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Published OnlineFirst January 16, 2020; DOI: 10.1158/1078-0432.CCR-19-3323
Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer:
Combination Therapy in the First-Line Setting
David H. Aggen1, Charles G. Drake2, and Brian I. Rini3
Recent FDA approvals of regimens targeting programmed
death 1 (PD-1) in combination with anti-CTLA-4 or with VEGF
tyrosine kinase inhibitors are reshaping front-line therapy for
metastatic kidney cancer. In parallel, therapeutics specific for
programmed death ligand 1 (PD-L1), one of the two major
ligands for PD-1, are under continued investigation. Surprisingly,
not all PD-1 and PD-L1 agents lead to similar clinical outcomes,
potentially due to biological differences in the cellular expression
The discovery of programmed death 1 (PD-1) and programmed
death ligand 1 (PD-L1) as a mechanism of peripheral T-cell tolerance
spurred the development of multiple therapeutics blocking their
critical interaction (1). In the context of kidney cancer, the PD-1–
specific therapies nivolumab (2, 3) and pembrolizumab (4), as well as
the PD-L1 antibody avelumab (5) are FDA-approved in combination
with other therapies for metastatic renal cell carcinoma (RCC). In the
past 14 months, four phase III trials have tested the hypothesis that
immunotherapy (I/O)-based combinations are efficacious as first-line
therapy in metastatic RCC (Table 1). Combination therapies based on
anti-PD-1 antibodies, pembrolizumab plus axitinib and nivolumab
plus ipilimumab, have improved overall (OS) relative to sunitinib (3, 4).
In contrast, combination therapies with anti-PD-L1 antibodies including avelumab plus axitinib (Javelin-101; ref. 5) or atezolizumab plus
bevacizumab (ImMotion 151; ref. 6) have not yet demonstrated an
overall survival benefit. Overall survival data in these anti-PD-L1
combination trials are still immature, and ultimately a survival benefit
might be observed with further follow-up. Despite this finding, it is
notable that occasional complete responses were reported with both
anti-PD-1 and anti-PD-L1 combination regimens. Caution should be
exercised in cross-trial comparison due to potential differences in
baseline patient characteristics. However, the OS benefits documented
in anti-PD-1 combination therapy trials, but not in anti-PD-L1
immunotherapy studies, highlights potential advantages to targeting
PD-1 as compared with PD-L1 in specific clinical contexts.
Memorial Sloan Kettering Cancer Center, New York, New York. 2Herbert Irving
Cancer Center, New York-Presbyterian/Columbia University Medical Center,
New York, New York. 3Division of Hematology/Oncology, Vanderbilt University
Medical Center, Nashville, Tennessee.
Note: Supplementary data for this article are available at Clinical Cancer
Research Online (http://clincancerres.aacrjournals.org/).
Corresponding Author: David H. Aggen, Memorial Sloan Kettering Cancer
Center, New York, NY 10065. Phone: 646-422-4679; Fax: 646-227-2417; E-mail:
Clin Cancer Res 2020;26:2087–95
doi: 10.1158/1078-0432.CCR-19-3323
2020 American Association for Cancer Research.
and regulation of these targets. Here, we review current clinical
data on combination immune checkpoint inhibitor therapy in
metastatic kidney cancer and discuss the relevant biology of PD-1
and PD-L1. The design of future rational combination therapy
trials in metastatic renal cell carcinoma will rely upon an
understanding of this biology, along with an evolving understanding of immune cell populations and their functional states
in the tumor microenvironment.
Observations in other tumor types support the concept of nonequivalence between PD-1 and PD-L1 targeted therapeutics. In bladder cancer, the anti-PD-1 agent pembrolizumab showed an OS benefit
compared with second-line treatment in Keynote-045 (7), whereas the
anti-PD-L1 antibody atezolizumab did not show an OS benefit when
compared with second-line chemotherapy in a similar patient population in the IMVigor211 trial (8). In NSCLC, the anti-PD-1 antibody
pembrolizumab improved OS relative to second-line chemotherapy in
Keynote-010 (9), whereas the anti-PD-L1 antibody avelumab failed to
improve OS in a similar cohort of patients (10). Notwithstanding the
limitations of cross-trial comparisons, the discrepancies in clinical
outcome between PD-1 and PD-L1 antibodies beg a lingering question:
are these therapeutics equivalent?
