Cancer Treatment Reviews 57 (2017) 36–49

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Cancer Treatment Reviews

journal homepage: www.elsevierhealth.com/journals/ctrv

Complications of Treatment

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4):

Evaluation and management of adverse drug reactions
Jessica C. Hassel a,1, Lucie Heinzerling b,1, Jens Aberle c, Oliver Bähr d, Thomas K. Eigentler e,
Marc-Oliver Grimm f, Victor Grünwald g, Jan Leipe h, Niels Reinmuth i, Julia K. Tietze j, Jörg Trojan k,
Lisa Zimmer l, Ralf Gutzmer m,⇑
a
Department of Dermatology, University Hospital Heidelberg, Germany
b
Center for Internal Medicine, University Hospital Erlangen, Germany
c
Department of Internal Medicine III, University Hospital Hamburg Eppendorf, Germany
d
Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany
e
Department of Dermatology, Center for Dermatooncology, University Medical Center Tübingen, Germany
f
Department for Urology, University Hospital Jena, Germany
g
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany
h
Division of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik IV, University of Munich, Germany
i
Department of Thoracic Oncology, Asklepios Fachkliniken München-Gauting, Germany
j
Department of Dermatology and Allergy, University Hospital Munich, Munich, Germany
k
Division of Gastroenterology, Department of Internal Medicine, Goethe University Hospital, Frankfurt, Germany
l
Department of Dermatology, University Hospital University, Essen-Duisburg, Germany
m
Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Background: Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in
Received 10 March 2017 numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in
Received in revised form 5 May 2017 advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must
Accepted 6 May 2017
be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in
diagnosis and management might result in symptom worsening and further complications, clinicians
shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews
Keywords:
safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and pro-
Immunotherapy
PD-1, CTLA-4
vides a literature overview on published case reports for rare ADR with suspected potential underreport-
Nivolumab ing. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation
Ipilimumab and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically
Adverse drug reaction important side effects arising from combined ICB.
Background: Pooled safety data from 1551 patients with advanced melanoma, treated either with
3 mg/kg ipilimumab plus 1 mg/kg nivolumab (N = 407), or nivolumab alone (N = 787), or ipilimumab
alone (N = 357) demonstrate that immune-related ADR occur more frequently for the combination, with
a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic
use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and
refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted
or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience
in diagnosis and treatment of ADR is necessary.
Ó 2017 Elsevier Ltd. All rights reserved.

⇑ Corresponding author at: Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.
E-mail addresses: jessica.hassel@med.uni-heidelberg.de (J.C. Hassel), lucie.heinzerling@uk-erlangen.de (L. Heinzerling), aberle@uke.de (J. Aberle), oliver.baehr@med.
uni-frankfurt.de (O. Bähr), thomas.eigentler@med.uni-tuebingen.de (T.K. Eigentler), marc-oliver.grimm@med.uni-jena.de (M.-O. Grimm), Gruenwald.Viktor@mh-hannover.
de (V. Grünwald), jan.leipe@med.uni-muenchen.de (J. Leipe), n.reinmuth@asklepios.com (N. Reinmuth), julia.tietze@med.uni-muenchen.de (J.K. Tietze), trojan@em.
uni-frankfurt.de (J. Trojan), lisa.zimmer@uk-essen.de (L. Zimmer), gutzmer.ralf@mh-hannover.de (R. Gutzmer).
1
Shared first authorship.

