INTRODUCTION
Over the past decade, immunotherapy consolidated its role as one of the cornerstones
of cancer treatment, with unprecedented efficacy demonstrated across various clinical
settings. Distinct monoclonal antibodies targeting inhibitory coreceptors involved
in the modulation of the immune synapse have been approved by Brazilian health authorities,
including the anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) agent, ipilimumab; anti-programmed cell death receptor-1 (PD-1) agents, nivolumab, pembrolizumab, and cemiplimab; and anti-programmed- death ligand-1 (PD-L1) agents, atezolizumab, durvalumab, and avelumab. Clinical applications of
immunotherapy have significantly expanded as a result of the incorporation of these
agents into the management of patients with melanoma and other skin tumors, lung,
kidney, bladder, head and neck, breast, esophagus, and hematological malignancies,
among others. In addition, the use of these agents is no longer restricted to the
advanced/metastatic scenario, as recent approvals in the adjuvant setting have led
to the inclusion of these agents also at earlier stages. Besides the increased number
of available agents and indications, the enormous potential for combinatorial approaches
paved the way for an even greater expansion of indications in the coming years, with
some already incorporated into clinical practice, including ipilimumab/nivolumab,
atezolizumab/bevacizumab, pembrolizumab/axitinib, anti-PD-1 and anti-PD-L1/chemotherapy.
Along with response rates ranging from 10% to more than 50%
in different indications, the use of immune-checkpoint blockade yields the possibility
of lasting responses and long-term benefits.[1 ]-[5 ] In this context, knowledge of adverse events (AE) associated with this class of
drugs, their pathophysiological mechanisms and, above all, the proper management of
these AEs represent an essential skill for the oncologist, as well as for the team
involved in the care of patients with cancer.
In 2017, the “Brazilian guidelines for the management of immune-related toxicities
associated with checkpoint inhibitors” were issued by the Brazilian Society of Clinical
Oncology (SBOC), in its initial version.[6 ] In this article, we aimed to update general and specific aspects related to immune-related
adverse events (irAEs) associated with the use of immune-checkpoint inhibitors (ICIs),
including emerging evidences and updated algorithms for the most frequent clinical
manifestations. The purpose of this update is to review the evidence made available
since the original guideline was released, as well as to provide updated recommendations
for the management of irAE, thus promoting greater safety and increased chances of
therapeutic success for patients with cancer under treatment with ICIs.
Key aspects of the update
Objective: to update the “Brazilian guidelines for the management of immune-related toxicities
associated with checkpoint inhibitors” based upon a comprehensive literature review
encompassing the main studies addressing irAEs.
Incidence and presentation of irAEs: with the expansion of indications of ICIs, there has been an increasing number of
studies that aimed to determine the frequency of irAEs effects. Data from several
clinical trials and meta-analyses were included in order to better characterize the
incidence of irAEs, including emerging data on fatal and uncommon irAEs.
High-risk subgroups: evidence regarding the use of ICIs in groups of patients considered to be at increased
risk of irAEs has been updated, including patients with autoimmune disorders, those
receiving corticosteroids prior to the initiation of ICIs, patients with chronic viral
infections, older adults, and solid organ transplant recipients.
Re-exposure to immunotherapy: with greater understanding of adverse effects and their appropriate management, emerging
evidence has become available regarding the safety and efficacy of rechallenge following
treatment interruptions. Updated recommendations were defined to provide evidence
on treatment discontinuation and re-exposure to ICIs.
Specific adverse effects: recommendations for the management of frequent and relevant have been updated, with
new treatment algorithms for rare toxicities, including as cardiac, renal, hematological,
musculoskeletal/rheumatic, and neurological irAEs.
Overview of immune-related toxicities and pathophysiological mechanisms
General aspects and pathophysiological mechanisms of irAEs were previously published
in the first edition of the “Brazilian guidelines for the management of immune-related
toxicities associated with checkpoint inhibitors”.[6 ] Although the specific mechanisms underlying irAEs are not yet fully understood,
accumulated evidence suggests that the development of irAES is associated with the
disruption of immune coreceptors' role in the maintenance of immune homeostasis and
selftolerance. Different manifestations of irAEs reflect different pathophysiological
mechanisms including: 1. exacerbation of a subclinical autoimmune condition or upregulation
of pre-existing autoantibodies; 2. triggering of a new inflammatory or immune-related
condition resulting from the aberrant activation of autoreactive lymphocytes; 3. imbalance
in the local and systemic levels of cytokines, leading to an inflammatory and selfreactive
state; and 4. cytotoxic responses mediated by the interaction of monoclonal antibodies
with their target receptors (e.g., cytotoxic T-lymphocyteassociated protein 4
[CTLA-4] expressed by healthy tissues).[7 ] Data from translational studies suggest that irAEs usually develop through a combination
of these factors involving autoreactive T-lymphocytes, autoantibodies, and cytokine
production.[8 ] However, the magnitude to which each of these components contribute to the development
of irAEs remains poorly understood and may vary depending on the severity and profile
of the irAEs.
