The Current and Evolving Therapeutic Paradigm in the
Management of Metastatic Renal Cell Carcinoma
Thomas Hutson, MD1, Robert A. Figlin, MD, FACP2
1. Charles A. Sammons Cancer Center, Texas A&M College of Medicine, Dallas, TX.
2. Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Health System, Los Angeles, CA.
ABSTRACT
There has been tremendous progress in the treatment landscape of advanced
or metastatic RCC since the advent of efficacious targeted therapies, immunotherapies
and combinatorial regimens, leading to rapid expansion of therapeutic
armamentarium over the last two decades. New advances have offered considerable
improvement in prognosis, treatment-related toxicities, quality of life, and
survival for patients with mRCC. Despite such advantages, there is an unmet
need for developing novel biomarkers predictive of treatment response, optimizing
treatment selection, and also improving strategies to overcome therapeutic
resistance in heterogenous RCC tumors. Herein, we outline currently available
first- and later-lines treatment strategies, unprecedented changes, and also discuss
challenges in the treatment landscape of RCC.
INTRODUCTION
Renal cell carcinoma (RCC) remains
one of the top ten most
frequently diagnosed neoplasms
with an incidence of over 403,000
new cases and 175,000 deaths globally.1
In the United States alone, about 73,750
new cases of kidney cancer were diagnosed,
accounting for an estimated 14,830
deaths. In patients with RCC, about
30% of patients present with metastatic
disease at the time of initial diagnosis
typically requiring systemic therapy.
Almost 30% of patients who are treated
for localized RCC develop a recurrent
disease during the follow-up and
the 5-year survival rate remains 12% in
patients with mRCC.2 Given that RCC
is chemo-resistant and radiation-resistant,
and only a minority of patients
with metastatic RCC surviving past 5
years, the treatment for the late-stage
recurrent metastatic RCC remains highly
challenging.
The precise treatment selection
for patients with advanced or metastatic
ccRCC has been guided by risk stratification
models during the initial evaluation
of patients. The Memorial Sloan
Kettering Cancer Center (MSKCC) and
the International Metastatic Renal
Cell Carcinoma Database Consortium
(IMDC) are the most used nomograms
and both frameworks have significant
prognostic implications. Initially developed
in the era of cytokine therapy,
the MSKCC nomogram-based risk
stratification has been updated for upfront
decision-making in the current
era of targeted therapies and immunotherapy.
A modified version of the
MSKCC nomogram was developed for
decision-making in patients with previously
treated RCC.3 Per MSKCC guidelines,
patients are categorized into risk
groups based on five criteria: good-risk
(0 risk factors), intermediate-risk (1–2),
or poor-risk (≥ 3). The IMDC or Heng
criteria wer developed in the era of targeted
therapies and it overlaps with the
MSKCC model. IMDC also classifies patients
into three risk groups. Favorable
risk (0 factors) with a median OS of 43.2
months, intermediate risk (1–2 factors)
with a median OS of 22.5 months, and
poor risk (3+ factors) with a median OS
of 7.8 months. Despite the widespread
utility of the IMDC model as a risk stratification
tool for clinical trials involving
VEGFR TKI and combination regimens,
its applicability to IO therapies is rather
limited. Although not widely used, other
clinical practice guidelines have been
issued by the National Comprehensive
Cancer Network (NCCN), the European
Society for Medical Oncology (ESMO),
the European Organization for Research
and Treatment of Cancer (EORTC), and
the European Association of Urology
(EAU).
Figure 1. Advances in Evolving Landscape of First-line Systemic Therapies for Metastatic
Renal Cell Carcinoma
FIRST-LINE THERAPIES
Given the large armamentarium of targeted
therapies available alone or in
combination, survival benefit is prolonged,
and tolerability is enhanced for
patients with metastatic clear cell renal
cell carcinoma over almost two decades.
And yet, physicians currently have to go
through the difficult task of choosing the
most optimal therapeutic regimen for
first-line therapy. In the rapidly evolving
therapeutic landscape of mRCC,
this complexity is clear owing to enormous
treatment options and access to
new drugs arising from the latest clinical
trials that lack real-world evidence.
Especially, patient characteristics and
survival outcomes in randomized trials
may not accurately reflect a real-life clinical
practice scenario. For the preferred
treatment selection, IMDC risk stratification
and PD-L1 biomarker status
may provide some guidance. Treatment
selection depends on several factors
that include the patient’s performance
status, comorbidities, cancer subsets,
and extent of disease burden as well as
non-clinical factors namely, cost-effectiveness,
and institutional availability,
etc. Therefore, standardizing algorithms
for optimized treatment sequencing remains
a challenge. In recent years, the
first-line treatment landscape has transitioned
from recombinant cytokines to
tyrosine kinase inhibitors (TKI), mammalian
target of rapamycin (mTOR) inhibitors,
and most recently, the immune
checkpoint inhibitors (ICI).3 In this
review, we highlight some of the recent
and ongoing trials of ICI, ICI/TKI combinations,
and novel HIF-2α inhibitor
agents that may potentially prolong survival
benefits in patients with advanced
and metastatic RCC.
Table 1. Summary of phase III front-line combination trials in Renal Cell Carcinoma. Abbreviations: ATEZO: ATEZOlizumab; AVEL: AVELumab; AXI: AXItinib; BEV: BEVacizumab; CABO: CABOzantinib; CI: confidence interval; EVERO: EVEROlimus; HR: hazard ratio; IMDC: International Metastatic Renal Cell Carcinoma; int: intermediate; inv: investigator; IPI: IPIlimumab; IRC: independent review committee; ITT: intention to treat; LENV: LENVatinib; mo: month(s); NA: not applicable; NIVO: NIVOlumab; NR: not reached; ORR: objective response rate; OS: overall survival; PD-L1: programmed cell death ligand 1; PFS: progression free survival; Ph: phase; q3wk: every 3 weeks; qd: once daily; r: randomized; Sun: sunitinib; wk: week.