http://dx.doi.org/10.1016/j.ctrv.2017.05.003
0305-7372/Ó 2017 Elsevier Ltd. All rights reserved.
 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49
Introduction
Therapy with immune checkpoint has been established for various
cancers. Monoclonal antibodies that target the cytotoxic
T-lymphocyte-associated antigen (CTLA-4, also known as CD152),
the programmed cell death protein 1 (PD-1, or CD279) or PD-L1 (or
CD 274) are in clinical use since 2011, when ipilimumab was
approved for treatment of unresectable or metastatic melanoma [1,2].
PD-1 inhibitors nivolumab and pembrolizumab were approved
for the treatment of melanoma in the year 2014 [3–5]. Since, PD-1
inhibition became an established therapeutic option within a num-
ber of other tumor entities, including non-small cell lung cancer
(NSCLC) [6–8], RCC [9], squamous cell carcinoma of the head &
neck (SCCHN) [10,11] and Hodgkin’s lymphoma [12]. Ate-
zolizumab, a monoclonal antibody targeting the programmed cell
death protein ligand 1 (PD-L1), has been approved recently for
use in bladder carcinoma [13] and NSCLC [14] as well.
The combined use of a CTLA-4 plus a PD-1 antagonist was more
efficacious than the respective monotherapies in advanced mela-
noma resulting recently in the approval of a combination
immunotherapy regimen [15,16]. While CTLA-4 agonists centrally
affect the control of T cell priming, PD-1 inhibitors target T cell acti-
vation in the periphery, i.e. in the tumor environment [17]. Distinct
immunological effects occurring during combined blockade of both
targets have recently been demonstrated in vivo, enforcing the ratio-
nale of combined ICB [18]. The extended follow-up of the pivotal
study CheckMate-067, leading to registration of nivolumab plus ipil-
imumab for the treatment of patients with melanoma, revealed for
the combination a response rate of 59%, a two-year progression-
free survival of 43% and a two-year overall survival of 64% [19].
For monotherapy arms, the respective numbers were 45%, 37% and
59% for nivolumab and 19%, 12% and 45% for ipilimumab.
Since combined ICB also induces a higher number of side
effects, its clinical use can be challenging [20,21]. The present
review summarizes and analyzes the available incidence and
safety data for combined ICB with nivolumab and ipilimumab
and provides recommendations for the evaluation and manage-
ment of adverse drug reactions.
Methods and materials
Data for frequencies of adverse events (AE), adverse drug reac-
tions (ADR) and selected, immune-related adverse events from
registration trials were extracted from publicly available reports
from the European Medicines Agency (EMA) [22–24]. Data were
cross-checked with literature reports [2,3,15,16]. Extracted data
for pooled registration studies in advanced melanoma were ana-
lyzed and compared with data from further anti-PD-1/CTLA-4
combination therapy trials currently under investigation in other
cancer indications, as published prior to January 2017.
The methods for assessment of immune-related adverse events,
also referred to as ‘‘adverse events of specific interest” (AEOSI) –
based on internationally recognized definitions, classification and
reporting standards for ADR – were described previously [25]. This
retrospective, non-experimental analysis of anonymized, pooled
patient data did not require institutional review board approval.
Standard recommendations to enhance the quality of evidence-
based judgements were followed [26].
Results
Overall incidences of AE/ADR/AEOSI
Virtually all patients in the advanced melanoma registration tri-
als treated with either ipilimumab, nivolumab, or their combina-
37
tion experienced adverse events (Table 1). ADR and AEOSI (all
grades) were more frequent for the combination regimen. Discon-
tinuations due to ADR of any grade were as high as 39% in the
pooled combination regimen arms of trials CheckMate-067 and -
069 [15,16], mainly resulting from grade 3–4 events. The rate of
drug-related deaths was 0.7% (3 events) in the pooled combination
regimen arms and 0.1% (1 event) in the nivolumab arms of pivotal
studies; for iplimumab, one event (0.3%) has been reported.
Table 2 displays the AEOSI frequencies in pooled trials
CheckMate-067 and -069 [15,16], comparing the combination with
the monotherapies. For nivolumab, data from melanoma registra-
tion trials CheckMate-037 and -066 were analyzed [3,4]. Events
are categorized according to standard organ classes (SOC) [27]. In
most organ classes, frequencies for the combination of nivolumab
1 mg/kg plus ipilimumab 3 mg/kg can be assigned primarily to
one of the compounds, e.g. ipilimumab-induced gastrointestinal
toxicities. In contrast, the overall frequency of hepatic AEOSI was
much higher in the pooled combination therapy group (29%), when
compared with the pooled nivolumab group (7%) or the ipili-
mumab group (0.7%); a quasi-synergistic pattern is also found for
grade 3–4 hepatic AEOSI (17 % versus 2 % or 0.1%).
The kinetics of occurrence and resolution of AEOSI are summa-
rized in Fig. 1, depicting that in general events occur earlier and
resolve later in patients receiving the combination regimen, when
compared to nivolumab. Regarding ipilimumab, data on AEOSI
time patterns is scarce [28,29], in line with reporting inconsisten-
cies when these events were new [30].
Dosing regimen dependency of AE/ADR/AEOSI
In order to evaluate ADR and AEOSI frequencies with regard to
dosing schedules, studies in other cancer indications were ana-
lyzed (Supplementary Table 1). Although clinical evidence here is
still premature, the biweekly nivolumab 3 mg/kg (plus ipilimumab
1 mg/kg q6w) combination regimen seems to be less toxic than the
nivolumab 1 mg/kg regimen (3qw until week 12, then 3 mg/kg
biweekly until progression or undesirable toxicity) regimen, co-
administered with ipilimumab 3 mg/kg (q3w, until week 12).
Fig. 3 provides an overview on approved dosing schedules plus dif-
ferent dose regimens currently studied in clinical trials.
Immune-related, organ-specific adverse drug reactions
Frequencies and timing of potentially immune-related ADR of
combined ICB are well-characterized for frequently affected organ
systems (Fig. 1). For rare and very rare events, guidance for evalu-
ation and management is still scarce. Here, clinical recommenda-
tions are provided for the evaluation and management of
immune-related ADR.
Skin events
With a frequency of up to 62%, cutaneous side effects are the
most commonly occurring ADR of combined ICB comprising pruri-
tus, rash, dermatitis, erythema, palmoplantar erythrodysaesthesia,
photosensitivity reaction, urticaria, vitiligo, bullous pemphigoid
and lichenoid dermatitis. In contrast to the frequent occurrence,
their severity is normally low (Table 2). Pruritus is the leading
cutaneous adverse event in 33% (6% Grade 3–4) of patients treated
with nivolumab and ipilimumab, in 18% of patients treated with
nivolumab (1.1% Grade 3–4) and 55% (2.5% Grade 3–4) treated with
ipilimumab. Also, with 31% (Grade 3–4: 3%) rash was observed
mostly in cohorts treated with combined ICB followed by patients
treated with ipilimumab (all grades 22%; Grade 3–4: 1.4%) and
nivolumab (all grades 17%; Grade 3–4: 0.4%).
Routinely, rash induced by checkpoint inhibitors can be treated
with topical glucocorticosteroid-containing ointments in addition
38 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49

Frequencies of adverse events (AE), adverse drug reactions (ADR) and immune-related adverse events of specific interest (AEOSI) in the safety population of pooled pivotal trials in melanoma. Patients were included independently of

1 subject receiving nivolumab + ipilimumab died due to pneumonitis on day 152, 39 days after last dose, 1 subject died due to ventricular arrhythmia on day 29, 29 days after last dose (both: CM-069), 1 subject in CM-069 died
after database lock (‘‘sudden death” on day 262 after therapy start and on day 86 after last dose); 1 subject on nivolumab (CM-067) died due to neutropenia on day 152, 39 days after last dose; 1 subject on ipilimumab (CM-067)
to urea- or glycerin-containing creams or lotions. In case of persis-

Grade 5 ( )
tent pruritus, oral antipruritics (mainly antihistamines) can be

1d (0.3%)
0c (0.0%)
administered [31,32]. In case of unusual clinical appearance or
>grade 2 cutaneous ADR, interruption of checkpoint inhibitor ther-

nr

nr
nr
apy and consultation of an experienced dermatologist should be
considered, as triggering of cutaneous disorders has been
173c (55.6%) described, such as psoriasis [33], toxic epidermal necrolysis [34],
85c (27.3%) lichen planus like inflammation [33,35], autoimmune bullous dis-
58c (18.6%)

47 (13.2%)
Grade 3–4
CheckMate-067 & -069 [15,16]

ease [36] or sclerodermoid reactions [37].

nr

Gastrointestinal events
The frequency of gastrointestinal toxicities of any grade is
higher for ipilimumab (42%) than for nivolumab (18%), reaching
268c (86.2%)
229c (73.2%)
308c (99.0%)

46% for the combination regimen (Table 2). Grade 3–4 events
Ipilimumab

54 (15.1%)

occurred in 16% for nivolumab plus ipilimumab, in 12% of ipili-

N = 357

mumab and 1.7% of PD-1 inhibitor treated patients, respectively.

Any

nr

The main immune-related gastrointestinal events are diarrhea

and colitis (Table 2), which often represent the same ADR. Diar-
rhea/colitis can be accompanied by abdominal pain and gastroin-
testinal bleeding and can result in intestinal perforation. In
Grade 5 ( )
42 (5.3%)
1d (0.1%)

addition, fever, weight loss and nausea/vomiting can occur [38].

