of IMDC risk factors (37).
Thanks to the data reported, the combination of nivolumab
and ipilimumab was approved by ESMO guidelines in
intermediate- and poor-risk prognostic subgroups of mRCC.
Moreover, a post-hoc analysis of nivolumab plus ipilimumab
or sunitinib in IMDC intermediate/poor-risk patients with
previously untreated mRCC with sarcomatoid features showed
an ORR of 56.7% (CI = 43.2–69.4, p < 0.001) in the combination
arm against 19.2% (9.6–32.5) of standard treatment and a rate of
complete response (CR) of 18.3% in the experimental group,
whereas no CR was observed in the sunitinib arm (38).
Elderly patients with pre-treated mRCC may benefit from
therapy with nivolumab or nivolumab plus ipilimumab as a first-
line option (7,39), and salvage-line cabozantinib may offer the
best survival outcomes, although evidence suggests that the
majority of first-line treatments have worse efficacy in older
patients than in younger patients (40,41).
Despite the undeniable benefits of ICIs in the treatment of
mRCC, some aspects must be considered: i) only a subset of
patients achieves objective responses, ii) some patients have a
delayed response, and iii) a significant number of patients do not
benefit even clinically. In detail, although the so-called ‘combo’IO is
particularly active as the upfront treatment in patients with
intermediate/poor prognosis, it cannot be a universal choice for
all patients, but only for those patients ‘fit’for a more intensive
combined treatment. Moreover, the ipilimumab–nivolumab
combination was less effective than sunitinib in patients over 75
years of age, who represent most of those we met in clinical practice.
Therefore, IO is an important strategy both as first- and second-line
treatment in patients with mRCC, but TKI agents remain the
central focus of mRCC treatment in all therapeutic lines. Several
hypotheses have been formulated regarding the lack of efficacy of
ICIs in all patients, and among these, tumor heterogeneity and the
dynamism of the tumor microenvironment typical of renal cancer
cells seem to be the main conditions (29,42).
Roberto et al. Metastatic Renal Cell Carcinoma Management
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576395

The Combination of VEGF-Targeting
Agents With ICIs
The upfront combination of VEGF-targeting agents with ICIs is
emerging as a therapeutic alternative that could overcome the
limitations of IO alone as well as target both the cascade of
angiogenesis and the tumor microenvironment (Figure 1). Anti-
VEGFR inhibitors, in addition to their intrinsic anti-angiogenic
effect, showed immunomodulatory effects: unlocking the
inhibitory brake of VEGF, promoting infiltration and
activation of effector cells, and inhibiting immunosuppressive
cells (43). Although the initial studies of sunitinib or pazopanib
associated with nivolumab had negative results for the high rates
of liver and gastrointestinal toxicity (44), new combinations are
proving to be active and well tolerated (45–47).
In the IMmotion151 study, the anti-PD-L1 atezolizumab
combined with the anti-VEGF bevacizumab performed better
than sunitinib monotherapy in patients with PD-L1-positive
tumors (HR = 0.74 [95% CI = 0.57–0.96]; p = 0.02]; however,
in the intention-to-treat (ITT) population, the median OS was
33.6 months in the combination arm vs 34.9 months in the
sunitinib arm, and the results (HR = 0.93) had not yet crossed the
significance boundary (45). A pre-specified subgroup analysis of
IMmotion151 demonstrated a significant benefit in terms of PFS
in patients with mRCC with sarcomatoid features in the
bevacizumab plus atezolizumab treatment arm when compared
with the sunitinib treatment arm (48).
Other promising combinations always used as first-line
treatment are axitinib plus avelumab and axitinib plus
pembrolizumab, tested in the Javelin Renal 101 (46) and the
Keynote-426 (47) trials, respectively.
The Javelin Renal 101 randomized 442 and 444 patients to
the avelumab plus axitinib and sunitinib arms, respectively, and
showed that the combination treatment was higher than
sunitinib monotherapy in terms of PFS and ORR, regardless
of the PD-L1 status and prognostic risk category (46). The last
update of the study confirmed previous results; in particular, in
the overall population, the median PFS was 13.3 (95% CI =
11.1e15.3) vs 8.0 months (95% CI = 6.7e9.8), HR = 0.69 [95%
CI = 0.574–0.825]; p < 0.0001); moreover, the combination
prolonged PFS2 compared with sunitinib. However, OS data
(primary endpoint of both studies) are still immature (49).