Incidence and presentation of irAEs
The incidence and kinetics of onset of irAE may be influenced by the type of monoclonal
antibodies used and regimen (combination vs monotherapy), the underlying malignancy
and patient's intrinsic risk factors. Immune-related AEs may occur at any time during
treatment, including the period after treatment discontinuation, and may range in
severity from mild to severe, and even life-threatening events. Available data on
irAEs are based primarily on toxicities documented in clinical trials and, more recently,
on the results of several meta-analyses dedicated to the study of such events and
reallife cohorts. Considering all grades and agents, the most common irAEs were fatigue
(18.26%), pruritus (10.61%), and diarrhea (9.47%). The most common grade ≥3 irAEs
are fatigue (0.89%), anemia (0.78%), and elevated aspartate aminotransferase (AST)
(0.75%). No statistically significant relationship between irAE rates and primary
cancer type has been identified to date, although the highest incidence of irAEs has
been described in patients with melanoma and the lowest in patients with lung cancer.[9 ] However, it is important acknowledge that the available evidence on the incidence
of such events may be limited by variations in the screening protocols used to detect
irAEs in each study and also in clinical practice, as such protocols dynamically evolve
with increasing knowledge about irAEs. In general, the rates of any grade and grade
≥3 irAEs associated with monotherapy with anti-PD-1/ PD-L1 agents (60-75% and 10-15%,
respectively) are lower than those associated with ipilimumab monotherapy, whose expected
rates of any grade and grade ≥3 irAEs, usually reported in the ranges of 75-80% and
20-25%, depending on the dose of anti-CTLA-4 used.[9 ]
[10 ]
Possible exceptions include specific endocrinopathies, such as thyroiditis/thyroid
dysfunction, which have been more frequently reported with anti-PD-1/PD-L1 administration.
A meta-analysis including patients from 19 randomized clinical trials compared the
rates of AEs related to anti-PD-1 versus anti-PD-L1 monoclonal antibodies. The incidence
of irAEs was similar between with anti-PD-1 and anti-PD-L1 agents (relative risk = 1.24;
95% confidence interval [CI] = 0.79-1.93), as was the incidence of irAEs leading to
death (relative risk = 1.38; 95% CI = 0.11-16.89).[11 ] On the other hand, combinatorial strategies such as nivolumab/ipilimumab are associated
with a significant increase in the incidence of toxicities (any grade: 95%; grade
3 or higher: 55%) and higher treatment discontinuation rates.[12 ]-[15 ] Combinations of ICI with other classes of antineoplastic agents, such as anti-angiogenic
drugs and/or chemotherapy, do not significantly increase the incidence of irAEs but
are associated with increased overall toxicity due to the addition of AEs from each
treatment class. Chemoimmunotherapy combinations, when compared to immunotherapy alone,
have a higher incidence of grade 3-4 AEs (relative risk =
1.32; 95% CI = 1.12-1.55), with no significant impact on mortality rates.[16 ]
Regarding the time to onset of irAEs, patients treated with ipilimumab usually experience
a new AE within the first 12 weeks of treatment and resolution in 6-8 weeks (approximately
7 weeks for grade 3-4 AEs), but 5-15% of patients may experience persistent irAEs
after 24 months, most of which grades 1-2.[17 ] Similarly, most irAEs associated with the use of antiPD-1/PD-L1 agents occur within
the first 4 months after initiating therapy; however, the interval to onset tends
to be shorter for combinations of anti-CTLA-4 and antiPD-1/PD-L1 drugs.[18 ] Combination treatments with chemotherapy or anti-angiogenic agents do not appear
to impact the onset, duration, or resolution of irAEs.[16 ]
[19 ]
The frequency of fatal irAEs was evaluated in a meta-analysis including more than
19,000 patients, which demonstrated a mortality rate of 0.36% with anti-PD-1 therapy,
0.38% with anti-PD-L1, 1.08% with anti-CTLA-4, and 1.23% with the combination of anti-PD-1/PD-L1
and anti- CTLA-4. Colitis is the most frequent cause of death following anti-CTLA-4
therapy. Pneumonitis, hepatitis, and neurological events are the main causes of death
associated with anti-PD-1/PD-L1 therapy. Colitis and myocarditis are the most frequent
causes of death due to irAEs in combination regimens, although we must acknowledge
that there may be an overlap of severe and potentially fatal AE from both types of
agents.[20 ] The onset of fatal AEs also appears to be early in most cases, with a median for
onset of 40 days with anti-PD-1/PD-L1 agents in monotherapy and less than 15 days
for those treated with the combination of ipilimumab and nivolumab.
A possible association between the development of irAEs and better treatment outcomes
in patients treated with ICI has been documented in different studies. Two recent
meta-analyses demonstrated a positive association between the development of low-grade
irAEs and response rates (RRs), progression-free survival (PFS), and overall survival
(OS) in patients treated with immunotherapy regardless of the primary site, immunotherapy
used, and irAEs. High-grade irAEs (grade 3 or higher) were associated with higher
RR but lower OS.[21 ]
[22 ] One of the challenges in confirming this association is the fact that patients who
achieve greater benefit from immunotherapy may eventually be exposed to therapies
for a longer period, inducing a bias related to the duration of exposure. However,
evidence of a true association between irAEs and better treatment outcomes is suggested
by the fact that, as previously mentioned, irAEs tend to occur in the first few months
of treatment and that this association persists after applying statistical methods
to minimize this bias.