9 (1.1%)
0 (0.0%)

Based on the authors’ experience, the endoscopic appearance and

nr

distribution of colitis following treatment with ipilimumab plus

nivolumab is not different from ipilimumab monotherapy showing
CheckMate-037, -066 & -067 [3,4,16]

usually a pancolitis with ulcerations in severe cases [39].

In general, the time course of symptom onset makes diagnosis
108 (13.7%)
319 (40.5%)
Grade 3–4

24c (7.7%)

16c (5.1%)
65 (8.3%)

of a treatment related autoimmune event very likely. Median time

Reported for CheckMate-067 only (N = 313 for combination regimen and nivolumab mono arm, N = 311 for Ipilimumab mono arm).
Regardless of causality and reported within 30 days of last dose, including events due to or in line with progressive disease (PD).

to symptom onset was around week 5 for ipilimumab plus nivolu-

mab, and week 8 for nivolumab monotherapy (Fig. 1). However,
infectious causes have to be ruled out (stool tests for Clostridium
difficile and/or bacterial/viral pathogens).
194c (62.0%)

A polymerase chain reaction (PCR) performed in blood can diag-

768 (97.6%)
609 (77.4%)
Nivolumab

91 (11.6%)
24c (7.7%)

nose cytomegalovirus (CMV) reactivation. In addition, in severe

N = 787

grade, steroid-refractory or recurring colitis a colonoscopy is help-

Any

ful and biopsies can be analyzed for CMV [40,41]. Management rec-
ommendations of gastrointestinal ADR of the combination
treatment are similar than for ipilimumab. However, time to reso-
lution is longer in patients treated with the combination compared
Grade 5 ( )
18 (4.4%)

to patients with nivolumab monotherapy (3 versus 1.5 weeks), but

3d (0.7%)

7 (1.7%)
0 (0.0%)

shorter than for ipilimumab (5 weeks) (Fig. 1).

nr

Hepatic events
Hepatic events are very frequent under immunotherapy with
ipilimumab plus nivolumab with up to 17% grade 3–4 AEOSI com-
124c (39.6%)
138 (33.9%)
128 (31.4%)
280 (68.8%)
220 (54.1%)
Grade 3–4
CheckMate-067 & -069 [15,16]

pared to 2% with nivolumab and 0.1% with ipilimumab. Since they

BRAF mutation status and mainly untreated (except for CheckMate-037).

are rarely symptomatic, rising transaminases are diagnostic. Differ-

Nivolumab + Ipilimumab

ential diagnoses include viral hepatitis, such as HBV, HCV, CMV or

Epstein Barr virus (EBV), which can be evaluated by PCR. Further-
more, progressing liver metastases, drug-related hepatitis due to
concomitant medications, or alcohol have to be considered. The
275c (87.9%)
385 (94.6%)

158 (38.8%)
406 (99.8%)

died due to cardiac arrest (time patterns not reported).

175 (43.0%)

median time of onset was about 6 weeks for ipilimumab plus nivo-
N = 407

lumab and about 12 weeks after nivolumab monotherapy. Deteri-

Any

i.e. reactions within 30 days after last dose.

orating liver function can be measured as an increase in

international normalized ratio (INR) and bilirubin and a decrease
of albumin and cholinesterase.
Management of hepatitis is similar to nivolumab-induced hep-
ADRb leading to discontinuation
AEa leading to discontinuation

atitis and includes the use of corticosteroids and, depending on the

severity, additive immunosuppressant agents as e.g. mycopheno-
late mofetil [25].In the experience of the authors, addition of
Legend: nr, not reported.

mycophenolate mofetil is more often needed compared to hepati-

tis caused by monotherapy but this has not been systematically
Pooled studies

evaluated yet. Time to resolution of the ADR was 5 weeks for the
Sample size
CTC-Grade

combined ICB and 4 weeks for nivolumab. No treatment-related

deaths were reported so far due to hepatic or gastrointestinal
AEOSI
ADRb
Table 1

Aa,b

events in the combination regimen or monotherapy pivotal trials

b
a

d
c

[25] apart from casuistic reports [42].

 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49 39

Table 2
Frequencies of immune-related adverse events of specific interest (AEOSI), as related essentially to six different standard organ classes (SOC), in pooled trials for advanced
melanoma. Reported are overall cases and frequencies as ‘per patient’. Additional information is provided ‘per medical term’ for those event types that either occurred with a
frequency
2.0% (any CTC grade) and/or with any frequency at grade 3–4.