First-line VEGF- Targeted Therapies
Before the advent of targeted therapies,
cytokine-based traditional therapies i.e.
interferon-alpha (IFN-α) or interleukin-
2 had been the mainstay of the RCC
landscape until 2005. These therapies
provided only a modest survival in the
majority of patients but also resulted in
a substantial incidence of high-grade
adverse events.4, 5 With the improved
understanding of implications of von
Hippel–Lindau (VHL) gene mutations
in angiogenic pathways, many VEGFbased
TKIs were developed and eventually
they evolved as defacto choice of
first-line systemic therapy since 2005.6
Currently approved VEGF-targeted
therapies either selectively inhibit VEGF
receptors (eg, sorafenib, sunitinib, pazopanib,
axitinib), or target circulating
VEGF ligands (eg, bevacizumab), and
block tumor angiogenesis. Whereas
agents like everolimus and temsirolimus
agents exert cytotoxic effects by inhibiting
mTORC1, blocking protein synthesis,
and cell-cycle progression.
For more than a decade, sunitinib,
an orally administered multitargeted
TKIs remained as the standardof-
care and as the main comparator arm
to clinical trials in first-line mRCC treatment.
The survival benefit of sunitinib
was evident in the pivotal randomized
phase III trial in which sunitinib treatment
resulted in improved PFS as compared
with interferon in the first-line
setting (11.0 vs. 5.0 months; p < 0.001).7
Although a higher OS in patients treated
with sunitinib was observed compared
with those treated with IFN-α
(26.4 versus 21.8 months, respectively),
it lacked statistical significance.7 Based
on the outcome, sunitinib was approved
multinationally for the first- and second-
line treatment of metastatic renal
cell carcinoma (mRCC).
Here we will discuss results
from important clinical trials involving
VEGF targeting agents such as
sorafenib, pazopanib, bevacizumab, and
tivozanib as first-line therapy. A phase
3, randomized, double-blind, placebo-
controlled study (TARGET) showed
that treatment with sorafenib, a multikinase
inhibitor results in improved
progression-free survival (PFS) versus
placebo in the second-line setting after
cytokine therapy (5.5 vs. 2.8 months;
P(0.01).8
Sorafenib therapy improved
progression-free survival (PFS) in patients
with advanced clear-cell renal-cell
carcinoma in whom previous therapy
has failed. However, sorafenib treatment
is associated with increased toxic
effects; rare serious adverse events such
as hypertension and cardiac ischemia
were more common in patients receiving
sorafenib than in those receiving
placebo.8 In other international, phase 3
study (COMPARZ), pazopanib and sunitinib
therapy had comparable efficacy as
compared with placebo or interferon.
Pazopanib was non-inferior to sunitinib
regarding PFS with similar OS between
two arms. However, in terms of the
patients perspective based on PISCES
trial, more treatment-naive patients
preferred pazopanib over sunitinib due
to quality of life and safety.9 In the randomized
phase III study (VEG105192;
NCT00334282), pazopanib demonstrated
statistically and clinically meaningful
improvement of PFS versus placebo
(9.2 vs. 4.2 months; p<0.0001)
in patients who had progressed after
cytokines. Based on this data, the FDA
approved both pazopanib and bevacizumab
in combination with interferon
in 2009. In a phase III
AVOREN trial of bevacizumab,
a monoclonal
antibody directed
against the VEGF
receptor (VEGFR) plus
interferon-α-2a (IFN
α-2a) showed significant
improvements in PFS
(10.2 vs. 5.4 months, p
= 0.0001) in contrast
to treatment with interferon-
α monotherapy in
mRCC.10 Median OS was
23.3 months with bevacizumab
plus IFN and 21.3
months with IFN plus
placebo. Although bevacizumab-
IFN showed
OS benefit, its use was
limited by the toxicity of
the regimen.10 Overall, this AVOREN
trial confirmed that bevacizumab plus
IFN remains the first-line standard of
care for patients with mRCC.
Similarly, a randomized
controlled TIVO-1 trial has shown
that tivozanib, a potent VEGFR-1,
VEGFR-2, and VEGFR-3 inhibitor
prolongs PFS (12.7 months) as compared
with sorafenib (9.1 months)
in the prespecified subpopulation of
treatment-naive patients.11 Similarly,
cabozantinib is an oral TKI that targets
multiple tyrosine kinases, including
hepatocyte growth factor (cMet),
VEGFRs, and AXL. In CABOSUN trial,
cabozantinib therapy improved PFS
(8.2 vs. 5.6 months) and ORR (46% vs.
18%) and reduced the rate of progression
or death as compared to sunitinib
in treatment-naïve patients with intermediate
and poor IMDC risk group.12
Currently, cabozantinib represents a
suitable targeted first-line agent especially
among patients who are not eligible
to receive immunotherapy.
Front-Line mTOR Inhibitor
Therapy
In parallel to the development of VEGF
inhibitors, mTOR inhibitors were
also evolved in the mRCC landscape.
Temsirolimus, a potent mTOR inhibitor,
was approved for the treatment of
advanced RCC after the multicenter,
phase 3 ARCC trial (NCT00065468).
In this, treatment with temsirolimus
has improved OS compared with interferon
(10.9 vs. 7.3 months; p = .008) in
treatment-naïve and poor risk mRCC
patients. Temsirolimus monotherapy
yielded longer OS (HR for death,
0.73; 95% CI, 0.58 to 0.92; P=0.008)
and PFS (P<0.001) as compared to interferon alone.13 However, the combination
of interferon with temsirolimus
also did not improve PFS or OS and
only a modest improvement regarding
PFS versus interferon (5.5 vs. 3.1
months) was observed.13 Based on this,
temsirolimus was approved by the FDA
for the first-line treatment of advanced
RCC in May 2007. A more pronounced
survival advantage was observed only in
patients with non-clear cell histology.