Recommendations for irAEs screening
Before initiating therapy with ICIs, all patients should be assessed for susceptibility
to developing irAEs, as toxicity can potentially involve any organ or tissue. Subclinical
manifestations can make the diagnosis of irAE especially challenging for physicians.[23 ]
[24 ] Therefore, both patients and the multidisciplinary team must be aware of the potential
risks, thus allowing early identification of irAEs ([Figure 1 ]).[25 ]
[26 ]
It is recommended that all patients receiving ICIs be followed closely and carefully,
and undergo periodic evaluations, including detailed anamnesis and a physical examination
performed before each treatment administration. It is also recommended that laboratory
tests be performed before the initiation of treatment and repeated throughout treatment
as summarized in [Table 1 ].[27 ] The frequency of tests can be modified based on individual assessments, the occurrence
of AEs, and clinical suspicion. Nonetheless, no ideal screening strategy is unanimously
accepted as a standard of care and, consequently, many of the current routines have
been adapted from the clinical research protocols that led to the approval of these
agents.
Table 1
Laboratory testing recommended at baseline and during immune-checkpoint inhibitor
therapy (anti-CTLA-4 and/or anti-PD-1/PD-L1)
Frequency
Complete blood count (CBC/ blood clotting tests
Urea/ creatinine
Urinalysis/ urine protein test
Electrolyte tests (Na/K/Mg Ca)
AST ALT Bilirubin Alkaline phosphatase
Blood glucose
Amylase Lipase
TSH T4L
T3L
ACTH Basal cortisol test
FSH LH Testosterone (men)
HIV serology Hepatitis B and C serology[* ]
Before treatment
X
X
X[** ]
X
X
X
X[** ]
X
-
-
-
X
Each cycle
X
X
-
X
X
X
X[** ]
X[* ]
-
-
-
-
Special situations
-
-
If clinically indicated
-
-
-
If clinically indicated
-
If clinically indicated
If clinically indicated
If clinically indicated
If clinically indicated
* Every 3 to 6 weeks (alternating cycles, if the drug is administered every other week,
is acceptable), and less frequently after the 6th month of treatment;
** Optional testing (there are no precise recommendations on the best interval to perform
the test); #: Despite evidence suggesting the safety of treatment with ICIs in patients
with viral hepatitis or HIV infection, screening can be useful for patient monitoring,
evaluation of adverse events and differential diagnoses; CBC: Complete blood count;
ICIs: Immune-checkpoint inhibitors.
Figure 1 General approaches to minimize the impact of immune-related adverse events.
Recommendations for high-risk subgroups
Patients with a history of autoimmune disease are at increased risk of developing
an irAE or a “flare” of the underlying autoimmune condition, therefore requiring greater
attention and closer monitoring. As this is a very heterogeneous group, encompassing
a wide range of pathologies and severity of manifestations, individualizing treatment
is essential in the therapeutic decision-making process, and the benefit of each intervention
should be considered along with the risk of toxicity and exacerbation of the autoimmune
condition. Data showing the safety and efficacy of ICIs in patients with autoimmune
diseases are limited. Retrospective data suggest that patients with stable autoimmune
diseases may receive antiPD-1 therapy. Although the risk of irAEs is higher in this
population and that patients with preexisting autoimmune diseases may experience flares
when treated with both anti-CTLA-4 and anti-PD-1 agents, such exacerbations occur
at a rate of approximately 20 to 40%, and tend to be manageable, provided they are
immediately recognized and managed appropriately. In addition, the RRs in this subgroup
appear to be similar to those achieved in the general population.[28 ]-[31 ] However, the use of ICIs should be avoided in patients with severe active autoimmune
disease or those using high-dose corticosteroids or immunosuppressants since any additional
immune activation can be potentially life-threatening. Two ongoing clinical trials,
one on lung cancer (NCT03656627) and the other on several tumor types (NCT03816345),
are prospectively evaluating the use of ICIs in patients with underlying autoimmune
disease.
Regarding the use of corticosteroids, retrospective studies suggest that the use of
prednisone ≥10mg/ day or equivalent when initiating therapy with antiPD-1/PD-L1 is
associated with lower RR, PFS, and OS. A multivariate analysis adjusted for Eastern
Cooperative Oncology Group performance status, smoking, and presence of brain metastases
showed that corticosteroids were associated with worse survival.[32 ]
[33 ] Thus, caution is recommended when using corticosteroid therapy before the initiation
of ICIs until more robust evidence is available. Importantly, the use of corticosteroids
or immunosuppressants for the management of irAEs after the beginning of treatment
does not seem to affect the outcomes of patients receiving ICIs, although this is
still controversial. In an analysis of efficacy and safety of patients with advanced
melanoma and lung cancer who discontinued immunotherapy due to irAEs, the use of corticosteroids
was not associated with worse RR, PFS, or OS.[34 ]-[37 ]
Patients with chronic viral infections were excluded from most clinical trials to
date. However, the safety of ICI in patients with hepatitis B or C has been suggested
by an increasing number of case series demonstrating hepatotoxicity rates similar
to those seen in the general population.[38 ] Similarly, a phase I/II study evaluating the safety and efficacy of nivolumab in
patients with hepatocellular carcinoma showed an acceptable safety profile in patients
with chronic viral infection.[39 ]
Regarding patients with HIV infection, a systematic review identified 73 patients
treated with ICIs. In patients with melanoma and lung cancer the effectiveness was
similar between patients with or without HIV infection, with RRs of 27% and 30%, respectively.