Fundamental differences in the biologic mechanisms of anti-PD-1
and anti-PD-L1 may underlay these potentially disparate clinical
outcomes; thus, understanding these nuances is critical to the design
of next-generation combinatorial strategies. Herein, we describe some
key distinctions in PD-1 and PD-L1 biology in terms of cell type–
specific expression, differential regulation, and the physiologic effects
of blockade. The relative contribution of antibody directed cell cytotoxicity (ADCC) for PD-L1 therapeutics is also discussed. Finally, we
summarize ongoing clinical activity using these therapeutics in combination regimens.
The PD-1/PD-L1 Interaction Attenuates
a T-Cell Response
T-cell activation is initiated by the engagement of a T-cell receptor
(TCR) with its cognate peptide-MHC complex—along with an appropriate costimulatory signal (Signal 2). In this setting, the primary
biologic function of PD-1 is to maintain a desirable range of T-cell
activation so as to prevent rampant autoimmunity (11). Upon T-cell
activation, PD-1 is upregulated within 12 to 36 hours and its interaction with PD-L1 and/or PD-L2 downmodulates T-cell proliferation
and effector function (Fig. 1; ref. 12). Biochemically, PD-1 binding to
either PD-L1 or PD-L2 (13) activates the tyrosine phosphatase SHP-2
in the PD-1–expressing cell; this directly dampens T-cell activation by
dephosphorylating the TCR and costimulatory molecules like
CD28 (14). In the setting of chronic antigen stimulation, PD-1
preserves T-cell clones that might otherwise undergo activationinduced cell death. As a consequence of its biology, PD-1 expression
is both a marker of initial T-cell activation as well as a marker of several
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Aggen et al.
Table 1. Summary of completed phase III trials in metastatic RCC evaluating combination immune therapies.
PD-L1þ (%)a
PD-L1 assay/cutoff
Risk category
Liver metastases (%)
Median follow-up (months)
PFS (months)
Combination arm
Sunitinib arm
OS (months)
Combination arm
Sunitinib arm
Nivolumab þ Ipilimumab
Pembrolizumab þ Axitinib Avelumab þ Axitinib
Atezolizumab þ Bevacizumab
CheckMate 214
Dako 28-8 (1% TC)
Keynote 426
Dako 22C-3 (CPS 1%)
Javelin 101
Ventana SP263 (1% IC)
ImMotion 151
Ventana SP-142 (>1% IC)
0.85 (95.0% CI, 0.73–0.98) 0.69 (95% CI, 0.57–0.84)
0.69 (95.0% CI, 0.56–0.84) 0.83 (95.0% CI, 0.70–0.97)
0.71 (95.0% CI, 0.59–0.86)
0.78 (95% CI, 0.55–1.08)
0.53 (95% CI, 0.38–0.74)
0.93 (95% CI, 0.76–1.14)
Note: HR with statistically significant confidence intervals are in bold.
Abbreviations: CPS, combined positive score calculated as the number of (total PD-L1 þ TC and IC)/divided by total number of TC x 100; IC, immune Cells; NR, not
reported; TC, tumor cells.
Percent PD-L1 positive in combination I/O arm. PD-L1 cutoff and compartment evaluated differs in each trial.
ORR and CR rate in combination I/O arm.
states of functional exhaustion. Those states are defined in part by the
coexpression of additional immune checkpoint molecules like LAG-3
and TIM-3 (15). Consequently, not all PD-1–expressing T cells behave
as functionally exhausted T cells, and additional cell surface markers
and epigenetic signatures are required to more completely define
immune cell subsets with diminished effector capacity (recently
reviewed in detail; ref. 16).
PD-1 and PD-L1 Protein Expression:
Shared but Distinct Cellular
In general, PD-1 is expressed on activated/exhausted CD8 and CD4
T cells, although expression has been reported on a number of other
populations including B cells and macrophages (17). PD-L1 may be
expressed on both tumor cells or other cells in the TME, including
dendritic cells, macrophages, and other myeloid populations (18).