However, the RECORD-3 trial subsequently
showed everolimus was inferior
to sunitinib across IMDC risk groups.
Given such modest results and also
due to its weekly intravenous injection
limitation, temsirolimus is not a widely
used therapy in front-line for patients
and its utility has been relegated to second
or later lines of therapy with mRCC
who have poor risk prognostic features.
Another mTOR inhibitor everolimus
has been evaluated in ESPN study for
the first-line setting in patients with
metastatic nccRCC. In this, everolimus
failed to yield a survival advantage as
sunitinib had better mPFS than that of
everolimus (6.1 months vs, 4.1 months,
p=0.25).14 Therefore, everolimus is not
recommended in the first-line treatment
for nccRCC.
ICI Based First-Line Therapies
Owing to their robust and clinically relevant
survival benefits, immune checkpoint-
inhibitor (ICI) proteins including
anti-programmed death receptor 1 (PD-
1), anti-programmed death receptor
ligand 1 (PD-L1), and anti-cytotoxic T
lymphocytes antigen-4 (CTLA-4) have
been integrated into the therapeutic
landscape as the first-line as well as
second-line treatment for moderate to
high-risk mRCC.3 For instance, since
the approval of the CTLA-4 antibody ipilimumab
in patients with melanoma in
2011, the footprints of ICIs also expanded
across the RCC landscape following
studies of several PD-1/PD-L1 inhibitors
including nivolumab, pembrolizumab,
atezolizumab, durvalumab, and
avelumab as well as the CTLA-4 inhibitor
ipilimumab. Similarly, nivolumab a
humanized IgG4 anti-PD-1, was the first
ICI in kidney cancer space approved by
FDA in 2015. Such developments revolutionized
the ICI-based immunotherapies
in patients with refractory mRCC.
CheckMate 214 (NCT02231749)
is the first trial in the RCC landscape to
evaluate the CTLA-4 blocker (ipilimumab)
and PD-1 inhibitor (nivolumab)
combination in the IMDC intermediate
or the high-risk population.15 The
results validated the proof of concept
that PD-1 inhibitor plus CTLA-4 blocker
combination can deliver synergistic
benefit as compared to the anti-VEGF
TKI sunitinib in the first-line metastatic
RCC setting. Improved response
rates (42%, 9% CR vs 27%, 1% CR;
p<0.001), PFS (11.6 mo vs 8.4 mo, HR
0.82, p=0.03) and OS (NR vs 26.6 mo;
HR 0.66; 95% CI 0.54–0.80; p <0.0001)
were observed in combination arm as
compared to sunitinib. In particular, the
addition of ipilimumab to nivolumab resulted
in significantly better overall survival
and improved ORR as compared
to sunitinib, secured a place in the firstline
treatment algorithm.15 In phase III,
randomized keynote-426 trial, treatment
with pembrolizumab plus axitinib
resulted in significantly longer OS and
PFS, as well as a higher ORR, than treatment
with sunitinib among patients
with previously untreated advanced renal-
cell carcinoma.16 Pembrolizumab
plus axitinib therapy resulted in better
OS (median not reached) as compared
to therapy with sunitinib (35.7 months;
HR 0.68, p=0.0003) and higher PFS
(median 15.4 months vs 11.1 months,
HR 0.69; p<0.0001). As compared to
sunitinib arm, the combination arm also
had better CR (9% versus 3%) and ORR
(59.3% vs 35.7%, p<0·0001).16 This
study validated the benefit of pembrolizumab
+ axitinib combination therapy.
Similarly, pembrolizumab monotherapy
for treatment naïve patients has
also demonstrated promising efficacy
and acceptable tolerability in patients
with accRCC in the KEYNOTE-427
(NCT02853344) trial.
HIF inhibitor based therapies
Belzutifan, a highly selective hypoxia-
inducible factor inhibitor (HIF-2α),
offers a novel approach, taking a different
path than commonly used, to
treat RCC. Most recently, the open-label
study 004 (NCT03401788) has
evaluated the efficacy of belzutifan in
patients with VHL-associated RCC.17
In patients with VHL-associated RCC
(n=61), belzutifan resulted in an ORR of
49% (95% CI, 36%-62%); all responses
were partial responses. Median DOR
had not yet been reached (range, 2.8+ to
22.3+ months); among responders, 56%
(n=17/30) were still responding after at
least 12 months. Median TTR was eight
months (range, 2.7-19 months). Based
on these data, FDA approved belzutifan
for adult patients with VHL disease
who require therapy for RCC and other
tumors.17 Currently belzutifan was investigated
in phase III trials as part of
combination first-and second-line therapies
for advanced clear cell renal cell
carcinoma and also as monotherapy for
previously treated patients.
Combinatorial Therapies: ICI Plus
TKI
Tumor angiogenesis is largely driven
by VEGF-mediated mechanisms in
kidney cancers. Apart from exerting a
proangiogenic effect, VEGFs also mediate
immunosuppression in the tumor
microenvironment. Interestingly, by
promoting the accumulation of myeloid-
derived suppressor cells and regulatory
T cells and also by impeding the
migration of T lymphocytes towards the
tumor microenvironment, VEGFs potentially
drive angiogenesis. Disruption
of VEFG has been shown to facilitate
promote cytotoxic T-cell infiltration into
the tumor microenvironment and also
decrease the activity of T-regulatory
cells and myeloid-derived suppressor
cells, thereby enhancing responsiveness
to immunotherapy.18 Such synergistic
effectiveness of ICI agents in combination
with either multi-kinase inhibitors
or other monoclonal antibodies (CTLA4
and PD-1) have gained momentum and
have been rapidly integrated into the
first line treatment landscape.