Patients living with HIV did not show an increased incidence of AEs, and the viral
load remained undetectable in 93% (26 of 28) of the patients who did not have a detectable
viral load prior to treatment initiation.[40 ]
Thus, treatment of patients with chronic viral infection with ICI appears to be safe,
although close and multidisciplinary follow-up are of paramount importance.
Multidisciplinary management is also important in the complex setting of patients
with a history of solid organ transplantation being considered for treatment with
ICI. Safety and efficacy data are even more scarce in this population and limited
to a small number of case reports or case series. Despite reports about safe administration
of these agents in selected cases, recent case series suggested that the risk of rejection
can exceed 40%, leading to mortality rates as high as 40-50%, depending on the organ
transplanted.[41 ]
[42 ] Thus, therapeutic decisions involving the use of ICIs in solid organ transplant
recipients should always be shared with the patients and other teams involved in their
care and take into consideration the risk of transplant rejection, potential benefits
from ICI therapy, and available therapeutic alternatives.
Regarding the indication of ICI for elderly patients, age alone should not be a contraindication
to this therapeutic approach. Despite being underrepresented in randomized controlled
trials, subgroups analyses in prospective and retrospective studies suggested that
the efficacy and safety of immunotherapy in the older adults are similar to that of
general population.[43 ]
[44 ] Importantly, factors such as comorbidities and potential drug interactions should
be carefully considered in this population. Geriatric and frailty assessments are
important predictors of irAEs and worsening quality of life, and both are recommended
in this subgroup.[45 ]
Early approach to irAEs: overview
Early symptom recognition and rapid intervention remain critical factors in the management
irAEs. In the initial evaluation, the exclusion of differential diagnoses (such as
infections) is essential. Invasive procedures for obtaining tissue samples (bronchoscopy,
endoscopy, skin biopsies, etc.) are frequently indicated. The temporary discontinuation
of ICIs is often necessary, and the use of corticosteroids and symptomatic therapy
remain the pillars of irAEs management. The use of corticosteroids to control irAEs
does not seem to affect the efficacy of cancer treatment,[13 ]
[24 ]
[34 ] and the definitive discontinuation of immunotherapy is still indicated in severe
cases.
Permanent discontinuation is usually not required for endocrine toxicities such as
glandular dysfunction (even grade 4) provided that adequate hormonal replacement is
initiated and the patient's clinical condition is stable. For patients with severe
AEs that are refractory to oral or intravenous corticosteroid therapy, subsequent
lines of treatment include monoclonal antibodies such as infliximab, rituximab, or
tocilizumab (among others), mycophenolate mofetil, or other immunosuppressants (such
as azathioprine and cyclosporine), particularly if no improvement is seen after 3-5
days of intravenous corticosteroid therapy. In selected cases, particularly those
with neurological or hematological complications, plasmapheresis or intravenous immunoglobulin
are therapeutic alternatives. It should be noted that the early recognition of refractory
cases and the timely introduction of the appropriate therapy (corticosteroids, usually
in addition to other treatments, when indicated) are crucial to the management of
irAEs. In these situations, or even in cases of lower grade events, an evaluation
by a specialist (such as endocrinologist or gastroenterologist) is encouraged, preferably
a specialist who is familiar with the management of irAEs. Corticosteroids should
be slowly tapered after adequate improvement of the irAE is achieved, usually over
4 weeks, with the possibility of extension for 6-8 weeks or longer in cases of pulmonary
or hepatic irAEs.
Patients treated with corticosteroids and/or immunosuppressive agents are at risk
for opportunistic infections and tuberculosis reactivation, and, when appropriate,
should receive antimicrobial prophylaxis as well as be monitored for signs of infectious
conditions. The initial approach and management of irAEs are summarized in [Figure 2 ]. The doses of the drugs more commonly used in this clinical setting are described
in [Appendix 1 ].
Evaluation after discontinuation and rechallenging of immunotherapy
Figure 2 Simplified algorithm: initial approach and management of immune- related adverse
events. irAEs: Imune-related adverse events; *According to CTCAE v. 4; #: Persistent
grade 2 toxicities may require approaches similar to grade 3-4 irAEs; §: If cutaneous
or endocrine irAES, treatment may be continued.
With greater access to immunotherapy and better understanding and management of irAEs,
the possibility of rechallenging with new exposure to ICI after temporary discontinuation
is increasingly frequent. Prospective data from randomized controlled trials supporting
this strategy are scarce because most prospective studies used management algorithms
that established permanent discontinuation of treatment for severe irAEs. In a cohort
of 93 patients treated with anti-PD-1/PD-L1 who had grade 2 or higher irAEs, 40 were
re-exposed to the same agent, 55% of which had a recurrence of one or more irAEs.