Controversy exists regarding the most important PD-L1 expressing
population—with some studies suggesting that tumor expression is
most critical (19, 20) and other studies highlighting expression on
myeloid populations (21, 22). The second major PD-1 ligand, PD-L2,
has a more restricted expression pattern with predominant expression
on endothelial cells, monocytes, and dendritic cells. In a study evaluating PD-L2 expression in seven distinct tumor types, RCC had
among the lowest level of tumor PD-L2 expression with relatively high
stromal and endothelial cell expression of this ligand (23). The
expression of PD-L2 in the TME is in general under-appreciated,
especially as PD-1 has a higher binding affinity for PD-L2 than for PDL1 (24). Indeed, the potential of PD-L2 to promote T-cell tolerance
provides one potential explanation for the lack of OS benefit with PDL1 combination therapies in kidney cancer.
2088 Clin Cancer Res; 26(9) May 1, 2020
PD-1 and PD-L1 Are Dynamically
Regulated by Cell Extrinsic and Intrinsic
As described above, PD-1 expression is initiated by T-cell
activation. Expression is further modulated by a number of signals
in the TME including TGFb (25), and IFNa, which promote
upregulation of PD-1 on both T cells and macrophages (26).
PD-1 biology is somewhat complex, with at least 10 transcriptional
factor complexes that function in modulating PD-1 activity dependent on the state of T-cell activation (reviewed in detail elsewhere;
ref. 27). In acute infection, antigen clearance leads to eventual
downregulation of PD-1, whereas in the context of cancer and
chronic viral infection persistent antigen exposure drives continued
PD-1 expression on antigen-specific T cells (28).
PD-L1 expression on immune and tumor cell subsets is largely
induced by TH1 cytokines like IFNg. Following IFNg exposure,
tumor and immune cells upregulate PD-L1 through a transcriptional program involving the JAK1/STAT signaling pathway (29).
Clinically, this is important, because mutations in the JAK/STAT
pathway and antigen presentation machinery have been implicated
in primary and acquired resistance to PD-1 therapy in melanoma (30). At the genomic level, copy-number alterations (CNA) in
the PD-L1 gene in tumor cells may also lead to increased levels of
PD-L1 expression. CNA in PD-L1 at chromosome 9p24 are associated with increased tumor mutation burden (31) and are enriched
in a rare but unique RCC subset with sarcomatoid pathologic
features (32). The latter is of keen interest as gene signatures
associated with sarcomatoid RCC pathology were enriched in
patients responding to atezolizumab and bevacizumab in IMMotion
151 (33). Subgroup analysis of patients with sarcomatoid pathologic
features from Checkmate 214 (nivolumab þ ipilimumab; ref. 34)
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Published OnlineFirst January 16, 2020; DOI: 10.1158/1078-0432.CCR-19-3323
Combination PD-1 and PD-L1 Immunotherapy for Kidney Cancer
CD8 T cell
Figure 1.
PD-1/PD-L1 targeted therapeutics in renal cell carcinoma. Overview of current immunotherapy targets in renal cell carcinoma. The PD-1 antibodies pembrolizumab,
nivolumab, and spartalizumab prevent interaction with PD-L1 and PD-L2. In contrast, the PD-L1 antibodies avelumab, atezolizumab, and durvalumab prevent PD1
ligation, but leave PD-1 and PD-L2 ligation unopposed.
and Keynote 426 (pembrolizumab þ axitinib; ref. 35) also demonstrated improved ORR and OS relative to sunitinib.
Additional tumor intrinsic factors may also drive PD-L1 expression
to promote immune tolerance and tumor immune evasion. In clear cell
RCC, HIF2a activation secondary to Von Hippel Landau (VHL)
deficiency promotes PD-L1 expression in vitro (36, 37). However,
clinical data supporting this association are not yet available. VHL
inactivation is estimated to occur in >90% of patients with RCC either
through direct mutation or promoter hyper-methylation, and one
would anticipate the number of PD-L1 expressing tumor samples in
RCC would be dramatically higher if this association were absolute (38). For example, in Checkmate 214, only 20% to 30% of patients
with RCC had PD-L1 positive tumor cells (3). Similarly, in the
COMPARZ trial evaluating pazopanib versus sunitinib, 36% of
patients had PD-L1–positive specimens (39). As a consequence, the
association between PD-L1 expression and VHL deficiency certainly
requires additional investigation.
Metabolic and Epigenetic Programs
Modulated by the PD-1/PD-L1 Axis
PD-1 ligation with PD-L1 or PD-L2 induces T cell functional
exhaustion by causing distinct metabolic changes within the T cell.