There are several ongoing clinical
studies based on doublet and triplet
regimens for treatment-naïve metastatic
or advanced ccRCC. In a phase
II, randomized study (IMmotion150)
by McDermott et al. investigated the
combination of atezolizumab, an anti-
PD-L1 antibody, with bevacizumab,
an anti-VEGF agent as compared to
sunitinib monotherapy in mRCC19. In
ITT patient population, improved median
PFS was noted with atezolizumab
plus bevacizumab combination group
(11.7 vs. 8.4 months).19 Besides, in PDL1
positive patients, the combination
arm had a PFS of 14.7 months versus
7.8 months with sunitinib. The ORR in
PD-L1+ patients was 43% in the combination
arm as compared to 35% in the
sunitinib arm. The CR rate in the PDL1+
patients was 9% in the combination
arm as compared to 4% in the sunitinib
arm.19 In a phase III IMmotion 151 trial
(NCT02420821), similar survival benefits
were obtained. Similarly, CheckMate
016, a phase I, open-label, parallel-cohort,
dose-escalation study investigated
the efficacy and safety of nivolumab
plus ipilimumab in combination, and
nivolumab plus a TKI. ORR was 40.4%
in both arms, with ongoing responses
in 42.1% and 36.8% of patients in the
N3I1 and N1I3 arms, respectively. This
combination demonstrated manageable
safety, notable antitumor activity,
and durable responses with promising
OS in patients with mRCC progressed
after prior therapy. In another clinical
trial (NCT03075423), a combination of
pembrolizumab plus axitinib resulted
in significantly longer OS and PFS, as
well as a higher ORR, than treatment
with sunitinib16. After a median follow-
up of 12.8 months, the estimated
percentage of patients who were alive at
12 months was 89.9% in the pembrolizumab–
axitinib group and 78.3% in the
sunitinib group. Median PFS was 15.1
months in the pembrolizumab–axitinib
group and 11.1 months in the sunitinib
group. The objective response rate was
59.3% in the pembrolizumab–axitinib
group and 35.7% in the sunitinib group
(P<0.001).16
Similarly, pembrolizumab was
also being evaluated in the KEYNOTE
427 phase II trial. Similarly, durvalumab
is being evaluated in combination with
savolitinib, a highly selective MET tyrosine
kinase inhibitor, in the CALYPSO
phase II trial (NCT02819596). In another
randomized phase III JAVELIN
Renal 101 (NCT02684006) trial, Motzer
et al investigated the combination of
axitinib and avelumab in treatment-naive
RCC patients with metastatic or
advanced disease.20 Avelumab plus
axitinib arm had longer PFS and a significantly
higher objective response
rate than those who received sunitinib
monotherapy. Results showed that
mPFS in the combination arm was 13.8
months versus 8.4 months in sunitinib
arm (HR, 0.69; p< 0.001), and the ORR
and CR rate were 55% and 4% in the
combination arm versus 26% and 2%
in the sunitinib arm respectively.20 The
safety profile was comparable to the results
of the JAVELIN Renal 101 trial.
The subgroup analysis indicates that the
benefit of pembrolizumab plus axitinib
for OS, PFS, and ORR was observed in
the entire population irrespective of
IMDC prognostic group and PD-L1 tumor
expression.
In CheckMate-9ER study,
nivolumab plus cabozantinib combination
had significant benefits over sunitinib
in terms of PFS, OS in patients
with treatment naïve aRCC. The mPFS
was 16.6 months with nivolumab plus
cabozantinib and 8.3 months with sunitinib.
12 The probability of OS at 12 months
was 85.7% with the combination arm and
75.6% with sunitinib. An OR occurred in
55.7% of patients in the combination arm
versus 27.1% in sunitinib arm (P<0.001).
Efficacy benefits with nivolumab plus
cabozantinib were consistent across
subgroups.12 In another phase 3 trial,
patients with aRCC and no previous systemic
therapy were randomly assigned
to receive lenvatinib plus pembrolizumab,
lenvatinib plus everolimus, or sunitinib.
Lenvatinib plus pembrolizumab
therapy resulted in longer PFS (median,
23.9 vs. 9.2 months) and OS than with
sunitinib. However similar benefits were
not observed with lenvatinib plus everolimus
as compared to sunitinib. This
study demonstrated lenvatinib plus pembrolizumab
therapy was associated with
significantly longer PFS and OS as compared
to sunitinib. In a non-randomized
Phase Ib/II study, VEGF-TKI plus IO
(tivozanib plus nivolumab) combination
was assessed in patients previously treated
with one oral TKI (NCT03136627).
The ORR was 56%, with one patient
achieving a complete response. The
combination of tivozanib with nivolumab
prolonged disease control (median PFS
of 18.9 months) and also showed a tolerable
AE profile in both treatment-naïve
and previously treated metastatic RCC.21
In phase III CLEAR clinical trial,
lenvatinib plus pembrolizumab treatment
significantly improved PFS compared
to sunitinib (HR: 39, median =
23.9 vs 9.2 months). This combination
also improved the ORR compared to
sunitinib (71.0% vs 36.1%) with an impressive
complete response rate of 16.1%
and OS was also significantly longer than
sunitinib (HR = 0.66). Although lenvatinib
plus everolimus, in the third arm,
significantly improved PFS compared to
sunitinib (median = 14.7 vs 9.2 months,
HR = 0.65, 95% CI = 0.53–0.83), but
overall survival benefit was inconclusive
(HR = 1.15). Based on the promising
data, this combination became the fifth
immuno-oncology combination for the
first-line treatment of metastatic RCC,
in addition to nivolumab plus ipilimumab,
pembrolizumab plus axitinib, avelumab
plus axitinib, and nivolumab plus
cabozantinib.