Nivolumab + Ipilimumab Nivolumab Ipilimumab

Pooled studies CheckMate-067 & -069 CheckMate-037, -066 & -067 CheckMate-067 & -069
Sample size N = 407 N = 787 N = 357
CTC Gradea Any Grade 3–4 Any Grade 3–4 Any Grade 3–4
System Organ Class (SOC)b
Skin & subcutaneous tissue 252 (61.9%) 26 (6.4%) 302 (38.4%) 9 (1.1%) 195 (54.6%) 9 (2.5%)
Pruritus 136 (33.4%) 7 (1.7%) 145 (18.4%) 1 (0.1%) 123 (34.4%) 1 (0.3%)
Rash 126 (31.0%) 13 (3.2%) 133 (16.9%) 3 (0.4%) 77 (21.6%) 5 (1.4%)
Vitiligo 31 (7.6%) 0 (0.0%) 69 (8.8%) 1 (0.1%) 16 (4.5%) 0 (0.0%)
Erythema 12 (2.9%) 1 (0.2%) 20 (2.5%) 0 (0.0%) nr nr
Skin hypopigmentation 8 (2.0%) 0 (0.0%) 9 (1.1%) 0 (0.0%) nr nr
Gastrointestinal 189 (46.4%) 64 (15.7%) 139 (17.7%) 13 (1.7%) 151 (42.3%) 41 (11.5%)
Diarrhea 175 (43.0%) 36 (8.8%) 135 (17.2%) 10 (1.3%) 120 (33.6%) 22 (6.2%)
Colitis 57 (14.0%) 39 (9.6%) 9 (1.1%) 5 (0.6%) 42 (11.8%) 30 (8.4%)
Enterocolitis 2 (0.5%) 2 (0.5%) 0 (0.0%) 0 (0.0%) nr nr
Respiratory & pulmonary 31 (7.6%) 5 (1.2%) 16 (2.0%) 1 (0.1%) 8 (2.2%) 2 (0.6%)
Pneumonitis 28 (6.9%) 5 (1.2%) 14 (1.8%) 1 (0.1%) 7 (2.0%) 2 (0.6%)
Interstitial lung disease 3 (0.7%) 0 (0.0%) 2 (0.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Endocrine 121 (29.7%) 20 (4.9%) 85 (10.8%) 5 (0.6%) 42 (11.8%) 9 (2.5%)
Hypothyroidism 42 (10.3%) 1 (0.2%) 54 (6.9%) 0 (0.0%) 20 (5.6%) 0 (0.0%)
Hyperthyroidism 35 (8.6%) 3 (0.7%) 25 (3.2%) 1 (0.1%) 3 (0.8%) 0 (0.0%)
Hypophysitis 35 (8.6%) 7 (1.7%) 3 (0.4%) 2 (0.3%) 15 (4.2%) 8 (2.2%)
Adrenal gland disorders 15 (3.7%) 6 (1.5%) 3 (0.4%) 1 (0.1%) nr nr
Diabetes 2 (0.5%) 1 (0.2%) 2(0.3%) 1 (0.1%) nr nr
Renal & urinary 19 (4.7%) 7 (1.7%) 12 (1.5%) 4 (0.5%) nr nr
Renal failure 1 (0.2%) 1 (0.2%) 3 (0.4%) 0 (0.0%) nr nr
Renal failure acute 4 (1.0%) 3 (0.7%) 3 (0.4%) 3 (0.4%) nr nr
Nephritis autoimmune 2 (0.5%) 1 (0.2%) 0 (0.0%) 0 (0.0%) nr nr
Nephritis tubulointerstitial 1 (0.2%) 1 (0.2%) 1 (0.1%) 1 (0.1%) nr nr
Creatinine " 12 (2.9%) 2 (0.5%) 4 (0.5%) 0 (0.0%) nr nr
Hepatic 118 (29.0%) 71 (17.4%) 54 (6.9%) 71 (2.2%) 24 (0.7%) 5 (0.1%)
Hepatitis 9 (2.2%) 8 (2.0%) 0 (0.0%) 0 (0.0%) nr nr
Hepatitis acute 1 (0.2%) 1 (0.2%) 0 (0.0%) 0 (0.0%) nr nr
Hepatitis autoimmune 6 (1.5%) 6 (1.5%) 2 (0.3%) 2 (0.3%) nr nr
Hepatic enzyme " 4 (1.0%) 2 (0.5%) 2 (0.3%) 1 (0.1%) nr nr
Transaminases increased 14 (3.4%) 11 (2.7%) 3 (0.4%) 1 (0.1%) nr nr
ALAT " 74 (18.2%) 34 (8.4%) 29 (3.7%) 9 (1.1%) 14 (3.9%) 5 (1.4%)
ASAT " 68 (16.7%) 24 (5.9%) 29 (3.7%) 6 (0.8%) 13 (3.6%) 2 (0.6%)
Alkaline phosphatase " 15 (3.7%) 2 (0.5%) 10 (1.3%) 1 (0.1%) nr nr
Gamma-GT " 9 (2.2%) 4 (1.0%) 4 (0.5%) 1 (0.1%) nr nr
Hepatotoxicity 10 (2.5%) 8 (2.0%) 2 (0.3%) 1 (0.1%) nr nr
Liver disorder 1 (0.2%) 1 (0.2%) 0 (0.0%) 0 (0.0%) nr nr
AEOSI other SOC
Pancreatitis 4 (1.0%)
2 (
0.5%) 4 (0.5%) nr nr nr
Guillain-Barré-Syndrome 2 (0.4%) 1 (0.2%) 1 (0.1%) 1 (0.1%) nr nr
Demyelination 0 (0.0%) 0 (0.0%) 1 (0.1%) 1 (0.1%) nr nr
Uveitis 5 (1.2%) 1 (0.2%) 6 (0.8%) nr nr nr
Hypersensitivity reactions 16 (3.9%) 0 (0.0%) 38 (4.8%) 2 (0.3%) nr nr
Infusion related reaction 10 (2.5%) 0 (0.0%) 20 (4.8%) 2 (03%) nr nr
(Drug) Hypersensitivity 6 (1.5%) 0 (0.0%) 8 (2.3%) 0 (0.0%) nr nr

Legend: CTC, Common Toxicity Criteria.

nr, not reported.
a
According to US National Cancer Institute, Common toxicity criteria for adverse events (CTCAE). Version 4.0; Published: May 28, 2009 (v4.03: June 14, 2010).
b
System Organ Classes according to Medical Dictionary for Regulatory Activities (MedDRA) classification [26].

Endocrine events
Immune-related endocrine with combined ICB have been
observed in up to 30% of patients with grade 3–4 events occurring
in 5% (Table 2). In 24% of the patients the thyroid gland is affected.
Pituitary dysfunction, mostly hypophysitis, was reported in 9%.
Adrenal insufficiency (AI) was observed in 4% with grade 3–4 in
2%. The frequency of hypophysitis and AI was considerably higher
in patients treated with nivolumab and ipilimumab (9% and 4%,
respectively) than in patients with nivolumab monotherapy (0.4%
and 0.4%, respectively). For type 1 diabetes the frequency was
low (0.5%) in the combination group as well as in the monotherapy
group. Median time to onset of endocrine disorders in the combi-
nation group was 1 to 4 months (Fig. 1).
Symptoms indicating endocrine dysfunction are not specific
and include fatigue, weight gain or weight loss, headaches, changes
in mood or behavior, dizziness or fainting, hair loss, feeling cold,
constipation, and a deeper pitch of the voice. In addition, an adre-
nal crisis must be considered if dehydration, hypotonia, or even
shock symptoms develop, which cannot be attributed to the cur-
rent status of cancer disease. A septic shock should then be
excluded; a stress test with intravenous mineralocorticoids could
help to assure the diagnosis. It is recommended to monitor thyroid
40 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49

2
A. Time to onset (median) B. Time to resolution (median)

≥ 1/10
(Skin, 2 wks) (Skin, 23 wks)
50%

(Skin, 3 wks)
(GI, 5 wks) (GI, 3 wks)
(GI, 9.5 wks) (GI, 5 wks)

Very common
(Skin, 6 wks) (Skin, 10 wks)
(Hep, 6 wks)
(Thyroid, 6 wks)
20%

(GI, 8 wks) (GI, 1.5 wks)

10%

(„Endocrine“, 11 wks) („Endocrine“,

1 (Thyr., 10 wks)
(Pituary, 12 wks) 24 wks)
(Pulm, 9.5 wks) (Pulm, 6 wks)

Common ≥ 1/100 – 1/10

(Hep, 13 wks)
5%

(Infusion reactions, 2 wks)