PD-1 binding switches the T cell energy source to fatty acid oxidation
with concomitant attenuation of glycolysis (40). This metabolic switch
assists in determination of T cell effector versus memory cell fates and
promotes the maintenance of functional CD8 exhaustion. Similarly,
attenuation of glycolysis in CD4 T cells, which may or may not be
independent of PD-1 signaling, promotes regulatory T cell commitment (41). Thus PD-1 and additional costimulatory molecules, such as
4-1BB, are implicated in driving immune cell metabolic programs that
lead to T cell dysfunction.
Ongoing PD-1 engagement with its cognate ligands also results in
epigenetic reprogramming of T cells, which may prevent effective
rescue by immune checkpoint blockade. These observations were
initially based on murine studies utilizing the LCMV virus that mimics
chronic antigen stimulation as is observed in cancerous states (42). In
LCMV murine models, functionally exhausted T-cell remained in a
PD-1HI exhausted state even after clearance of antigen, demonstrating
that epigenetic mechanisms likely underlie long-lived functional
exhaustion and PD-1 expression (43).
More recent data suggest that distinct epigenetic profiles define
states of functional T-cell exhaustion (16). Elegant work identified
the nuclear transcription factor TOX as a central regulator of
epigenetic and transcriptional programs driving T-cell exhaustion (44, 45). TOX expression increases following chronic antigen
stimulation, leading to a decrease in markers of self-renewal in T
cells—including the key transcription factor TCF1 (46). Conversely,
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deletion of TOX restored CD8 T-cell function and differentiation to
effector and memory phenotypes. Taken together, these studies
show that that TOX is a critical driver of early T-cell exhaustion.
Advancements in single-cell analysis (47) and epigenetic profiling
will be critical in further defining the functional and phenotypic
heterogeneity within these exhausted states, and clinical interventions aimed at altering the epigenetic phenotype of T cells remains
an area of active interest (48–50).
Functional Consequences of
PD-1/PD-L1 Blockade in the Clinic
Anti-PD-1 agents can restore the functionality of exhausted T
cells through direct ligation of PD-1 on CD4 and CD8 T lymphocytes, and based on that principle may rescue an immune response
relatively independent of tumor PD-L1 expression (Fig. 2A). Direct
T-cell binding by an anti-PD-1 therapeutic may afford significant
advantages relative to an anti-PD-L1 treatment, potentially via
more rapid T-cell expansion. In patients with melanoma treated
with anti-PD-1, peripheral blood profiling showed that expansion
of a PD-1þ effector T-cell pool after immune checkpoint blockade
correlated with clinical response (51). Relevant neoadjuvant studies
illustrate peripheral occupancy of PD-1, with peripheral blood
responses detected within 3 weeks on therapy (52). Peripheral
blood profiling also shows that anti-PD-1 therapeutics rapidly
stimulate T cells in the periphery, enabling tumor cell lysis,
relatively independent of tumor volume/burden. The kinetics of
T-cell expansion mediated by direct engagement of PD-1 on
effector T cells may not be achievable with anti-PD-L1 agents
A Prevents PD-L1 interaction
B Prevents PD-1 interaction
targeting tumor and immune cells. With adoption of immunotherapy into the neoadjuvant setting in clinical trials of kidney cancer
including PROSPER-RCC (53), we will gain further insights into
the mechanistic and kinetic differences in PD-1 and PD-L1 occupancy and immune blockade. Similarly, adjuvant trials for high-risk
RCC evaluating atezolizumab (NCT03024996) and pembrolizumab
(NCT03142334) have completed accrual, and peripheral blood
studies from these trials will enhance our understanding of the
relative benefit of perioperative PD-L1 and PD-1 blockade.
PD-L1–targeted therapies, in contrast, can induce immune
tumor rejection through multiple mechanisms (summarized
in Fig. 2B–D). First, anti-PD-L1 therapies prevent ligation with
PD-1 on immune cells like anti-PD-1 therapeutics. PD-L1 blockade
also prevents ligation with the costimulatory molecule B7.1 (CD80)
either in cis or in trans, which may provide a secondary mechanism
for T-cell reinvigoration (54). Second, anti-PD-L1 therapeutics may
also drive direct tumor cell killing through antibody-dependent
cellular cytotoxicity (ADCC), in this case via PD-L1 expressed on
tumor cells (Fig. 2C). In murine models, anti-PD-L1 that bind Fc
receptors that mediate ADCC led to tumor regression, whereas a
similar effect was not observed with anti-PD-1 therapies in those
models (55).