Although the combination of ICI
and antiangiogenics has shown encouraging
preliminary antitumor activity for
advanced or mRCC, high incidence of
toxicity along with less favorable tolerability
profile may compromise the benefits
in patients. For instance, in the phase
I study CheckMate 016 (NCT01472081),
the efficacy and safety of nivolumab in
combination with antiangiogenic tyrosine
kinase inhibitors or ipilimumab
for the treatment of mRCC.22 In this
study, the addition of sunitinib or pazopanib
to nivolumab resulted in a high
incidence of high-grade toxicities, limiting
its scope in future trials. Given the
possibility that long-term cumulative
adverse effects from antiangiogenic and
ICI-combinations may accumulate over
time and outweigh the benefits, such
combinatorial therapies warrant close
monitoring to avoid unprecedented
risks.
VEGF-TKI plus mTOR inhibitors
Targeted therapies directed towards
both VEGFR and mTOR pathways have
long been considered a potential synergistic
strategy in mRCC landscape.
However, only a few combinations
shown a successful synergy with the
benefits that outranged the combined
toxicities from the regimens involved.
Lenvatinib, a novel potent multi-target
TKI of VEGFR 1-3, PDGFR-β, RET,
c-KIT, and FGFR 1–4, was approved
in combination with everolimus for
the treatment of advanced RCC following
one prior antiangiogenic therapy.
In a phase 2 trial (NCT01136733),
153 patients with mRCC previously
treated with VEGF-TT were randomly
allocated to receive either the combination
of lenvatinib plus everolimus,
single-agent lenvatinib, or single-agent
everolimus. Lenvatinib plus everolimus
significantly prolonged PFS compared
with everolimus alone, but not compared
with lenvatinib alone.23 This trial
demonstrated that lenvatinib plus everolimus
and lenvatinib alone resulted in
a progression-free survival benefit for
patients with metastatic renal cell carcinoma
who have progressed after one
previous VEGF-targeted therapy.
VEGF inhibitor plus HIF inhibitor
The preliminary, interim results from a
phase II trial has shown that belzutifan
plus cabozantinib treatment resulted in
88% tumor shrinkage in target lesions
and a disease control rate of 90% for
patients with previously treated advanced
clear cell RCC, according to preliminary
results from cohort 2 in an ongoing
phase II study. The PFS rate was
78% at 6 months and 65% at 12 months.
Median progression-free survival was
16.8 months.
SECOND-LINE THERAPIES
Ideally, second-line therapies are
designed to address the resistance
mechanism obtained from first-line
treatments and utilize different treatment
modalities to gain better disease
control in the second-line setting. For
instance, for patients progressing despite
first-line immunotherapy, TKIbased
second-line therapy could deliver
better outcome. If a patient has progressed
on combination ICI/TKI treatment,
the second-line regimen could
include either a different TKI alone or
in combination with an mTOR inhibitor.
The different TKI is chosen based
on their capacit still VEGF-TT
y to challenge escape pathways that led
to treatment resistance to the prior TKI,
via AKT, MET, AXL, and FGF signaling.
6 For patients progressing after firstline
VEGF therapy, checkpoint inhibitors
is not the only favorable therapy;
TKI therapy can be also a viable option.
Cabozantinib, an orally bioavailable
TKI, inhibits VEGFRs, MET, and AXL
targets implicated in the pathogenesis
and progression of RCC. These favorable
results in TKI-refractory disease
support the hypothesis that the clinical
activity of cabozantinib in RCC may
result from combined inhibition of
VEGFRs and additional targets, such as
MET and AXL, that are not inhibited by
other TKIs.8,10 11 Another added advantage
is that the number of prior therapies
does not seem to affect the efficacy
of cabozantinib or nivolumab.
Second-line post VEGFI therapy
The following studies explored survival
benefits in patients who progressed
VEGFR TKI therapies. The international
randomized, open-label, phase III
METEOR trial assessed the efficacy and
safety of cabozantinib with the mTOR
inhibitor everolimus in patients with
advanced RCC following one or more
VEGFR TKI therapy. Treatment with
cabozantinib improved PFS, ORR, and
OS versus everolimus in patients with
aRCC. In cabozantinib arm, median OS
was 21·4 months (95% CI 18·7-not estimable)
as compared to 16·5 months
in everolimus arm. Cabozantinib
treatment also resulted in improved
progression-free survival and objective
response (17% with cabozantinib
vs 3% with everolimus; p<0·0001).
Cabozantinib treatment was also resulted
in improved clinical outcomes in
patients who had received both VEGFR
TKI therapy and an immune checkpoint
inhibitor. Cabozantinib may have added
advantage over other therapies especially
for patients with bone and brain
metastasis subgroups that derived
increased benefit, that is, elderly, good
and intermediate-risk patients. In the
METEOR trial, cabozantinib therapy
resulted in better median PFS of 7.4
months and 5.6 months as compared to
2.7 months and 1.9 months with everolimus
in those with bone metastasis
and bone and visceral disease, respectively.
The rate of post-randomization
skeletal-related events was lower (16%)
with cabozantinib as compared to 34%
events with everolimus. Taken together,
these data strongly support the use
of cabozantinib in mRCC patients with
bone and brain metastasis.
The IO agent nivolumab can
be given as a preferred second-line
monotherapy option for patients who
progressed on first-line anti-VEGF
therapies. The CheckMate-025
(NCT01668784) trial has demonstrated
that nivolumab delivers better
PFS, overall response rate and overall
survival, paving the way for the use of
nivolumab as second-line therapy.24
In a randomized open-label, phase III
study, a total of 821 advanced ccRCC
patients who had received previous
treatment with one or two regimens of
antiangiogenic therapy were randomly
assigned either nivolumab or everolimus.