(Ren, 11 wks) (Ren, 2 wks)
(Infusion reactions, 3 wks) (Adrenal, 16 wks) (Infusion reactions, 0.1 wks)
lg x

2%

(Pulm, 9 wks) (Pulm, 4 wks)

(Ren, 15 wks) (Ren, 5.5 wks)

1%

Uncommon ≥ 1/1,000 – 1/100

0.5%

(Pituary, 18 wks) (Adrenal, 24 wks)

Legend
0.2%

= Nivolumab = Ipilimumab
= Nivolumab + Ipilimumab
0.1%

-1
//

6 12 wks 18 wks 24 wks 0 6 12 wks 18 wks 24 wks

wks wks wks

Fig. 1. Time patterns for occurrence and resolution of AEOSI. Medians reported for the combination and nivolumab rely on data for pooled trials CheckMate-067 and -069
[22]. For ipilimumab, time patterns have not been studied/reported systematically during pivotal trials; available data have been incorporated from US Food and Drug
Administration’s medical review document [30] and from the FDA-approved prescription information [127].

function by thyroid stimulating hormone (TSH), free triiodothy- should be initiated if hypophysitis is suspected. In case of
ronine (fT3) and free thyroxine (fT4) prior and during treatment hypophysitis with clinical symptoms, methylprednisolone (or
with nivolumab and ipilimumab. equivalent) can be started at 1 mg/kg body weight and tapered
Autoimmune thyreoiditis usually presents as chronic lymphatic by 10 mg per week. Without clinical symptoms, hydrocortisone
thyreoiditis [43] leading to a destruction of the gland. Autoimmune replacement is usually recommended with doses of 25–40 mg
antibodies such as anti-thyroid peroxidase, anti-thyroglobulin per day (e.g. 15–10–0 mg daily).
antibodies as well as anti-TSH receptor antibodies have been In rare cases the posterior pituitary lobe can be affected leading
reported to become detectable or increase with combination ther- to diabetes insipidus. Patients will report increased liquid uptake
apy. Destruction of the gland leads to release of thyroid hormones and urine volumes. Serum levels of sodium may be elevated. Syn-
and hyperthyroidism which should preferentially be treated symp- thetic antidiuretic hormone (ADH) is the recommended therapy.
tomatically, e.g. with beta blockers; the use of glucocorticosteroids Type 1 diabetes mellitus can present in a similar way as diabetes
can be considered but is not supported by clinical evidence yet insipidus. In addition weight loss usually occurs and in severe
[44]. cases diabetic ketoacidosis develops. Type 1 diabetes should be
Thyroid inhibitor therapy such as methimazole can usually not considered if glucose exceeds 126 mg/dl (fasting) or 200 mg/dl
stop the inflammatory destruction but limit symptoms. However, (non-fasting condition). Measurement of pH value in plasma helps
if hyperthyroidism is based on anti-TSH receptor antibodies as in to acutely differentiate between type 1 and type 2 diabetes. Newly
Grave’s disease, thyroid inhibitors should be considered. discovered type 1 diabetes requires immediate insulin treatment
Immune-related hypophysitis is commonly associated with low and intensive clinical care [48,49].
TSH, fT3, and fT4, decreased cortisol, and hyponatremia [45,46]. In general, despite endocrine events, combination therapy with
Dosage of L-thyroxine should aim to achieve an fT4 in the reference nivolumab and ipilimumab can usually be continued in conjunc-
range (blood draw needs to be prior to intake of L-thyroxine). tion with hormone replacement therapy.
Hypocortisolism, either due to hypophysitis and resulting
hypopituitarism, or AI [47], can be excluded if cortisol measured Pulmonary events
at any time during the day exceeds 180 mg/l. If cortisol is lower Pneumonitis is the most common respiratory adverse drug
than 50 mg/l, hypocortisolism is likely. In case of unclear laboratory reaction reported in trials with ICB [50]; in melanoma trials, the
test results, while clinical findings suggest hypocortisolism, corti- incidence is lower [25]. Clinical symptoms include dyspnea
sol should be measured at 8 o‘clock in the morning or further ana- (53%), cough (35%), fever (12%), and chest pain (7%) [51]. However,
lyzed by dynamic testing. Sella magnetic resonance imaging (MRI) one third of patients were asymptomatic, with only radiologic
 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49
changes at the onset of pneumonitis [50]. Infectious causes (e.g.
bacterial or virus-related; in particular chlamydiae or mycoplas-
mosis) have to be excluded. Diagnostic procedures include lung
function tests with blood gas analysis and radiologic imaging.
Chest CT scans typically show diffuse, patchy ground-glass attenu-
ation and centrilobular nodules with areas of air-trapping.
With nivolumab or ipilimumab monotherapy, incidences up to
2% and 3% were reported, respectively. In contrast, nivolumab plus
ipilimumab induced pneumonitis in 9% of melanoma patients
including 1.2% with grade 3 events or higher (Table 1). These num-
bers may be even higher in patients with lung cancer treated with
this combination, however, data from large clinical studies are
pending. With considerable variations between individual patients,
the median times to onset (2.2 months from initiation of therapy)
and resolution are comparable between mono- and combination
ICB (Fig. 1).
For successful treatment of pneumonitis, early diagnosis, cessa-
tion of treatment with ICB and initiation of oral or intravenous cor-
ticosteroids is essential. In case of lack of response, additional
immunosuppressive agents such as mycophenolate mofetil, but
also infliximab may be considered [25,51,52].
Immunosuppressive therapy should be guided by clinical
response, pulmonary function and radiographic imaging within
3 day-intervals by chest X-ray until improvement. Restart of ICB
should be carefully balanced to progressive, irreversible lung dis-
ease. In the CheckMate-069 clinical study [15], one patient in the
combination arm died of respiratory ADR.
Renal events
Reporting renal events using CTC-AE criteria is mainly based on
creatinine increase eventually resulting in renal failure with dialy-
sis. Only a minority of the patients with acute kidney injury under-
went renal biopsy allowing the diagnosis of ‘‘nephritis”. Other
potential causes for creatinine increase in cancer patients treated
by ICB, e.g. dehydration due to diarrhea/colitis, should be consid-
ered. While renal events appear to be less frequent in patients with
ipilimumab treatment alone (<2% [53]) a rate of approximately 3%
including 0.5% grade 3–4 events are observed with nivolumab – a
finding that might be explained by differences in terms of crea-
tinine clearance among trials’ inclusion criteria.
For patients being treated with the nivolumab and ipilimumab
combination and despite the fact, that in general a higher baseline
kidney function (estimated glomerular filtration rate (GFR)