Despite these theoretical advantages, there are now two randomized
phase III trials in metastatic RCC using anti-PD-L1 therapeutics that
have not yet shown an OS benefit (Table 2). OS data in these trials is
still immature and longer follow-up is awaited. Although the mechanisms underlying this difference may be challenging to dissect, one
possibility is that interaction between PD-1 and PD-L2 is unaffected by
PD-L1 blockade, such that interactions between PD-L2 in the TME
C ADCC on tumor cell
PD-1 Blockade
Direct T-cell engagement
Direct tumor engagement
= Anti-PD-1
T cell
D ADCC on immune cell
PD-L1 blockade
Direct tumor engagement
= Anti-PD-L1
T cell
Direct T-cell engagement
= Anti-PD-L1
= Anti-PD-L1
• Allows metabolic and
epigenetic reprogramming
of T cells
• Blocks interaction between
PD-1 and PD-L1/PD-L2
• Blocks interaction with PD-1 on
immunocytes and B7.1 (CD80)
• Does not interact directly with T
Lytic enzymes
Lytic enzymes
T cell
• Anti-PD-L1 binds to tumor
cells expressing PD-L1
• Tumor cell killing via Fc-receptor
mediated antibody-dependent
cellular cytotoxicity
• Anti-PD-L1 binds to immune
cells expressing PD-L1
• Potential for immune cell
killing and depletion of either
immunosuppressive cells (M2like TAMs, MDSCs)
Figure 2.
Mechanisms of PD-1 and PD-L1 targeting immunotherapy. A, PD-1 blockade exerts direct effects on immune cells upon ligation by driving distinct metabolic and
epigenetic programs that reverse T-cell dysfunction. B, PD-L1 blockade on immune cells masks PD-1 ligation. PD-1 can bind PD-L2. C, ADCC from PD-L1 ligation on
tumor cells permits tumor cell killing. D, PD-L1 expression on T cells permits ADCC of immune cells overexpressing PD-L1.
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Combination PD-1 and PD-L1 Immunotherapy for Kidney Cancer
Table 2. Prospects and limitations of anti-PD-1 and anti-PD-L1 immunotherapies for combination therapy in RCC.
Targets T cells directly
Distinct metabolic and epigenetic changes upon PD-1
binding reverse T-cell exhaustion
Does not require tumor PD-L1 expression for activity
PD-1 occupancy on T cells observed within 3 weeks on
Targets tumor cells directly
May permit ADCC of tumor cells
May also target immunosuppressive TAMs that express PDL1 in the TME
and PD-1 on T cells provides some level of ongoing suppression. A
second theoretical concern involves binding to nontumor cell expressing isoforms of PD-L1, sequestering antibody that might be important
in blocking the PD-1/PD-L1 interaction. Accordingly, relevant data
suggest that PD-L1 expression on exosomes (56) and secreted variants
of PD-L1 (57) may suppress anti-PD-L1 responses. A final potential
mechanism of interest is that expression of PD-L1 on immune cells
might deplete immune effector cells through ADCC in certain circumstances (Fig. 2D, reviewed below).
Antibody Isotype Effects on Clinical
An underappreciated aspect of immune checkpoint blockade is
the relative contribution of T-cell–mediated tumor killing versus
the potential for ADCC or complement-dependent cytotoxicity. In
ADCC, FC gamma receptors (primarily FcgRIII) on the surface of
macrophages and NK cells bind to the Fc portion of antibodies
resulting in depletion of tumor or subsets of immune cells (Fig. 2C
and D). Specific IgG subtypes are more likely to promote ADCC,
with IgG1 and IgG3 antibody subtypes with a higher binding
affinity for Fc receptors (Supplementary Table S1; ref. 58). Thus,
anti-PD-L1 antibodies of the IgG1 isotype may lead to depletion of
both tumor and immune cells. Indeed, avelumab, an IgG1 isotype
antibody, can mediate ADCC and lead to effective direct tumor cell
killing. In theory, ADCC can also occur on PD-L1–positive CD8
effector cells leading to elimination of immune effectors. However,
no definitive evidence of the latter phenomena has been appreciated
clinically. Importantly, recently presented subgroup analysis from
the Javelin-101 showed no difference in activity of combination
avelumab plus axitinib treatment in patients with FcgRIII polymorphisms, demonstrating that ADCC may be only a minor
mechanism in anti-PD-L1 immunotherapy (59).