There was no increase in irAE severity on re-exposure, and approximately 20% of patients
developed different types of irAE from the previous ones.[46 ] These data are in line with those of other previously published cohorts[47 ] and suggest that rechallenge with anti-PD-1/PD-L1 agents can be considered with
proper monitoring.
Recommendations regarding the discontinuation of immunotherapy and rechallenging are
summarized in [Table 2 ]. It should be noted that irAEs may have late onset, even after the discontinuation
of the immunotherapy; therefore, monitoring for these adverse effects should be continuous,[48 ] and re-evaluations of toxicity (anamnesis, physical examination, and laboratory
tests) after the discontinuation of treatment are suggested every 3-4 months in the
first year and every 6 months thereafter.[12 ]
[48 ]
[49 ]
Selected AEs
Gastrointestinal irAEs
Gastrointestinal events may present as diarrhea, abdominal cramps, hemorrhage, and
urgency. Other manifestations include pancreatitis, cholangitis, and enteritis. Although
the time for the onset of diarrhea/
colitis varies, this toxicity usually arises from the sixth to the eighth week after
the beginning of ipilimumab (or its combinations) or 3-6 months after the initiation
of anti-PD-1/PD-L1 agents.[50 ]
[51 ]
The incidence of diarrhea appears to be dose-dependent in patients receiving anti-CTLA-4
therapy. Patients receiving a combination of anti-CTLA-4 and anti-PD-1/PD-L1 are at
a higher risk of developing this adverse event.[15 ]
Clinical management is based on symptom severity ([Appendix 1 ], Supplementary Material). For patients who do not respond to corticosteroid therapy
within 3-5 days, the use of infliximab or vedolizumab is indicated. Early use of immunosuppressants
is associated with better clinical outcomes in patients developing colitis. It is
important to emphasize that infliximab should not be used in cases of sepsis or in
patients with a suspected or confirmed intestinal perforation; thus, laboratory tests
and stool tests (culture, stool ova and parasite test, Clostridium difficile , cytomegalovirus, or other viral etiologies) must be performed. Improvement in symptoms
following infliximab usually occurs within 1-3 days, and its administration may be
repeated after 2 weeks if necessary.[52 ]
[53 ]
Vedolizumab, an anti-integrin agent, was recently compared to infliximab in a single-center
retrospective cohort including 150 patients. Vedolizumab was associated with clinical
rates of diarrhea remission similar to those obtained with infliximab but with a lower
rate of gastrointestinal AE recurrence. Interestingly, patients who received vedolizumab
also had better cancer outcomes, with higher PFS and OS than those who received infliximab.[54 ]
Despite the limitation of being a retrospective study and requiring prospective validation,
the use of vedolizumab in this clinical setting should be considered.
Colonoscopy is recommended for patients with persistent grade 2 or severe diarrhea.
Endoscopic findings such as ulcerations or pancolitis are associated with a lower
likelihood of response to corticosteroids alone, so the addition of immunosuppressants
such as infliximab, vedolizumab, or mycophenolate is often required.[52 ]
[55 ] No prophylactic treatment for diarrhea induced by these ICI is currently validated.
The clinical impact of elevations in lipase and amylase levels remains uncertain,
and ordering laboratory tests to determine their levels in asymptomatic patients is
questionable because a discontinuation of therapy is not usually recommended based
on these laboratory findings alone.[56 ]
However, in symptomatic patients with elevated pancreatic enzymes, additional laboratory
and radiologic workup are recommended in addition to a thorough clinical examination
to exclude pancreatitis.[24 ]
Hepatic irAEs
The estimated incidence of hepatic irAEs is low, occurring in about 2-7% of patients
treated with anti-PD-1/PD-L1 or anti-CTLA-4 alone, and the most common presentation
is asymptomatic elevation of liver tests, such as aspartate aminotransferase, alanine
aminotransferase, gamma- glutamyl transferase, or bilirubin.[14 ]
[15 ]
[17 ]
[57 ] However, there is a significant increase in the risk of hepatic AEs when dual immune
checkpoint blockade is used (any grade,
15-30%; grades 3/4, 6.0-18.8%).[15 ]
[57 ] The initial presentation with acute liver failure is rare and the onset of symptoms
typically occurs between 4-12 weeks.[58 ] Treatmentrelated liver toxicity is usually the diagnosis of exclusion, and viral
and cancer- related causes for liver abnormalities should be ruled out. Unlike autoimmune
hepatitis, hepatotoxicity caused by immunotherapy is not predominant in women. Antinuclear
antibody (ANA) may be present in up to 50% of patients, usually at low titers (1:80),
whereas anti-smooth muscle antibody (SMA) test results are rarely positive. Liver
biopsy shows no or few plasma cells and fewer CD20+ and CD4+ lymphocytes when compared
with autoimmune hepatitis.[58 ]
Table 2
Recommendations for treatment discontinuation and rechallenge
Permanent discontinuation
ICI rechallenge
Grade 4 toxicity (potentially fatal)[* ] Recurrent grade 3 toxicity. Specific grade 3 toxicity (pneumonitis, hepatitis, nephritis).