24 Results showed that ORR
was greater with nivolumab than with
everolimus (25% vs. 5%; p < 0.001) and
median PFS was better with nivolumab
than with everolimus (4.6 months
vs 4.4 months; p = 0.11).24 Results
indicated that the nivolumab arm had
25.0 months median OS as compared
to 19.6 months in the everolimus arm.
Nivolumab’s OS benefit was evident
across prespecified MSKCC risk and
PD-L1 subgroups. Taken together,
these results especially obtained from
METEOR and CheckMate 025 trials
highlight the broad clinical utility of
cabozantinib or nivolumab as a preferred
second-line therapy for previously
treated patients with advanced
RCC in the post VEGFI setting.
In a randomized, open-label
trial, patients who received at
least two previous systemic treatments
(including at least one previous
treatment with VEGFR inhibitor)
were randomly assigned to receive
tivozanib or sorafenib.25 Median PFS
was significantly longer with tivozanib
(5·6 months) than with sorafenib
(3·9 months). This study showed that
tivozanib as third-line or fourth-line
therapy improved progression-free
survival and was better tolerated compared
with sorafenib in patients with
metastatic renal cell carcinoma. In
other randomized, phase 2, open-label,
lenvatinib, everolimus, or their combination
as a second-line treatment were
assessed in patients with mRCC who
had received treatment with a VEGFtargeted
therapy. Lenvatinib plus everolimus
significantly prolonged PFS
compared with everolimus alone (median
14·6 months vs 5·5 months), but
not compared with lenvatinib alone
(7·4 months). Single-agent lenvatinib
significantly prolonged PFS compared
with everolimus alone. Lenvatinib plus
everolimus and lenvatinib alone resulted
in a PFS benefit for patients with
mRCC who have progressed after one
previous VEGF-targeted therapy.
Second-line post IO therapy
For those patients who progressed
after initial ICI therapy, the second-
line option would be VEGFRTKI.
Currently, preferred second line
choice was the inhibitor of the mammalian
target of rapamycin pathway
(mTOR) everolimus in 53.3% of cases.
Besides, alternative options including
VEGFR-TKI options (cabozantinib) or
mTOR combinations (lenvatinib plus
everolimus) for a later rescue line are
also considered. Similarly, RECORD-1
study shown demonstrated benefits
from everolimus in patients who had
received at least one prior treatment
with sunitinib and/or sorafenib. The
median PFS for everolimus was 4.0 vs
1.9 months with placebo. No OS impact
was seen in the trial although the crossover
rate was over 90%.26 For those
who receive either pazopanib or sunitinib
in the first-line therapy, a mammalian
target of rapamycin (mTOR)
inhibitor and a TKI could be a possible
choice of second-line therapy. Another
interesting question will be the possibility
of ICI rechallenge and elucidating
the use of cytoreductive nephrectomy
within the context of new immunotherapeutic
interventions.
For patient progressed on firstline
ICI/TKI combination, a second-line
combination mTOR inhibitors/TKIs
could be another option available.
Although single-agent temsirolimus
versus sorafenib yielded a lack of benefit
after progression on a VEGF-TKI in
the second-line setting14, a randomized
phase II Study 205 trial supported the
use of lenvatinib plus everolimus vs
lenvatinib alone vs everolimus alone in
this setting.15 A superior PFS was noted
at 14.6 months vs 5.5 months with
everolimus alone, but it lacked a statistically
significant difference when compared
with the lenvatinib arm (PFS, 7.4
months). The study results led to the first
FDA-approved combination of a TKI
and an mTOR inhibitor. However, highgrade
toxicities that occurred in the combination
arm warrant newer-generation
multi-TKI/mTOR such as vorolanib to
identify better-tolerated regimens.16
Currently, a phase 1 trial involving vorolanib/
everolimus combination in the
second-line setting is underway.
Despite the robust profile of
the anti-PD-1/anti-CTLA-4 dual checkpoint
blockade, some mRCC patients
do not respond well to the therapy and
would have intermediate- and poor-risk
IMDC factors. Given that the tumor is
still VEGF-TT naïve in these subsets of
patients, TKI approved for the first-line
may have a role. For these patients, axitinib,
cabozantinib, or the combination
of lenvatinib + everolimus could be used
as a second-line, depending on clinical
and non-clinical factors. For patients
who progressed after ICI therapy including
ipilimumab/nivolumab, a phase 2
nonrandomized trial (n = 38) has shown
that axitinib may provide clinical efficacy
(PFS 9.2 mo, ORR 40%). Besides, small
retrospective studies that shown median
PFS of 8 months using TKI after dual
checkpoint blockade, supported the use
of cabozantinib compared with sunitinib
in this specific population. In a retrospective
analysis involving 86 patients
who received cabozantinib after progression
on ICI alone, ICI plus VEGFIs or
other therapies. Cabozantinib arm had
ORR of 36% with no complete response
and 43% achieving stable disease; 21%
had primary progressive disease. The
median OS was 13.1 months with OS rate
of 12 months.