Ongoing efforts are focused on improving the efficiency of antibody-induced cellular cytotoxicity with immune checkpoint blockade
antibodies. Through modification of glycosylation and fucosylation
sites, antibodies can be engineered to have differential effects on ADCC
and cellular depletion (60). To promote ADCC, an Fc-modified (nonfucosylated version) of anti-CTLA-4 is in early-phase clinical trials
with the goal of regulatory T-cell depletion (NCT#03110107). Future
No direct tumor effects from antibody
In vitro VEGF TKIs increase PD-1 expression on immune cells providing a
potential resistance mechanism
Does not block PD-1 binding to PD-L2
PD-L1 exists on exosomes and in soluble forms which may act as a “decoy”
receptor for antibody therapy
VEGF TKI treatment permits PD-L1 upregulation on tumor cells providing a
potential resistance mechanism
Limited engagement of anti-PD-L1 with PD-L1þ tumor T cells allows for
continued T cell dysfunction
Potential for ADCC and elimination of PD-L1þ positive immune cells subsets
(NK cells, DCs, antitumor TAM)
Kinetics of PD-L1 occupancy are not yet defined and complete saturation to
block PD-1 ligation may not be possible
immunotherapy combination approaches may leverage the ability to
selectively deplete immunosuppressive cell subsets and potentiate
antitumor responses.
PD-1 Versus PD-L1 in Combination with
In RCC, the addition of a VEGF TKI to an anti-PD-1 or PD-L1
antibody exploits a number of potentially synergistic mechanisms.
VEGF in the tumor ecosystem promotes immunosuppression
by decreasing T-cell trafficking to tumors, increasing immunosuppressive cytokines and initially increasing regulatory T cells. Treatment with anti-angiogenic therapies mitigates a number of the
immunosuppressive effects of VEGF in preclinical models (61, 62).
For example, the use of sunitinib in a preclinical RCC model
decreases immunosuppressive myeloid-derived suppressor cells
(MDSC), a potential mechanism of adaptive immune resistance to
PD-1 immunotherapy (63). More recent preclinical data with
axitinib showed antitumor efficacy not only through vascular
remodeling but also through depletion of tumor-promoting mast
cells and tumor-associated macrophages (64). In human RCC
specimens, treatment with antiangiogenic therapy increased infiltration of CD4 and CD8 effector T cells, supporting the hypothesis
that VEGF inhibition might potentiate the response to immune
checkpoint blockade by promoting T-cell infiltration (65). Clearly,
the immune effects of VEGF TKIs support nonredundant mechanisms of immune activation distinct from the PD1/PD-L1 axis,
with TKI immune remodeling affecting the myeloid and T-cell
Although the MDSC-specific effects of TKIs provide a good rationale for combining anti-PD-L1 with VEGF therapy, there are
some data suggesting that VEGF TKIs may dampen a T-cell response
to cancer. Chronic inhibition of VEGF with TKIs can induce a hypoxic
state within the TME with a concomitant accumulation of HIF1a (66).
Multiple studies show that HIF1a accumulation induces a compensatory immunosuppressive state through recruitment of MDSCs (67),
tumor-associated macrophages (68, 69), and Tregs (70). In addition,
accumulation of HIF1a alters PD-L1 expression on immune
cell subsets (71). That observation is supported by data from human
RCC samples showing that TKIs may decrease PD-L1 expression,
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Aggen et al.
rendering anti-PD-L1 blockade more challenging. Of note, ontreatment biopsies from patients treated with pazopanib or sunitinib
showed transient decreases in PD-L1 expression by IHC (72).
In some model systems, VEGF TKIs also decrease immune cell PD1 expression (73). The decrease in PD-1 expression, however, is not
absolute, and blockade of remaining PD-1 on T cells with anti-PD-1
therapeutics may explain the improved OS noted with combination
anti-PD-1 with VEGF TKIs. Taken together, these collected observations lend support to a hypothesis that limited or intermittent VEGF
TKI therapy in combination regimens might allow an even greater
immune response, but at present all TKI combinations in the phase III
setting have been taken continuously. Further, HIF1 inhibition may be
a therapeutic approach to enhance the clinical benefit of VEGF TKIbased combinations.