The Keynote 426 study is a phase 3 trial that randomly
assigned 861 patients with previously untreated advanced RCC
to receive pembrolizumab plus axitinib or sunitinib. The primary
endpoints were the OS and PFS in the ITT population. The key
secondary endpoint was ORR. After a median follow-up of 12.8
months, this study observed a significant benefit in terms of PFS
(15.1 vs 11.1%, HR = 0.69; 95% CI = 0.57–0.84; p = 0.001) and
ORR (59.3 vs 35.7%, p = 0.001) in favor of the combined
treatment arm, disregarding the status of PD-L1 and the
prognostic risk category (47).
The results of the extended follow-up of the randomized
phase III study KEYNOTE-426 (median follow-up 30.6
months) confirmed the benefit for the experimental arm,
which was proven statistically significant in terms of median
OS [not reached with pembrolizumab and axitinib vs 35.7
months (95% CI = 33.3–not reached) with sunitinib; HR =
0.68 (95% CI = 0.55–0.85), p = 0.0003], median PFS [15.4
months with pembrolizumab and axitinib (12.7–18.9) vs 11.1
months for sunitinib (95% CI = 9.1–12.5); HR = 0.71 (95% CI =
0.60–0.84), p = 0.0001], and ORR (60% in the combo arm vs 40%
in the sunitinib group). Although the trial was not designed to
observe differences between risk categories, it should be noted
that the benefit in terms of OS was particularly evident in the
population at intermediate and unfavorable risk
[pembrolizumab plus axitinib vs sunitinib: HR = 0.63 (95%
CI = 0.50–0.81)], while it was not significant in the favorable
risk group [HR = 1.06; (95% CI = 0.60–1.86)]. Moreover, in
terms of toxicity, no significant news emerged with the continued
follow-up of patients in the study. The most frequent treatment-
related grade 3 or higher adverse events (10% of patients in both
groups) were hypertension [95 (22%) of 429 patients in the
pembrolizumab group plus axitinib vs 84 (20%) of 425 patients
in the sunitinib group], increased alanine aminotransferase levels
[54 (13%) vs 11 (3%)], and diarrhea [46 (11%) vs 23 (5%)] (50).
The fact that the advantage in OS for the combination,
already known from the first analysis, is maintained over time,
although half of the patients randomized to only sunitinib had
then received progression IO (vs. 8% in the experimental arm),
suggests the synergistic activity of the combination of
pembrolizumab plus axitinib, which may therefore not be
reproducible by their use in sequence. With regard to drug
synergy, the role of a single agent in the overall result may also
be different: while axitinib is more responsible for shrinkage,
pembrolizumab could then be more decisive in maintaining the
volumetric reduction effect over time (51).
Furthermore, although all the front-line combination trials
enrolled patients with clear cell RCC, exploratory post-hoc
analyses from these studies demonstrated that patients with
sarcomatoid differentiation, which has historically been
associated with worse prognosis, derive marked benefits from
ICI-based therapy. Based on these data, the Food and Drug
Administration (FDA) and EMA in 2019 approved the axitinib–
pembrolizumab combination as the first-line treatment for
patients with clear cell mRCC in the all-risk category.