For patients who progressed on
prior PD-1/PD-L1 or ICI/TKI therapy
may benefit from the combination of lenvatinib
and pembrolizumab. The phase
II KEYNOTE-146 trial has evaluated the
benefit of lenvatinib plus pembrolizumab
after up-front therapy with nivolumab/
ipilimumab.12,27 The 12-month rate
of PFS was 45%, with a median value
of 11.7 months, and the corresponding
values for overall survival were 77% and
not reached. The ORR was 55% for those
given only PD-1 or PD-L1 inhibitors, and
59% and 47% for patients who had also
received a VEGR inhibitor or nivolumab
plus ipilimumab, respectively.27 For patients
who progressing after either firstline
IL-2 or temsirolimus, the preferred
second-line therapy could be pazopanib
or sunitinib. However, the treatment
choice remains unclear for patients previously
treated with ICI. In this setting,
the preferred treatment choice could be
VEGFR-TKI not previously used in combination
with ICI therapy. For third-line
therapy 63.5% of patients received TKI,
primarily sorafenib and axitinib (23.5%
each), whereas 36.5% of patients received
everolimus. For fourth-line and
beyond, sorafenib was used in 21.2%
of patients as fourth-line therapy, and
both sunitinib and everolimus were
used equally as fifth-line therapy, in
23.8% of patients. A pivotal phase III
CONTACT-03 study (NCT04338269) is
currently underway in patients who received
prior ICI as a first- or second-line
treatment in RCC. For the patients who
are ineligible to receive either nivolumab
IO therapy or cabozantinib, axitinib
is recognized as another appropriate
second-line option according to the international
guidelines and recommendations.
Axitinib is recognized as another
appropriate second-line option in
this setting based on AXIS trial. In this,
23 patients with one prior therapy were
randomized to axitinib or sorafenib, axitinib
was established as the preferred
second-line choice.28 The median PFS
for axitinib was 8.3 vs 5.7 months with
sorafenib, although no statistical difference
in OS was observed.
CONCLUDING REMARKS
Over the last decade, there has been
tremendous progress in the treatment
landscape of mRCC with new and efficacious
monotherapies and combinatorial
regimen, leading to an expansion of
therapeutic armamentarium. With the
continuous implementation of several
first-line therapies (eg. cabozantinib,
tivozanib, sunitinib or pazopanib, ipilimumab/
nivolumab, pembrolizumab/
axitinib, cabozantinib/nivolumab, axitinib/
pembrolizumab, axitinib/avelumab,
pembrolizumab/lenvatinib), the
treatment landscape is rapidly shifting,
paving the way for optimal management
in subsequent lines of therapy.
Conversely, the rapidness of emerging
therapies with the advent of novel
agents in the pipeline is adding further
complexity to the already overwhelming
mRCC landscape. The precise treatment
selection remains a debated issue in the
absence of head-to-head comparison
among the randomized trials. This complexity
reinforces the need for optimal
therapeutic sequencing, patient selection,
and the implication of prognostic
risk models for both initial management
and systemic therapy paradigms. The
quest for optimizing sequence strategies
that deliver robust survival, safety, while
preserving the quality of life and the
ability to tailor therapy to the individual
patient remains. An equally important
aspect to consider is that the identification
of better biomarkers for response
to ICIs and TKIs before individualizing
therapies corresponding to tailored
personalized treatments in mRCC paradigm.
Future studies will explore another
novel ICI/TKI, TKI, HIF-2a, and
combinatorial therapies galvanized with
personalized treatment approaches to
deliver promising and meaningful therapeutic
management in patients with
advanced and metastatic RCC.
REFERENCES
1. 1. Bray F, Ferlay J, Soerjomataram I,
Siegel RL, Torre LA, Jemal A. Global cancer statistics
2018: GLOBOCAN estimates of incidence and
mortality worldwide for 36 cancers in 185 countries.
CA Cancer J Clin. Nov 2018;68(6):394-424.
doi:10.3322/caac.21492
2. Czarnecka AM, Kornakiewicz A, Kukwa
W, Szczylik C. Frontiers in clinical and molecular
diagnostics and staging of mccRCC. Future Oncol.
May 2014;10(6):1095-111. doi:10.2217/fon.13.258
3. Wang J, Li X, Wu X, et al. Role of immune
checkpoint inhibitor-based therapies for
mRCC in the first-line setting: A Bayesian network
analysis. EBioMedicine. Sep 2019;47:78-88.
doi:10.1016/j.ebiom.2019.08.006
4. Fyfe G, Fisher RI, Rosenberg SA, Sznol
M, Parkinson DR, Louie AC. Results of treatment
of 255 patients with mRCC who received highdose
recombinant interleukin-2 therapy. J Clin
Oncol. Mar 1995;13(3):688-96. doi:10.1200/
JCO.1995.13.3.688
5. McDermott DF, Regan MM, Clark JI,
et al. Randomized phase III trial of high-dose
interleukin-2 versus subcutaneous interleukin-2
and interferon in patients with mRCC. J Clin
Oncol. Jan 1 2005;23(1):133-41. doi:10.1200/
JCO.2005.03.206
6. Jonasch E. Implications of VHL-HIF
pathway dysregulation in renal cell carcinoma:
current therapeutic strategies and challenges.
Kidney Cancer Journal. 2020;18(1):6-10.
7. Motzer RJ, Hutson TE, Tomczak P, et al.
Overall survival and updated results for sunitinib
compared with interferon alfa in patients with
mRCC. J Clin Oncol. Aug 1 2009;27(22):3584-90.
doi:10.1200/JCO.2008.20.1293
8. Escudier B, Eisen T, Stadler WM, et al.
Sorafenib in advanced clear-cell renal-cell carcinoma.
N Engl J Med. Jan 11 2007;356(2):125-34.
doi:10.1056/NEJMoa060655
9. Motzer RJ, Hutson TE, Cella D, et al.
Pazopanib versus sunitinib in metastatic renal-cell
carcinoma. N Engl J Med. Aug 22 2013;369(8):722-
31. doi:10.1056/NEJMoa1303989
10. Escudier B, Bellmunt J, Negrier S, et
al. Phase III trial of bevacizumab plus interferon
alfa-2a in patients with mRCC (AVOREN):
final analysis of overall survival. J Clin Oncol.