Grade 2 toxicity without resolution after 3 months of proper treatment. Specific grade
2 toxicity (cardiac, neurological)
Previous toxicity, currently if recover to Grade 1 or less Corticosteroid <10mg/day
of prednisone or equivalent. No other immunosuppressant is needed.
* Exception to grade 4 endocrine toxicity adequately controlled with hormone replacement
alone.
The management of hepatotoxicity includes the use of systemic corticosteroids and,
in more severe cases, other immunosuppressants such as mycophenolate mofetil ([Appendix 2 ], Supplementary Material).
Infliximab is contraindicated because of the intrinsic potential for hepatic toxicity.
The added value of performing liver biopsy remains controversial, and is based on
expert recommendations. Liver biopsy can be considered in patients with low risk of
bleeding and in corticosteroid-refractory cases, concomitant use of other hepatotoxic
medications or suspected liver metastases. The main limitation of liver biopsy, in
addition to its cost and being an invasive procedure, is the fact that there are no
pathognomonic histological findings and that, in most cases, the biopsy does not change
the management of this irAE.[59 ]
Pulmonary irAEs
Although pulmonary toxicity is relatively uncommon, it is a potentially life-threatening
event and should be considered in patients with new onset of respiratory symptoms.[12 ]
[49 ] Of note, real-world data suggest that the incidence of pneumonitis is higher than
that reported in clinical trials, and as high as 8-19% in patients with non-small
cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 agents.[60 ]
[61 ] Also, pneumonitis is the most common fatal irAE, representing about 35% of the causes
of death due to the use of anti-PD-1/PD-L1.[20 ]
Retrospective and post hoc analyses suggest that patients previously exposed to chest
radiotherapy may be at increased risk for pneumonitis and radiation recall and, therefore,
require closer surveillance. In KEYNOTE-001 trial evaluating pembrolizumab in patients
with NSCLC, the incidence of pneumonitis was numerically higher in the patients who
had received previous thoracic radiotherapy versus those with no previous thoracic
radiotherapy (8% vs. 1%; p =0.15).[62 ] However, in the PACIFIC study, which evaluated the addition of durvalumab after
chemoradiotherapy in patients with stage III NSCLC, the use of immunotherapy numerically
increased the risk of pneumonitis, radiotherapy- induced pneumonitis, or any grade
pneumonia but did not increase the risk of grade 3-4 pneumonitis (3.4% vs. 2.6%, respectively).[63 ]
Pneumonitis treatment must be adapted to the severity of the condition ([Appendix 3 ], Supplementary Material). In this population, the concomitant use of empirical antibiotic
therapy is frequent. Nevertheless, the exclusion of differential diagnoses using tests
such as bronchoscopy or lung biopsy should be considered when the diagnosis is uncertain.
Cutaneous irAEs
Dermatologic toxicities, including pruritus, xeroderma, rash, psoriasiform lesions,
and lichenoids, are the most common irAEs in patients treated with ICIs. They are
more common in patients treated with anti-CTLA-4 agents and combination regimens.
Although most cases are grade 1 or 2, serious events may occur, such as toxic epidermal
necrolysis or Stevens-Johnson syndrome. Psoriasiform lesions and maculopapular eruptions
are often the irAEs of earliest onset, with a median manifestation of 2-5 weeks after
the initiation of therapy.[64 ]
On the other hand, lichenoid dermatoses, bullous (bullous pemphigoid), and hypopigmentation/
depigmentation vitiligo-like lesions tend to have later onset.[64 ] A higher incidence of cutaneous irAEs is observed in patients with advanced melanoma
than other neoplasms, particularly vitiligo-like changes, which are strongly associated
with higher PFS and OS.[13 ]
[48 ]
The management of cutaneous irAEs follows the same principles recommended for other
irAEs. Consultation with a dermatologist is often recommended, with a low threshold
for skin biopsies ([Appendix 4 ], Supplementary Material). Most cases can be managed using topical steroids combined
or not with antihistamines, and ICI treatment usually does not need to be discontinued.
For patients with pruritus, the use of GABA receptor agonists, such as pregabalin
or gabapentin, or the NK-1 receptor antagonist aprepitant may be considered. In refractory
or severe cases, a skin biopsy is crucial, and strategies such as systemic corticosteroid
therapy, immunosuppressants, or monoclonal antibodies may also be necessary for therapeutic
management.[65 ]
Endocrine irAEs
Endocrine irAEs are diagnosed in up to 10% of patients treated with ICIs. A high level
of suspicion is recommended, since the symptoms may be nonspecific.[66 ]
The onset of endocrine irAEs usually occurs at between the 4th
and the 18th weeks of treatment (median: 11 weeks), but late manifestations can also occur.[67 ] A meta-analysis of 38 randomized controlled trials compared the incidence of endocrine
irAEs resulting from different immunotherapies. Patients who received a combination
of anti-PD-1/ PD-L1 and anti-CTLA-4 had a higher incidence of thyroid dysfunction
than those who treated only with ipilimumab. Comparisons between anti-PD-1 and ipilimumab
as monotherapies demonstrated that the use of anti-PD-1 was more likely to induce
hypothyroidism, while the use of ipilimumab was associated with a higher incidence
of hypophysitis. Other endocrine irAEs, including primary adrenal insufficiency and
insulin-dependent diabetes mellitus, were uncommon and occurred in 0.7% and 0.2% of
patients, respectively.[66 ] In patients receiving ICIs and presenting with hypotension/shock, nausea, vomiting,
and mental confusion, the possibility of an adrenal crisis must be ruled out, although
it is an extremely unusual event. The approach and management of the most common endocrine
irAEs are summarized in [Appendix 5 ] (Supplementary Material). It is worth mentioning that the use of corticosteroids,
except for hormone replacement, is controversial in cases of endocrine toxicity and
usually not recommended (except for the control of local symptoms/mass effects).