CheckMate-9ER is a randomized controlled trial comparing
the combination of nivolumab and cabozantinib vs sunitinib as a
first-line treatment for mRCC with a clear cell component and
any IMDC risk group. In the first analysis of the study, the
superiority of the combination arm over standard treatment was
shown to meet all three efficacy endpoints, with a 40% reduced
risk of death [HR = 0.60 (98.89% CI = 0.40–0.89); p = 0.0010;
median OS not reached in both arms]. In patients treated with
the combination cabozantinib and nivolumab, the median PFS,
the primary endpoint of the study, is doubled compared to
patients who received only sunitinib: 16.6 months compared to
8.3 months [HR = 0.51 (95% CI = 0.41–0.64), p = 0.0001]. In
addition, cabozantinib in combination with nivolumab showed a
higher ORR (56 vs 27%) and 8% of patients compared to 5% who
achieved a complete response. Moreover, the combination
treatment was associated with a longer response duration
compared to sunitinib, with a median duration of 20.2 months
Roberto et al. Metastatic Renal Cell Carcinoma Management
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576396

compared to 11.5 months. In addition, patients treated with the
combination showed a lower rate of discontinuation of treatment
than those treated with sunitinib (44.4 vs 71.3%) and a
significantly lower rate of discontinuation for disease
progression than sunitinib (27.8 vs 48.1%). All these key
efficacy results are consistent in pre-specified subgroups and all
risk categories according to the IMDC and PD-L1 expression
(52,53). Based on this study, the ESMO guidelines proposed the
combination of nivolumab and cabozantinib as a valid first-line
therapy in all prognostic subgroups (52).
Unlike the KEYNOTE 426 trial, no significant results were
obtained in terms of OS when the experimental arm was compared
with the standard treatment in the other phase III studies. In fact, in
the Javelin Renal 101 study, OS data were immature in the 2019
publication, while in the IMmotion-151 trial, OS was not met.
Among the new drug combinations tested in mRCC, there is
also the one examined in the phase Ib/II TiNivo study, which
evaluated the efficacy and safety of combination therapy with
nivolumab plus tivozanib, a highly potent and selective VEGFR-
TKI approved by the European Medicines Agency (EMA) for
first-line treatment of patients with mRCC (54), and showed a
generally tolerable profile and promising anti-tumor efficacy (55).
HOW THERAPEUTIC ALGORITHM HAS
CHANGED IN MRCC TREATMENT WITH
THE APPROVAL OF COMBO?
For a decade, it has been wondered what the best sequence
treatment between TKI–mTORi–TKI vs TKI–TKI–mTORi is.
However, the next future question will be much more complex
since there are no comparative studies, clear prognostic factors,
or predictive markers, thus making a weighted choice between
the various options available in the first- and second-line
very difficult.
The new treatment strategies range from molecular targeted
agents such as cabozantinib, able to overcome some anti-
angiogenic mechanisms of resistance, through ICIs, such as
nivolumab, as a single agent, up to the combinations of ICIs
(nivolumab + ipilimumab), or between ICIs with VEGF-
targeting agents (atezolizumab + bevacizumab, pembrolizumab +
axitinib, avelumab + axitinib, cabozantinib + nivolumab, and
others under investigation).
The paradigm of first-line treatment in advanced RCC, firmly
occupied for more than 10 years by monotherapy with anti-
angiogenic TKIs, such as sunitinib or pazopanib, has changed,
and combinations of ICIs, either with each other or with TKIs,
have shown efficacy compared to monotherapy with TKIs. In
light of the results of recent combinations, except for
comorbidity and clinical contraindications, in the first-line, the
therapeutic proposal is to administer all prognostic classes the
combination TKI/IO (axitinib plus pembrolizumab/nivolumab
plus cabozantinib) or IO/IO (nivolumab plus ipilimumab), and
considering the combination IO/IO for patients with
sarcomatoid components, whereas all other cases remain valid
for TKI monotherapy, in particular, cabozantinib in the
intermediate- and high-risk subgroups unfitforcombo
treatment, and pazopanib or sunitinib in the good risk unfit
for combo (56).
Whether the objective is to achieve a complete response (CR)
as well as a long survival (or possible cure), ipilimumab plus
nivolumab or nivolumab plus cabozantinib would be the
treatment of choice. In fact, the CR rates in CheckMate 214,
CheckMate9ER, Keynote426, and Javeline Renal 101 were 9, 8,
5.8, and 3.8%, respectively. In contrast, we should also consider
that a higher rate of progressive disease (PD) was observed as the
best response to treatment in the CheckMate 214 trial, while the
lowest was observed in CheckMate9ER. The toxicity profile is a
further discriminant in the choice of combination treatment. In
fact, for the IO–IO combination, the major toxicities are limited
to the induction phase with ipilimumab, while for the combination
of an ICI and a VEGFR-TKI, safety issues tend to persist over time
due to the prolonged administration of both agents.