40 ml/min/kg) was required in pivotal clinical trials, the rate of
‘‘kidney injuries” is slightly higher and appear to be more fre-
quently severe (any grade 4%, with grade 3/4 as 0.9 and 0.7%,
respectively).
Histological findings from renal biopsies revealed acute intersti-
tial nephritis, granulomatous tubulointerstitial nephritis and
membranous lupus nephritis. In nephritis cases, a slight creatinine
elevation associated with mild proteinuria may precede severe
kidney function deterioration and should prompt close(r) monitor-
ing. Most cases resolve with corticosteroid treatment, in rare cases
the use of mycophenolate mofetil and/or dialysis was reported
[54,55].
Hypersensitivity and infusion reactions
The incidence of hypersensitivity and infusion reactions of any
grade have been reported to be similar in patients receiving nivo-
lumab plus ipilimumab compared to patients receiving monother-
apy (4% versus 5%). The vast majority of infusion reactions were
mild to moderate (Table 2).
Musculoskeletal events
Musculoskeletal events primarily include arthralgia, myalgia
and arthritis. For nivolumab and ipilimumab, the incidence of the
41
main musculoskeletal event – arthralgia – is 6% for nivolumab as
well as for ipilimumab, but slightly higher with 11% in the nivolu-
mab plus ipilimumab group, respectively. In a study analyzing data
from 24 clinical trials with different checkpoint inhibitors, the rate
of reported arthralgias varied between 1% and 43% [56].
Myalgia is the second most reported adverse event in the
pooled data analysis and appeared in 4% of the patients treated
with nivolumab, 13% treated with ipilimumab and in 10% of the
nivolumab plus ipilimumab group, respectively. In a review of 12
clinical trials using ICB myalgia was reported with a rate between
1 and 20% [56].
Regarding arthritis, no data were published for the 4 trials form-
ing the pooled safety data base due to the low incidence of the side
effect [2,3,15,16]. Two ADR were noted in the EMA’s public assess-
ment report for the combination regimen [22]. Hence, like for
arthralgia and myalgia, the true incidence of immune-related
arthritis is not yet determined. To date, no observational studies
of large cohorts have systematically monitored patients for inflam-
matory arthritis with confirmation by rheumatologists. One obser-
vational study, applying PET/CT before and after therapy with
CTLA-4 inhibitors, demonstrated a 3.4% arthritis rate on imaging
[57]. Clinically, arthritis mainly presents rheumatoid arthritis-like
(polyarthritis), spondyloarthritis-like (oligoarthritis, inflammatory
back pain) and polymyalgia rheumatic-like (bilateral shoulder,
hip pain) [58,59].
Cases of myositis were described, mainly characterized by prox-
imal muscle weakness and substantially elevated creatinine kinase
(CK) levels [60].
Virtually all musculoskeletal AEs were reported as grade 1–2
toxicities. So far, for musculoskeletal events no management algo-
rithm was published. Nevertheless, from extrapolation of treat-
ment standards of rheumatic conditions and experience from
case series [56], recommendations can be suggested. For mild
symptoms of arthralgia or myalgia, non-steroidal anti-
inflammatory drugs (NSAID) should be applied; for moderate
symptoms like e.g., in case of monoarthritis, dose delays of ICB
can be considered or low dose glucocorticoids potentially adminis-
tered intra-articularly; for severe forms (e.g. polyarthritis or
myositis), ICB might be stopped after use of moderate-high dose
(1 mg/kg) corticoidsteroids. If symptoms persist, corticoidsteroid-
sparing therapies like methotrexate, or biologicals like TNF-
inhibitors might be considered.
Hematological events
With regard to changes in peripheral blood counts, the current
Summary of Product Characteristics (SmPC) [53] lists the following
for grade 3 or 4 incidences for combined ICB: anemia 2.8% (all
grade 3), thrombopenia 1.2%, leukopenia 0.5%, lymphopenia 6.4%,
neutropenia 0.7%, eosinophilia 1–10%.
Anaemia could be related to the immunotherapy, particularly in
case of rapid onset at the beginning of the immunotherapy, and
other causes such as progression of the underlying malignancy or
iron deficiency have been ruled out. If immune-related anaemia
is considered, either an auto-antibody mediated pathogenetic
mechanism with increase of reticulocytes and indirect bilirubin
as well as a positive direct agglutinin (Coombs) test, or a lympho-
cytic infiltration of the bone marrow as pathogenetic mechanism
have been described [61]. Thus, for a diagnostic workup complete
blood counts including reticulocytes, direct and indirect bilirubin,
lactate dehydrogenase, direct agglutinin test, and if necessary a
bone marrow analysis are recommended. In the few published
reports of autoimmune haemolytic anaemia after treatment with
nivolumab, pembrolizumab or ipilimumab monotherapy, the
patients responded to corticosteroids [62–64], in one case with
additional immunoglobulins [65].After tapering of the corticos-
42 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49
teroids, one of the patients tolerated continuation of nivolumab
without further problems [64].
Leukopenia including neutropenia and agranulocytosis are very
rare events [66–68] that can be life-threatening and led to death in
one published case [16]. Another case of agranulocytosis with skin
infection (ecthymata) after nivolumab was reported, not respon-
sive to filgrastim and intravenous immunoglobulins, but slowly
responding to high doses of corticosteroids (methylprednisolone
3 mg/kg daily i.v.) [69].Single patients with autoimmune thrombo-
cytopenia after ipilimumab or pembrolizumab responded slowly to
corticosteroids and immunoglobulins. [70,71].
Ocular events
Ocular events occurred in 1.4% of patients treated with nivolu-
mab plus ipilimumab and in 0.8% of patients with nivolumab and
manifest mostly as uveitis (Table 2). Corneal perforation after dete-
riorated dry eye under treatment with nivolumab [72],
ipilimumab-associated retinopathy [73], bilateral neuroretinitis
[74], peripheral ulcerative keratitis and orbital inflammation [75],
thyroid-like ophthalmopathy [76] and choroidal neovasculariza-
tion [77] have been reported. Symptoms include eye pain, redness,
photophobia or loss of vision and occurred most frequently after
the second treatment cycle. In any case, an ophthalmologist should
be consulted. Treatment with topical corticosteroids sometimes
combined with oral corticosteroids or in some cases topical cyclos-
porine and discontinuation of treatment proved to be successful.
Cardiac events
Autoimmune mediated cardiovascular events during ICB are
rare but can be life-threatening and have caused fatalities [78];
therefore they deserve special awareness of the treating physician
and cardiologist. For ADR, rates of 1.3% for tachycardia, 1.1% for
hypertension, 0.4% for arrhythmias and 0.2% for atrial fibrillation
were reported in patients treated with nivolumab plus ipilimumab
[22]. The incidence for myocarditis after nivolumab plus ipili-