May 1 2010;28(13):2144-50. doi:10.1200/
JCO.2009.26.7849
11. Mehta A, Sonpavde G, Escudier B.
Tivozanib for the treatment of renal cell carcinoma:
results and implications of the TIVO-1
trial. Future Oncol. Aug 2014;10(11):1819-26.
doi:10.2217/fon.14.120
12. Choueiri TK, Halabi S, Sanford BL,
et al. Cabozantinib Versus Sunitinib As Initial
Targeted Therapy for Patients With mRCC
of Poor or Intermediate Risk: The Alliance
A031203 CABOSUN Trial. J Clin Oncol.
Feb 20 2017;35(6):591-597. doi:10.1200/
JCO.2016.70.7398
13. Hudes G, Carducci M, Tomczak P, et al.
Temsirolimus, interferon alfa, or both for aRCC.
N Engl J Med. May 31 2007;356(22):2271-81.
doi:10.1056/NEJMoa066838
14. Tannir NM, Jonasch E, Albiges
L, et al. Everolimus Versus Sunitinib
Prospective Evaluation in mNCRCC (ESPN):
A Randomized Multicenter Phase 2 Trial. Eur
Urol. May 2016;69(5):866-74. doi:10.1016/j.
eururo.2015.10.049
15. Motzer RJ, Tannir NM, McDermott DF,
et al. Nivolumab plus Ipilimumab versus Sunitinib
in aRCC. N Engl J Med. Apr 5 2018;378(14):1277-
1290. doi:10.1056/NEJMoa1712126
16. Rini BI, Plimack ER, Stus V, et al.
Pembrolizumab plus Axitinib versus Sunitinib for
aRCC. N Engl J Med. Mar 21 2019;380(12):1116-
1127. doi:10.1056/NEJMoa1816714
17. Hasanov E, Jonasch E. MK-6482 as a
potential treatment for von Hippel-Lindau disease-
associated ccRCC. Expert Opin Investig
Drugs. May 2021;30(5):495-504. doi:10.1080/13
543784.2021.1925248
18. Kwilas AR, Donahue RN, Tsang KY,
Hodge JW. Immune consequences of tyrosine kinase
inhibitors that synergize with cancer immunotherapy.
Cancer Cell Microenviron. 2015;2(1)
doi:10.14800/ccm.677
19. Rini BI, Powles T, Atkins MB, et al.
Atezolizumab plus bevacizumab versus sunitinib
in patients with previously untreated metastatic
renal cell carcinoma (IMmotion151): a multicentre,
open-label, phase 3, randomised controlled
trial. Lancet. Jun 15 2019;393(10189):2404-2415.
doi:10.1016/S0140-6736(19)30723-8
20. Motzer RJ, Penkov K, Haanen J, et
al. Avelumab plus Axitinib versus Sunitinib for
aRCC. N Engl J Med. Mar 21 2019;380(12):1103-
1115. doi:10.1056/NEJMoa1816047
21. Albiges L, Barthelemy P, Gross-Goupil
M, Negrier S, Needle MN, Escudier B. TiNivo:
safety and efficacy of tivozanib-nivolumab combination
therapy in patients with mRCC. Ann
Oncol. Jan 2021;32(1):97-102. doi:10.1016/j.
annonc.2020.09.021
22. Amin A, Plimack ER, Ernstoff MS,
et al. Safety and efficacy of nivolumab in combination
with sunitinib or pazopanib in aRCC:
the CheckMate 016 study. J Immunother
Cancer. Oct 22 2018;6(1):109. doi:10.1186/
s40425-018-0420-0
23. Hamieh L, Beck RL, Le VH, Hsieh JJ. The
Efficacy of Lenvatinib Plus Everolimus in Patients
with mRCC Exhibiting Primary Resistance to
Front-Line Targeted Therapy or Immunotherapy.
Clin Genitourin Cancer. Aug 2020;18(4):252-257
e2. doi:10.1016/j.clgc.2020.03.003
24. Motzer RJ, Escudier B, McDermott
DF, et al. Nivolumab versus Everolimus in
Advanced Renal-Cell Carcinoma. N Engl J Med.
Nov 5 2015;373(19):1803-13. doi:10.1056/
NEJMoa1510665
25. Rini BI, Pal SK, Escudier BJ, et al.
Tivozanib versus sorafenib in patients with advanced
renal cell carcinoma (TIVO-3): a phase
3, multicentre, randomised, controlled, open-label
study. Lancet Oncol. Jan 2020;21(1):95-104.
doi:10.1016/S1470-2045(19)30735-1
26. Bono P, Oudard S, Bodrogi I, et al.
Outcomes in Patients With Metastatic Renal Cell
Carcinoma Who Develop Everolimus-Related
Hyperglycemia and Hypercholesterolemia:
Combined Subgroup Analyses of the RECORD-1
and REACT Trials. Clin Genitourin Cancer.
Oct 2016;14(5):406-414. doi:10.1016/j.
clgc.2016.04.011
27. Lee CH, Shah AY, Rasco D, et al.
Lenvatinib plus pembrolizumab in patients
with either treatment-naive or previously treated
metastatic renal cell carcinoma (Study 111/
KEYNOTE-146): a phase 1b/2 study. Lancet
Oncol. Jul 2021;22(7):946-958. doi:10.1016/
S1470-2045(21)00241-2
28. Rini BI, Escudier B, Tomczak P, et
al. Comparative effectiveness of axitinib versus
sorafenib in advanced renal cell carcinoma
(AXIS): a randomised phase 3 trial. Lancet.
Dec 3 2011;378(9807):1931-9. doi:10.1016/
S0140-6736(11)61613-9
Correspondence to: Robert A. Figlin, MD., FACP., Cedars-Sinai Medical Center,
8700 Beverly Blvd. Los Angeles, CA 90048. E-mail: robert.figlin@cshs.org
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