As the field stands now, the immuno-target combination
could represent a particularly valid opportunity, especially in
patients with a ‘cold’phenotype, whose tumor is characterized by
poor immune infiltration and are considered less likely to
respond to ICI-based treatment alone.
Given the lack of head-to-head comparative studies, both
experience and common sense must guide the choice of a
physician according to the following considerations: i) patient
characteristics, comorbidities, drug interactions with concurrent
therapy, occupation, preferences of patient, and side effects that
can affect the quality of life; ii) neoplasia features, its histology, if
it has a representative sarcomatoid components, the genetic
structure, the burden of cancer disease, and the location of the
metastases and their related symptoms; iii) balancing the risk and
benefit of treatment itself: for safety, we should consider that the
trade-off between efficacy and safety that a first-line patient is
willing to accept is usually unbalanced in favor of efficacy; iv)
biological aggressiveness of the tumor: in the case of an
aggressive disease, the combo IO/TKI seems a very reasonable
choice to control disease growth while waiting for the tail effect of
IO; otherwise, one could head for the long-term benefit of the
IO/IO combo, as well as for complete response, trying to spare
the additional toxicity derived from the continuous use of the
VEGFR-TKI.
Moreover, a recent meta-analysis network on the choice of
the first-line showed that cabozantinib is the best molecular
targeted agent for the advantage in terms of PFS in patients at
intermediate/poor risk compared to sunitinib, with a 91% chance
of giving the best benefit in PFS (57). Therefore, the choice will
be conditioned by our primary endpoints, even if they do not
always coincide with those of large clinical trials.
Taking into account that the IMDC prognostic model was
developed at the time of a first-line anti-VEGF-based therapy
(58) and that neither validated prognostic models in first-line
with ICIs or with the immuno-target combo nor data on the
second-lines are available, the therapeutic algorithm of mRCC
could be revised in the following way (Figure 2): i) for the first-
line, to assess whether the patient is considered ‘fit’for a
Roberto et al. Metastatic Renal Cell Carcinoma Management
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576397

combination strategy; ii) for subsequent lines, taking into
account what has been done previously (in immuno-naive
patients, the choice could fall on nivolumab or another TKI
such as cabozantinib, while in TKI-naive patients, the choice
could fall on an anti-VEGF TKI such as sunitinib, pazopanib, or
cabozantinib). Nevertheless, data on pazopanib or cabozantinib
as second-line treatment after ICI-based treatment are not
available. However, cabozantinib demonstrated impressive PFS
and OS when administered post-IO in patients with mRCC,
according to findings from the METEOR sub-analysis
33
and
recent retrospective real-world studies (59,60). After disease
progression to first-line TKI-based monotherapy, the factors that
could guide the choice towards a second-line of treatment in
favor of another TKI are low or intermediate risk, long duration
of first-line treatment with VEGFR-TKI, good tolerability to
previous treatment lines, low tumor burden, slow progression,
revascularization of pre-existing lesions, and high probability of
receiving further treatment lines. In favor of IO-based second-
line treatment, we have considered the following factors: high
risk, short duration of first-line treatment with VEGFR-TKI,
poor tolerability to TKI, dose reductions and interruptions, high
tumor burden, rapid progression, progression not guided by
angiogenesis, and low probability of receiving further therapy.
Currently, there are no data comparing the available strategies
that combine two IO agents or TKI plus IO, but increasing
evidence suggests that some biomarkers and genetic features
could guide optimal treatment options for patients.
WHAT TO EXPECT FROM
DIAGNOSTIC IMAGING?