Conditions affecting the thyroid, such as hypothyroidism, hyperthyroidism, or symptomatic
thyroiditis can occur, although the latter presentation is uncommon. Hypothyroidism
with the use of ICIs occurs in approximately 6.6%
of patients, with the lowest incidence (3.8%) reported with ipilimumab and the highest
incidence (13.2%) reported with combination therapies.
The risk of hyperthyroidism, but not hypothyroidism, appears to be greater with the
use of anti-PD-1 than with anti-PD-L1 (odds ratio [OR] = 5.36;
p =0.002), and it is often temporary.[66 ] Thyroid function tests should be monitored before each dose or monthly and then
every 6-12 weeks for 6 months after the completion of treatment. The median onset
of thyroid dysfunction was 4 weeks after the initiation of immunotherapy.[68 ] The recommended treatment is the standard: hormone replacement or antithyroid drugs
in selected cases.
Pituitary dysfunction is among the most commonly reported endocrine irAEs. The greatest
incidence occurs with anti-CTLA-4 agents and combined regimens. The incidence is dose-dependent
(1.0-4.0% with ipilimumab 3mg/kg and 16%
with ipilimumab 10mg/kg). It is a rare event with the use of anti-PD-1 monotherapy
(0.4%).[66 ]
Adrenal insufficiency is usually permanent and requires continuous hormone replacement.
It presents as high levels of adrenocorticotropin hormone in the presence of low cortisol,
differentiating it from hypophysitis. If adrenal insufficiency and hypothyroidism
are both present, corticosteroids should be started before thyroid hormone replacement
is administered due to the risk of adrenal crisis. Sepsis, for which broad- spectrum
empirical antibiotic therapy is usually required, should always be investigated.[69 ]
Autoimmune (type 1) diabetes is a rare event reported in approximately 0.4-0.9% of
patients using anti-PD-1 agents. Fasting blood glucose is the preferred test for patient
follow-up and surveillance. Importantly, the use of high-dose corticosteroids for
the treatment of other irAEs can induce or exacerbate hyperglycemia. Diabetic ketoacidosis
may occur, even in patients with a previous diagnosis of type 2 diabetes and may present
with symptoms such as increased thirst, pollakiuria, nausea, vomiting, mental confusion,
abdominal pain, and dehydration. Corticosteroid therapy is not recommended for the
treatment of type 1 diabetes since there is no evidence to support its use and it
may further worsen glycemic control.[69 ]
[70 ]
Regardless of the presentation of endocrine irAEs, the permanent discontinuation of
treatment is rarely recommended if hormone replacement therapy is initiated and the
symptoms resolve. Follow-up by an endocrinologist is recommended.
Uncommon irAEs
As previously discussed, irAEs presentations are extremely heterogeneous and any organ/tissue
could theoretically be the target of an immunemediated injury. With the expansion
of the use of immune coreceptor blockers, greater knowledge about rare irAEs has been
acquired.
Cardiac irAEs
Cardiac irAEs, including myocarditis, pericarditis, cardiac fibrosis, arrhythmias,
and heart failure, can occur even in patients without significant risk factors, and
are associated a high mortality rate.
The time to onset of these events is variable, and may occur after a single dose of
immunotherapy. Patients receiving combination therapies appear to be at an increased
risk for these AEs, followed by patients receiving anti-PD-
1 monotherapy.[71 ] The role of cardiac enzymes monitoring remains uncertain, despite being included
in more recent research protocols in addition to periodic echocardiography or other
imaging tests. The treatment of cardiac irAEs should be adapted according to the severity
of the clinical presentation ([Appendix 6 ], Supplementary Material). Permanent discontinuation of therapy is recommended, with
the initiation of high-dose corticosteroids (prednisone 1-2mg/kg). The timing of the
initiation of corticosteroid therapy in mild cases should be individualized considering
the lack of data in this setting. In refractory patients, doses of corticosteroids
similar to those used in cases of heart transplant rejection are usually indicated
(1g of methylprednisolone per day, for 3 to 5 days) in addition to the addition of
mycophenolate or infliximab.[72 ]
Hematologic irAEs
Hematological irAEs are rare, although a myriad of manifestations has been described.
An analysis of the World Health Organization pharmacovigilance database identified
168 cases of hematological irAEs. The most common cases were immune thrombocytopenic
purpura (68 cases) and hemolytic anemia (57 cases), including four cases in which
both conditions occurred concurrently.[73 ]
The incidence of anemia and thrombocytopenia appears to be higher in patients treated
with ICIs for refractory Hodgkin's disease, which may be partly related to the previous
use of myelotoxic therapies.[74 ] The treatment of hematological irAEs must be adapted to the condition's severity
([Appendix 7 ], Supplementary Material). In steroid-refractory presentations, a bone marrow biopsy
should be considered. In addition to the usual approaches, management of hematological
irAEs may also include transfusion support, rituximab, and plasmapheresis. Ruling
out alternative diagnoses for hematological conditions is of paramount importance,
and possible causes include disease progression, bone marrow infiltration, bleeding,
and AEs of other drugs.