mumab may reach 0.3% (8/2974 patients, 5 (0.17%) fatal), and
0.06% (10/17,620 patients, 1 (0.03%) fatal) after nivolumab
monotherapy as assessed in a review of the drug manufacturer’s
safety database [78]. Cardiotoxicity can occur early during treat-
ment, i.e. after a median of 17 days with nonspecific symptoms
such as fatigue, hypotension or dramatic with acute heart failure
and can be fatal [78,79]. Clinical symptoms and elevated creatinine
kinase should prompt further assessment, diagnosis might require
cardiac imaging including echocardiography or cardiac MRI, as
well as cardiac biopsy. Treatment with corticosteroids was suc-
cessful in some patients, whereas the course was fatal in others
[78–80]. Pericardial effusions or cardiomyopathies have been
described in single patients on PD-1 inhibitor monotherapy
[66,81], ipilimumab monotherapy [78,82,83] and nivolumab plus
ipilimumab [84].
Details on patients with cardiac arrhythmias have been
described in single, severe cases, such as a patient with cardiac
arrest during ipilimumab monotherapy in the CheckMate-067
study [16], a patient undergoing nivolumab plus ipilimumab
developed ventricular arrhythmia, ventricular tachycardia,
myocardial infarction with fatal outcome in CheckMate-69 [68]
as well as one patient with cardiac arrest after 9 administrations
of pembrolizumab, who recovered fully [79].
Pancreatic events
Elevated pancreatic enzymes such as lipase and amylase are
described in 1% of patients treated with nivolumab plus ipili-
mumab (Table 2). They can be grade
3 but are mostly asymp-
tomatic. However, cases of drug-induced diabetes mellitus have
been described and might be caused by pancreatitis. The onset of
pancreatitis is about 7 weeks for ipilimumab plus nivolumab.
Interestingly, time to onset for development of a diabetes mellitus
is similar. Clinically controversially discussed is the management
of increased pancreatic enzymes [85] and the timing to initiate
immunosuppressive treatment. Whereas mild increases can be
monitored without any treatment, symptomatic pancreatitis
should be treated with corticosteroids (e.g. 1 mg/kg prednisolone
p.o.). In general, symptoms resolve quickly with a time to resolu-
tion of about 4 weeks. Continuation of ICB after resolution of high
grade pancreatic enzyme elevation or pancreatitis has to be care-
fully balanced to a possible recurrence of the side effect.
Neurological events
Neurologic events associated with ICB are rare. Only 0.6% of the
adverse events after ipilimumab plus nivolumab and 0.2% after
treatment with nivolumab were reported to affect the nervous sys-
tem. But if they occur, they may be severe and require prompt
therapeutic intervention. The most frequently described events
have been Guillan-Barré-Syndrome, autoimmune encephalitis,
demyelination or myasthenic syndrome. Guillan-Barré-Syndrome
occurs most often (Table 2) using nivolumab plus ipilimumab or
nivolumab alone [86]. Furthermore three cases of Guillan-Barré-
Syndrome, including one fatal case, have been reported under
treatment with ipilimumab [1,87,88]. Three cases of autoimmune
encephalitis, one lethal, have been reported in patients treated
with nivolumab and with nivolumab in combination with ipili-
mumab [89,90]. A case of CNS demyelination has occurred after
four infusions of nivolumab in a patient pre-treated with ipili-
mumab. The patient died four months later despite cessation of
the treatment and immunosuppressive therapy [91]. Another case
of chronic inflammatory demyelinating polyradiculoneuropathy
after one infusion of ipilimumab has been reported [92].
Myasthenic syndromes have been reported in 4 patients. One
patient receiving both nivolumab and ipilimumab for the treat-
ment of small cell lung cancer died because of the myasthenic syn-
drome [93].In the remaining 3 patients, all receiving ipilimumab
alone, the myasthenic syndrome developed after the second infu-
sion [92,94]. Furthermore several other neurologic diseases such
as radiculoneuropathy, aseptic meningitis, neuritis of the optical
nerve, transverse myelitis, encephalopathy mostly caused by ipili-
mumab but some also caused by nivolumab treatment have been
described [90,95–97].
Varying neurologic symptoms involving the central or periph-
eral nervous system might occur with subacute or acute symptom
onset. Guillan-Barré-Syndrome is a demyelinating polyradicu-
loneuropathy typically presenting with progressive, symmetric
muscle weakness beginning in the feet and reduced tendon
reflexes. The main symptom of myasthenic syndromes is muscle
weakness that worsens after physical activity and towards the
end of the day. CNS demyelination could present with various
symptoms depending on the sites of demyelination. Sensory or
motor deficits as well as aphasia, ataxia or visual deficits can occur.
Behavioral disturbance should be a red flag for encephalopathy,
encephalitis or meningoencephalitis.
Brain metastasis should be excluded by MRI (with contrast
agent) in case of neurological symptoms. Further, laboratory
results and other examinations might differ from the classical dis-
eases not associated with immune checkpoint blockade and should
be performed in cooperation with a neurologist.
Treatment should include steroids even in diseases usually not
treated with steroids and might be intensified by early plasma-
pheresis, intravenous immunoglobulins or other immunosuppres-
sive drugs. However, in some cases the clinical course of the
adverse event might be refractory even under a multimodal
treatment
 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49
Other rare events
Sarcoidosis, a systemic granulomatous inflammatory disease
that may occur at different visceral sites, including lung, liver,
lymph nodes and skin, is associated with the use of ICB [98]. Cases
of sarcoidosis have been described with ipilimumab [99], PD-1
inhibitors [100,101], or the combination of both [102]. So far, lung
and skin manifestations prevail in these rare cases.
Importantly, the presentation of sarcoidosis may be mistaken
for disease progression with consequences in patient management
[99,101]. Treatment is not necessary if asymptomatic and sar-
coidosis can spontaneously regress. In the presence of symptoms
or decrease of organ function, corticosteroids may be given
[103,104]. Diagnosis should follow clinical recommendations for
sarcoidosis.
Vasculitis was reported in single organs, such as the retina [105]
and the uterus [106], or in form of giant cell arteriitis in two
patients treated with ipilimumab, for whom the ADR resolved with
prednisone monotherapy [107]. Vasculitis was also reported to be
associated with transient neurological deficits, requiring high-dose
steroids [108,109]. On the contrary, a patient with preexisting
Churg-Strauss vasculitis remained in remission throughout the
course of ipilimumab and pembrolizumab sequenced therapy
[110], indicating that autoimmune disease per se may not limit
the use of checkpoint inhibitors [111,112].
Discussion
The combination of immune check point inhibitors nivolumab
and ipilimumab induces ADR more frequently, earlier and of higher