The complex therapeutic scenario described above makes
imaging evaluation extremely challenging, both at the time of
diagnosis and in assessing the response to treatment. At the time
of diagnosis, owing to high intratumoral heterogeneity and
heterogeneity between the gene expression profiles of primary
cancer and its metastases, tumor genomic characterization is
necessary. Considering the technical difficulties and morbidity in
performing multiple renal biopsies (61), a solution may be
represented by radiogenomics. Radiogenomics, a result of
advances in both computational hardware and machine-
learning algorithms, is an emerging field in which quantitative
information is extracted from radiological images (radiomics)
and is correlated with tumor genomic profiling (62). Although
FIGURE 2 | Proposed therapeutic algorithm for the treatment of mRCC in and beyond the first-line setting. The choice of treatment is based on (1) i) patient
characteristics: comorbidities, potential drug interactions with the concomitant therapy, occupation, patient preferences and the side effects that can affect the quality
of life; ii) and tumor characteristics: histology, if it has a representative sarcomatoid component, the genetic structure, the tumor burden, site of metastases, and
related symptoms. (2) MSKCC/IMDC prognostic classification; *if not previously carried out, **if the patient does not have autoimmune disease in the active phase,
solid organ transplant, or interstitial pneumopathy or if the patient requires high doses of corticosteroids. TKI, tyrosine kinase inhibitor Pazopanib and cabozantinib
are still not indicated as second-line treatment after immunotherapy; however, real-world analysis of patients treated with cabozantinib after anti-PD-1 treatment
reported promising results.
Roberto et al. Metastatic Renal Cell Carcinoma Management
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576398

studies are still preliminary (63,64), it is expected that
quantitative imaging data might become a useful biomarker for
assessing tumor prognosis, treatment selection, and prediction of
treatment response.
With the advent of anti-VEGF and TKIs and then ICIs, the
evaluation of response to therapy made it necessary to introduce
new objective response criteria [i.e. modified Choi (65), SACT
(66), iRECIST (67)], since conventional RECIST (66) is not
adequate for categorizing patient response. However, there are
still open issues regarding the assessment of pseudo-progression
and dissociated response (68,69), both of which are strongly
associated with the clinical benefitofICIsandhyper-
progression. Further challenges will await radiology with the
advent of combined treatments. The solution will probably be
found in the integrated analysis of imaging data (from different
sources, including CT, MRI, and PET, combining morphological
and functional studies, targeting tumor perfusion and
cellularity), tumor mutational burden, and biological markers.
Once collected, this large amount of data will be processed by
high-speed processors driven by artificial intelligence.
POSSIBLE FUTURE PREDICTIVE AND
PROGNOSTIC BIOMARKERS
PD-L1 Expression
Several studies have demonstrated the negative prognostic role of
the expression of PD-L1 in the setting of mRCC (70–72). The
expression of PD-L1 on tumor cells was associated with a higher
tumor stage and a worse response to TKI therapy in two post-hoc
analyses of the COMPARZ study and the METEOR and
CABOSUN trials (28,72–74). In addition, a meta-analysis
including more than 1,300 patients showed that higher PD-L1
expression correlated with an approximately doubling risk of
death (75). In contrast, the predictive role of PD-L1 in response
to IO is still controversial, and the results obtained in the
exploratory analyses of clinical trials investigating ICIs are
inconclusive (7,8,45–47). In the CheckMate 025 trial, PD-L1
expression was associated with poor survival independent of the
treatment received, but not with response to nivolumab (7). The
CheckMate 214 trial showed a higher PFS in the ipilimumab plus
nivolumab arm than in the sunitinib arm for IMDC intermediate–
poor-risk patients, with PD-L1 expression in 1% or greater of cells
(median PFS 22.8 vs 5.9 months), but this advantage was not
observed when PD-L1 was less than 1% (median PFS, 11 vs 10.4
months). Conversely, a better ORR and OS for IO over an anti-
vascular agent was reported regardless of tumor PD-L1 expression
level (8). In the IMmotion 151 trial, the magnitude of benefit
derived from the combination therapy with atezolizumab plus
bevacizumab increased in patients with PD-L1 expression by more
than 1% of tumor-infiltrating lymphocytes compared with the ITT
population (45). In the JAVELIN Renal 101 and KEYNOTE-426
trials, the combination therapy showed a benefit over sunitinib
irrespective of PD-L1 expression (49,50).