Consensus First-Line Therapy
Approaches in Metastatic RCC
Both nivolumab plus ipilimumab and pembrolizumab plus axitinib
are now consensus first-line treatments for metastatic RCC. At present,
the choice of first-line therapy for a given patient is not driven by a
randomized, comparative trial, but rather by treatment side-effect
profile, prognostic risk group, perceived benefits of complete and
overall response rate and MD/patient preference. Avelumab plus
axitinib is also FDA approved for first-line RCC, but so far, an OS
benefit relative to sunitinib has not been documented. Finally, the FDA
application for drug approval of atezolizumab plus bevacizumab was
withdrawn by the manufacturer, although there may in fact be
subgroups of patients with specific gene signatures that benefit from
Table 3. On-going immunotherapy trials in RCC.
First-line metastatic RCC trials
Pembrolizumab þ Lenvatinib or Everolimus þ Lenvatinib vs. Sunitinib (CLEAR)
Nivolumab þ Ipilimumab Followed by Nivolumab Cabozantinib (PDIGREE)
Nivolumab þ Ipilimumab Cabozantinib (COSMIC-313)
Nivolumab þ Cabozantinib vs. Sunitinib
Nivolumab þ bempegaldesleukin (CD122 agonist) vs. Cabozantinib or Sunitinib
Nivolumab þ Ipilimumab vs. Nivo/IDO vs. Nivo/Anti-Lag3 (Relatlimab) vs.
Nivolumab þ CCR2/CCR5 dual agonist (BMS936558) FRACTION-RCC
Nivolumab þ Cabozantinib Ipilimumab
Nivolumab þ Ipilimumab or Pazopanib or Sunitinib (BIONIKK Biomarker Guided Trial)
Nivolumab with Salvage Nivolumab þ Ipilimumab
Nivolumab þ Bempegaldesleukin (CD122 agonist) Ipilimumab
Pembrolizumab þ Cabozantinib
Advanced (second-line or later) metastatic RCC trials
Arginase Inhibitor (INCB001158) þ Pembrolizumab
TLR 7/8 agonist (NKTR 262) þ bempegaldesleukin Nivolumab
Anti-CD73 (CPI-006) A2AR Antagonist or Pembrolizumab
Glutaminase Inhibitor (CB-839) þ Nivolumab
Anti-TIM3 (MBG453) Spartalizumab (Anti-PD1)
Durvalumab Tremelimumab or Savolitinib
ApoE Agonist (RGX104) þ Nivolumab
Anti-CSF1R (Cabiralizumab) þ Anti-CD40 (APX005M) Nivolumab
HIF-2a Inhibitor (PT2977) þ Cabozantinib
Axitinib þ Nivolumab
Sitravatinib þ Nivolumab
Angiopoietin-2 inhibitor (Trebananib) þ Pembrolizumab
Anti-IL1b (Gevokizumab) þ Cabozantinib
Guadecitabine þ Durvalumab
177Lu-J591 Anti-PSMA Radiolabeled Antibody
Anti-CD25 pyrrolobenzodiazepine toxin conjugate (Camidanlumab Tesirine)
IL-2 (Aldesleukin) þ Pembrolizumab
Perioperative (neoadjuvant RCC trials)
Nivolumab – PROSPER RCC
Royal Marsden
Avelumab þ Axitinib
Durvalumab Tremelimumab
Nivolumab þ Sitravatinib
Anti-IL1b (Canakinumab) þ Spartalizumab (anti-PD1)
Adjuvant RCC immunotherapy trials
Durvalumab vs. Durvalumab/Tremelimumab vs. Observation
Pembrolizumab vs. Observation
Nivolumab þ Ipilimumab vs. Observation
Atezolizumab vs. Observation
2092 Clin Cancer Res; 26(9) May 1, 2020
Trial ID
completion date
February 2021
September 2021
November 2021
May 2024
June 2024
January 2022
Early 2020
May 2020
February 2021
June 2021
June 2020
January 2020
December 2023
December 2023
Early 2020
Early 2020
Early 2020
Early 2020
October 2024
September 2022
April 2024
April 2023
August 2024
December 2023
December 2020
December 2019
July 2021
March 2021
November 2023
August 2020
Late 2019
August 2025
January 2020
December 2019
December 2037
December 2025
July 2023
April 2024
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Published OnlineFirst January 16, 2020; DOI: 10.1158/1078-0432.CCR-19-3323
Combination PD-1 and PD-L1 Immunotherapy for Kidney Cancer
this combination (74). Taken together, these data support the use of a
PD-1–based immunotherapy combination, either with pembrolizumab plus axitinib or nivolumab plus ipilimumab for first-line therapy
of metastatic RCC.