Neurologic irAEs
Approximately 14% of patients using ipilimumab plus nivolumab may develop neurological
irAEs, a significantly higher incidence than with anti-CTLA-4 or anti-PD-1 monotherapy,
which have an incidence of 1% and 3%, respectively. Guillain-Barré syndrome, myasthenia
gravis, aseptic meningitis, limbic encephalitis, transverse myelitis, reversible posterior
encephalopathy syndrome, enteric neuropathy, granulomatous inflammation of the central
nervous system, and Tolosa-Hunt syndrome have been reported. Severe cases of limbic
encephalitis were reported in patients with small cell lung cancer.
Neurological paraneoplastic syndromes or autoimmune encephalitis can be exacerbated
or revealed by the immune stimuli triggered by immunotherapy. Thus, tumors with a
greater propensity to develop neurological paraneoplastic syndromes, such as small
cell lung carcinoma and Merkel carcinoma, must be monitored with special attention
to the possibility of neurological irAEs.[75 ]-[77 ]
The management of neurologic irAEs is similar to that for other irAEs (Appendix 8,
Supplementary Material). In patients whose symptoms are suggestive of neurological
irAEs, corticosteroid therapy and discontinuation of immunotherapy should be considered,
even in mild presentations. Intravenous immunoglobulin and plasmapheresis may be considered
in addition to corticosteroids and immunosuppressants. Pyridostigmine may be considered
for patients with myasthenia gravis. Approximately one-third of patients with neurological
irAEs have residual sequelae.[77 ] Pre-existing neurological conditions should not contraindicate treatment; however,
individual risks should be evaluated before the use of ICIs.[78 ]
Rheumatic irAEs
The most common musculoskeletal and rheumatological symptoms are arthritis and polymyalgia,
but their incidence has not been precisely established, which reflects the difficulty
distinguishing between irAEs and musculoskeletal symptoms caused by other factors.
Arthralgias without clear inflammatory signs can also significantly impact quality
of life and require specific procedures. A meta-analysis that included clinical trials,
observational studies, and case reports or case series reported an incidence of arthralgia
of 1.0-43% and myalgia of 2.0-20%, showing a significant variability between reported
symptoms and diagnosed rheumatological irAEs. Anti-PD-1 therapy is more commonly associated
with rheumatologic irAEs. Myositis, although rare, can be fatal and present as a reactivation
of preexisting paraneoplastic polymyositis or dermatomyositis.
Depending upon the clinical manifestation, mild cases can be managed with anti-inflammatory
drugs, and in case of treatment failure, corticosteroids should be initiated. Disease-modifying
antirheumatic drugs (DMARDs) and even plasmapheresis may be used in steroid-refractory
patients, in addition to other rheumatological monoclonal antibodies commonly used
for autoimmune conditions.[79 ]-[82 ] The approach to rheumatological irAEs must be adapted according with the event's
severity ([Appendix 9 ], Supplementary Material). In a cohort of 65 patients, predominantly composed of
patients with lung cancer and melanoma who developed musculoskeletal symptoms, an
algorithm for the management of irAEs led to symptom control in 54.4% of patients
using prednisone 10 mg associated or not with non-steroidal anti-inflammatories (NSAIDs),
and 12.3% required the use of DMARDs.
Treatment was discontinued in 8.8% of cases and, as demonstrated in other immune-mediated
toxicities, complete disease remission in patients with melanoma was observed in 39%
of patients with rheumatologic irAEs, compared to 4% of patients without irAEs.[83 ]
Renal irAEs
Although initially characterized as rare (3.0-5.0% of patients), any renal grade irAEs
may occur in 1520% of patients treated with ICIs. Acute interstitial nephritis is
the most common finding in renal biopsies. Renal toxicities have an earlier onset
with combined regimens (2-3 months) than with antiPD-1 monotherapy (3-10 months).
In particular, patients being treated with platinum, pemetrexed, and pembrolizumab
combination regimen should be closely monitored due to an increased risk of renal
toxicity. The treatment of renal AEs should be tailored to the severity of the irAE
(Appendix 10, Supplementary Material).
Ophthalmic irAEs
Ocular irAEs include uveitis, episcleritis, and conjunctivitis.[84 ] In a pharmacovigilance database, ophthalmic events were rare, representing up to
3% of all irAEs reported, with visual disorders (30.8%) and uveitis (15%) being the
most common events. The combination of anti-CTLA-4 and anti-PD-1 results in the greatest
risk for the development of uveitis (OR=4.77; 95%CI=3.835.94). Regarding tumor types,
patients diagnosed with melanoma (OR=14.7;
95%CI=10.7-20.2) appear to be at higher risk of developing uveitis than those with
lung cancer (OR=2.67; 95%CI=1.68-4.23).[85 ]