The above-mentioned results suggest that the expression of
PD-L1 in mRCC cannot completely predict the responsiveness of
tumors to ICIs. Its role remains controversial and warrants
further investigation. Moreover, the assessment method and
tumor heterogeneity are the major limitations of the evaluation
of PD-L1 (76). The technique used for the IHC analysis has an
elevated variability among the different methods available, and
the scoring systems are not concordant for the target cells
evaluated, whether tumor cells, immune cells infiltrating the
neoplastic stroma, or a combination of both; additionally, there is
no validated positivity cut-off (77,78). Furthermore, PD-1 and
PD-L2 evaluation should be considered, and their role should be
clarified (79). Finally, the expression of PD-L1 is dynamic,
changing depending on the history of the disease and the
treatments received. In addition, intratumoral variability and a
different expression in the primitive tumor and metastases,
which would explain the high response rates obtained despite
the negativity of PD-L1 in the primitive lesion, should be
considered when the expression of this biomarker is
examined (80).
Tumor Mutational Burden
TMB is defined as the total number of mutations per coding area
of the tumor genome, measured as mutations per megabase
(mutations/Mb) (81). In tumors with high TMB, there is an
increased production of surface neoantigens that stimulate the
anti-tumor immune system response, which could explain the
potential association between TMB and response to ICIs (82). In
the setting of mRCC, TMB is variable, ranging from a very low
level in chromophobe type to a higher value in clear cell and
papillary tumors and is not concordant with the clinically
defined prognostic groups according to IMDC and MSKCC
(83). Regarding its prognostic role, the data in the literature
are discordant, since some studies observed a correlation
between improved survival and increased TMB, while others
demonstrated a negative prognostic role (84,85). Concerning the
predictive significance of TMB, no association between TMB and
survival, PD-L1 expression on tumor cells, or clinical benefit was
observed (86).
Microenvironment
RCC is characterized by a heterogeneous population of tumor-
infiltrating immune cells; however, conflicting data have been
obtained to date. Infiltration of effector T cells, such as CD8
+
lymphocytes, and M1 macrophages may be associated with a
better prognosis, whereas infiltration of regulatory T cells, such
as Tregs and M2 macrophages, have a poorer outcome (87–90).
In contrast, high intra- and peri-tumoral CD8
+
cell density was
also correlated with poor prognosis (91). It was demonstrated
that PD-L1 expression on tumor cells could lead to higher CD8
+
T cell infiltration, distinguishing two groups of tumors with
CD8
+
infiltrate, and the group with low expression of immune
checkpoints and localization of mature dendritic cells was
associated with a good prognosis (92).
Concerning the predictive role of the microenvironment, a
comprehensive analysis of patients enrolled in four clinical trials
on nivolumab demonstrated a poorer and greater response in
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Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 6576399

correlation to the overexpression of genes involved in metabolic
functions (e.g. UGT1A) and the increased expression of immune
markers (e.g. BACH2 and CCL3), respectively (93). Moreover, an
exploratory analysis of the IMmotion150 trial reported that a T-
effector immune gene in association with the expression of PD-
L1 and the infiltration of T CD8
+
cells correlates with a higher
ORR and prolonged PFS in the atezolizumab arm (45). In
particular, it was observed that VEGF blockade could promote
the infiltration of T cells into the tumor microenvironment, thus
potentiating the mechanism of action of ICIs (94).
Circulating Tumor Markers
Circulating tumor DNA (ctDNA) and circulating tumor cells
(CTCs) are peripherally detectable tumor-derived materials. These
markers could detect primary and metastatic sites non-invasively
and evaluate the response to therapy (95–97). Variable frequencies
of genomic alterations were detected in the front-line and second-
line treatment settings, showing an increased incidence of genomic
alterations, particularly those affecting TP53 and MTOR, after first-
line treatment with VEGFR-TKI therapy (96). These differences
could reflect treatment-selective pressures and the effect offront-line
therapy on ctDNA load, but might also simply depend on the
technical limitations of ctDNA assessment in this disease (98).