Future Combination Therapy
Approaches for Metastatic RCC
The impressive response rates and OS for patients treated with
combination anti-PD-1 plus anti-CTLA-4 or anti-PD-1 plus VEGF
TKI therapy with a favorable side-effect profile and tolerability begs the
question of utilizing a triplet therapy in the first-line setting (75).
Combination nivolumab, ipilimumab, and cabozantinib has been
administered safely across GU malignancies, and the activity of this
triplet will be tested in a phase II expansion cohort and a randomized,
phase III trial (76). Triplet therapy, however, likely over treats some
patients, such that biomarker-based strategies to select patients for the
appropriate mechanism and intensity of therapy is an unmet need.
One additional combination for first-line treatment, pembrolizumab
þ lenvatinib, is currently being tested in large phase III trials. Table 3
provides a complete listing of trials currently accruing for RCC.
A potential approach to mitigate the toxicities of I/O–I/O combinations is to incorporate other anti-inflammatory medications into the
first-line treatment regimens. To this end, clinical trials are on-going
exploring cytokine targets including anti-IL1b (NCT04028245), antiIL6, and anti-IL8 (NCT03400332; ref. 77) to augment the immune
response and potentially improve regimen tolerability. Another potential approach might be to block TNFa in the combination therapy
setting. A recent publication in animal models highlighted this
approach, demonstrating increased activity of combination immunotherapy when TNFa blockade was added to anti-PD-1 plus antiCTLA-4 (78). The wealth of treatment options available for RCC also
raises the questions of optimal therapeutic sequencing which will be
addressed in an upcoming trial (79). In contemporary cohorts of
patients with metastatic RCC, nearly 50% of patients will not receive a
second line treatment due to either disease progression or declining
performance status (80). In real-world data sets, it is estimated that
>80% of patients do not receive any second-line treatment (80, 81). As
a consequence, maximizing the efficacy of first-line therapy is of
utmost importance.
There are now three FDA-approved combination immunotherapies for the treatment of first-line kidney cancer, but only anti-PD1-based combinations to date have illustrated an OS benefit.
Blockade of PD-1 permits direct reprogramming of T cells, whereas
anti-PD-L1 exerts those effect in an indirect fashion and permits
binding between PD-1 and PD-L2. Although in contemporary
models, the activity of anti-PD-1 þ VEGF TKI appears to be
additive, the remarkable gains in ORR, PFS, and OS will likely
necessitate that anti-PD-1 therapeutics remain the backbone of
first-line treatment for renal cell carcinoma. For the foreseeable
future, the selection of first-line treatment will be guided by sideeffect profile, risk group, and patient preference, whereas the next
generation of first-line therapies may require clinically validated
biomarkers to select the appropriate treatment regimen.
Disclosure of Potential Conflicts of Interest
D.H. Aggen is a paid consultant for Boehringer Ingelheim. C.G. Drake is a paid
consultant for AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Merck, Novartis, and Pfizer, and reports receiving speakers bureau honoraria from Bristol-Myers
Squibb. B.I. Rini is a paid consultant for Pfizer, Merck, and Bristol-Myers Squibb, and
reports receiving commercial research grants from Pfizer, Merck, Roche, BristolMyers Squibb, and AstraZeneca. No other potential conflicts of interest were
Received October 9, 2019; revised December 6, 2019; accepted January 13, 2020;
published first January 16, 2020.
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Published OnlineFirst January 16, 2020; DOI: 10.1158/1078-0432.CCR-19-3323
Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer: Combination
Therapy in the First-Line Setting
David H. Aggen, Charles G. Drake and Brian I. Rini
Clin Cancer Res 2020;26:2087-2095. Published OnlineFirst January 16, 2020.
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