anisms that go beyond historically standard of care targeted
therapeutics inhibiting such signaling as vascular
endothelial growth factor (VEGF) or the mammalian target
of rapamycin (mTOR) pathway. Multiple mechanisms
evolve during tumorigenesis including systemic dysfunction
in T cell signaling and exploitation of immune
checkpoints.6-11 These mechanisms help tumors evade
specific immune responses despite the presentation of
tumor antigens to the immune system.12 Further elucidation
of these immune evasive mechanisms in the hosttumor
immune environment led to the development of
novel antibodies directed against immune checkpoint
proteins.13,14
Few agents have ushered in as much excitement as
that seen with FDA approval of the novel human immunoglobulin
G4 programmed death (PD-1) ICI that selectively
blocks the interaction between PD-1 and its
ligands PD-L1 and PD-L2.15 By blocking this negative regulator
on T cells, the first drug approved in this class,
nivolumab, ostensibly inhibits events that normally lead
to downregulation of a cellular immune response. The
important message from early phase clinical trials is that
nivolumab can enhance T-cell function and thus, result
in antitumor activity.16 The pivotal study demonstrated
benefits in progression-free survival, overall response rate
and overall survival, supporting the use of nivolumab as
monotherapy to restore T-cell immune activity in patients
with RCC.17
Although the precise pathophysiology underlying immune
related adverse effects is still unknown, various hypotheses
help delineate some potential mechanisms.
These adverse events may be related to the role that ICI
agents play in maintaining immunologic homeostasis. As
this connection has been explored, a better understanding
has emerged concerning the way in which unique
checkpoint blocks down regulate immunity.4 There are
some clear-cut distinctions proposed. For example the
checkpoint protein CTLA-4 is upregulated in the periphery
during immune priming.18 It is expected that varying
ir-AE arising from PD-1 blockade vs CTLA-4 blockade
might be related to timing or sight of action, for example,
PD-1 blockade is generally believed to inhibit T cells at
the site of the tumor.19,20 Additionally, mice lacking PD-
1 have variable autoimmunity including arthritis and cardiomyopathy.
21,22 The pathophysiology of ir-AE remains
highly controversial and we are only beginning to understand
why the effects of anti-CTLA-4 or anti-PD-1
blockade differ from one another in severity, timing, and
preponderance of specific ir-AE. This review will focus on
practical aspects and implications for managing ir-AE,
particularly in the setting of expanding FDA approval of
ICI in patients with RCC.
Spectrum of Therapy and Epidemiology
of Immune Related Adverse Events
Since 2011, beginning with the approval of the CTLA-4
antibody ipilimumab in melanoma, there has been an influx
into the market of drugs targeting both pathways including
44 Kidney Cancer Journal
the PD-1/PD-L1 inhibitors: nivolumab, pembrolizumab,
atezolizumab, durvalumab, and avelumab as
well as the CTLA-4 inhibitor ipilimumab. There are many
more in development.23 The incidence of any grade ir-AE
in clinical trials is reportedly as low as 15% to as high as
90%, and toxicities range from mild requiring treatment
with topical cream to severe enough that drug discontinuation
and the initiation of systemic immunosuppressive
medications occur 10–55% of the time.24,25
The reason for this huge variability may be due to the
lack of agreed upon uniform definitions as to what constitutes
a particular ir-AE, although recently there have
been attempts to standardize grading and criteria for ir-
AE.26-28 Possible underreporting of toxicities within clinical
trials may also lead to heterogeneity in the reported
incidence of these adverse events.29 While the spectrum
and rate of various ir-AE is different between PD-1/PD-L1
inhibitors and CTLA4 inhibitors, trials are increasingly
investigating the potential of using these drugs in combination,
which has been shown to be more toxic than
targeting either pathway alone.30,31 While there are many
combination regimens being tested in mRCC, the combination
of two uniquely targeting immunotherapy
agents or combination of an anti-VEGF agent with an immunotherapy
agent have recently been reported.31-33 Results
from the CheckMate 214 trial showed that overall
survival and objective response rates were significantly
higher with the combination of nivolumab and ipilimumab
vs sunitinib (risk of death was 37% lower with
nivolumab and ipilimumab and objective response rate
was 42% vs 27%). CheckMate214 also provided a detailed
analysis of the safety profile of this combination (nivolumab
and ipilimumab), now part of the first-line treatment
algorithm in intermediate- and poor-risk patients
with previously untreated RCC.31 The safety profile of
nivolumab plus ipilimumab was consistent with that in
previous studies in multiple tumor types, including advanced
RCC with a lower incidence of grade 3 and 4 treatment
related adverse events than observed with suniti=
nib. The frequencies of treatment-related gastrointestinal,
skin, and hepatic adverse events were lower than those
seen in a trial involving patients with melanoma, in
which a higher dose of ipilimumab (3 mg per kilogram)
and a lower dose of nivolumab (1 mg per kilogram) were
used.34 Patients in CheckMate214 reported better healthrelated
quality of life, as measured by the FKSI-19, with
nivolumab plus ipilimumab than with sunitinib. Dose delays,
treatment with glucocorticoids, and prompt diagnostic
workup to rule out noninflammatory causes were
used to manage toxic effects according to management
algorithms developed for immuno-oncology treatmentrelated
adverse events.27 Therefore, recognizing and treating
ir-AE promptly is of paramount importance.
Mapping Immune Related Adverse Events
by Organ System Involvement
New guidelines have been issued by groups like the European
Society of Medical Oncology (ESMO), the Ameri