Other circulating protein and lipid markers have
demonstrated predictive and prognostic value in advanced
disease. Based on 52 circulating markers, a cohort of 69
patients treated with first-line sorafenib was grouped by either
an angiogenic or an inflammatory signature, with correlations to
PFS (HR = 0.2 vs 2.25; p = 0.0002) (99). Additional markers in
serum have been investigated, such as soluble VEGF, circulating
microRNAs, carbonic anhydrase 9, and inflammatory markers,
such as IL-6 and IL-8, but most of these studies were conducted
in the era of targeted therapies (99–103), and new dedicated
investigations are required to address the dramatic changes in
treatment paradigms brought about by the advent of ICIs.
Genomic and Transcriptomic
Environments
There are three possible treatment strategies in the therapeutic
landscape of mRCC: angiogenic inhibitors at one end, IO at the
other, and combinations of the two classes in the middle. The
challenge, however, is identifying the subset of patients who
could benefit from one therapeutic class alone to avoid the
unnecessary toxicity of combination approaches.
Using RNA-based analyses, four distinct molecular subgroups
associated with different responses and survival were defined:
Cluster 3 had the best prognosis with high angiogenic gene
expression and was associated with a better outcome under anti-
angiogenic therapy (PBRM1 mutation was frequently associated)
(104); Cluster 4, with upregulation of the immune pathway, had a
worse prognosis, with a frequent sarcomatoid differentiation and
expression of PD-L1 (105); and Clusters 1 and2 were intermediate
clusters with a lower expression of angiogenic and immune genes.
These results may have the potential to inform treatment
personalization in patients with mRCC (106).
The phase 2 IMmotion150 trial investigated the efficacy, as
measured by PFS, of atezolizumab with or without bevacizumab
against sunitinib in patients with untreated mRCC and
correlated differential gene expression signatures (angiogenesis,
T-effector, and myeloid) with therapeutic response. Highly
angiogenic tumors, which coincided with tumors exhibiting
PBRM1 mutations, seemed to benefit more from sunitinib, but
not from atezolizumab either alone or in combination with
bevacizumab. The combination treatment improved clinical
benefits compared with sunitinib in T-effector high tumours.
Tumors with T-effector high and lower myeloid inflammation-
associated gene expression benefited from atezolizumab
monotherapy. Instead, in T-effector high tumors, a
concomitant high myeloid inflammation predicted a worse
response to IO alone. Myeloid inflammation is associated with
high expression of IL-6, prostaglandins, and the CXCL8 family of
chemokines, which suppress the anti-tumor immunity. The
improved clinical outcome associated with atezolizumab +
bevacizumab compared with atezolizumab monotherapy in this
subgroup suggests that the addition of bevacizumab to
atezolizumab may overcome innate inflammation-mediated
resistance in these tumors (104).
Based on the analysis of the angiogenic profile in comparison
with the immunological profile of the study IMmotion151, it is
possible to define subgroups of tumors that benefit from different
treatment strategies. Given the new associations, it would be
interesting to evaluate these aspects in other combinations of IO/
TKI and see if, for example, the addition of TKI modifies the
immunogenicity of these tumors.
CONCLUSIONS
Considering the continuously evolving scenario in the treatment
of patients with mRCC, the future goal will be to better
characterize renal neoplasia in all its complexity, from the trunk
to the last of its branches. However, to outline the most
appropriate treatment path for each patient, we cannot deny
that only clinical criteria are very likely to understand the needs
of patients. Given the significant improvement in therapeutic
options, prospective studies are needed that would elucidate:
what will be the most effective therapeutic algorithm and how
patients will be selected to hit more targets; will it be more effective
to use therapeutic agents in sequence or by focusing completely on
the first therapeutic line; will it be more effective to use a
combination strategy from the beginning of mRCC treatment?
Further studies are required to answer these questions.
AUTHOR CONTRIBUTIONS
All authors have read and agreed to the published version of the
manuscript. All authors listed havemadeasubstantial,direct,and
intellectual contribution to the work and approved it for publication.
Roberto et al. Metastatic Renal Cell Carcinoma Management
Frontiers in Oncology | www.frontiersin.org April 2021 | Volume 11 | Article 65763910

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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
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