grade (Fig. 1). The analysis of the publicly available data [22] and
the reviewed literature confirm that the majority of events is
reversible following the systemic use of glucocorticoids, and can
be well and safely managed. In case of long-lasting and/or refrac-
tory immune-toxicities, organ- or case-specific escalation of
immunosuppression is recommended.
In alignment with the recommendations provided by the pre-
scribing information [53], clinical management of immune-
related side effects follows the established algorithms and current
practice described for the mono regimens [113–119].
However, the analysis and discussion of the findings in our
inter-disciplinary expert panel witnessed that certain differences
are manifest and some suggestions become emergent. Fig. 2 (for
recommendations for routine laboratory testing see also Table 3)
summarizes our current ‘best-practice’ recommendations how to
diagnose, monitor and manage immune-related toxicities resulting
from combined ICB. In general, we propose for the combination
approach
 thorough baseline examinations – guided by existing recom-
mendations for monotherapy with supplementation of new
parameters (e.g. CK),
 additional, weekly monitoring between dates of drug dosing,
 prolonged, more frequent follow-up visits (up to 1 year after
end of therapy),
 ICB delay and discontinuation rules similar to monotherapy or
stricter
 corticosteroid therapy and, in case of non-resolving or recurrent
AEOSI, escalation therapy with immunosuppressant drugs to
start in case of doubt earlier, and maybe dose-intensified.
Further studies to advance the understanding of the pathologi-
cal causes of immune-toxicities and identify patients at risk are
needed. Similarly, results from future studies may support a better
distinction of the treatment component in combined ICB requiring
primarily treatment delay or discontinuation.
43
Another issue is the optimal dosage regimen. The present data
(Supplementary Table 1 and Fig. 3) indicate that the nivolumab
3 mg/kg plus ipilimumab 1 mg/kg regimen currently studied in
certain trials might be less toxic for patients than the nivolumab
1 mg/kg and ipilimumab 3 mg/kg dosing regimen approved for
use in advanced melanoma. The question is currently subjected
to clinical investigation; results of the ongoing CheckMate 511 trial
(registered as EudraCT 2015-04920-67) comparing both regimen
in patients with advanced melanoma – results from this phase
IIIB/IV safety trial will be available end of 2017 earliest – will hope-
fully shed more light on the issue. However, the optimal dosing
regimen might be different in different tumor entities [120,121].
Tumor-specific AE profiles are possible, but cannot be addressed
due to the lack of sufficient data. During PD-1 inhibitor monother-
apy, pulmonary events (pneumonitis) are observed more frequently
in NSCLC than in melanoma patients, whereas skin events like rash
or vitiligo are more common in melanoma than in lung cancer
patients [24]. Such impact of the underlying tumor disease on the
occurrence of immune-related side effects, reported also by Nishino
et al. [122], might be explained by changes in the tumor biology –
oncologists are aware that AE rates and disease symptoms generally
increase in tumor-affected organs as a direct result of disease pro-
gression. Future safety studies should help clarifying this aspect.
Currently, the extent of safety data for combined ICB is still lim-
ited. The present work which analyzed pooled trial data of around
1500 patients, rendered public in the context of drug authorization
processes in Europe, in line with an extensive evaluation of the lit-
erature, is hence an attempt to overcome these limitations and to
support clinicians with some early, interdisciplinary recommenda-
tions. The finite amount of safety data – especially for the more
rare and less reported and understood, potentially immune-
related ADR – is a limiting factor of our work with the concern
for bias in analysis and interpretation. In addition, systemic errors
in AE and ADR exist [123,124]; for the rather new, immune-related
side effects, methodological inconsistencies are also manifest with
a lack of a standardized tool for AEOSI reporting that accounts bet-
ter for tolerability, management and reversibility [125,126]. For
rare side effects of ICB, the systematic collection of ADR/AEOSI
through clinical practice networks [33,42,66,111], patient reg-
istries [115] and systematic literature analyses [97] may comple-
ment the ongoing phase IV safety studies (as e.g. in RCC
(CheckMate-920) or NSCLC (NCT02869789)). Finally, some report-
ing and analysis bias in EMA’s public assessment report that
focused for this ‘line extension’ of nivolumab on the comparison
of combined ICB regimen with nivolumab mono, is observable
[22], with limited reporting of the toxicities of the regimen’s
anti-CTLA-4 component.
Finally, further investigations to better characterize the patho-
genesis and associated pharmacological, immunological and phar-
macogenetic root causes that trigger the toxicities of mono and
combined ICB, acting on distinct lymphocyte subtypes and at dif-
ferent sites, are warranted [113]. Such investigations may help to
better understand effects like the observed quasi-synergistic aug-
mentations in hepatic toxicity [21] and ideally to identify biologi-
cal predictors of toxicity as circulating auto-antibodies that may
foster the early detection of AEOSI [117].
With regard to the recently reported follow-up efficacy data of
the pivotal trial [19] and the updated safety data – grade 3–4
treatment-related adverse events were noted in 58.5% of patients
undergoing therapy with nivolumab and ipilimumab, 20.8% for
patients treated with nivolumab and 27.7% of patients treated with
ipilimumab [19] – the higher efficacy of the combined ICB has to be
weighed against higher toxicity, and it will certainly be important
to identify subgroups of patients who require the combined ICD for
tumor control. Early diagnosis, good communication, close cooper-
ation with patients’ general practitioner or oncologist as well as
44 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49

Fig. 2. Summarized overview on potential difference in the diagnosis, monitoring and management of immune-related adverse drug reactions occurring during combined
immune checkpoint blockade (ICB), compared to PD-1 inhibition. For details, please consider always also detailed specifications and recommendations as outlined in the
Summary of Product Characteristics (European Union) or in the respective, official prescribing information documents (US and other regions outside European Union).
Incorporated icons are used on the basis of a free open license (Creative Commons) from Openclipart.

interdisciplinary networking is deemed indispensable for a suc-
cessful and safe management of patients receiving combined ICB.
Conflicts of interest
The authors declare to have following potential conflicts of
interest:
 JCH: Personal fees: Amgen, Bristol-Myers Squibb, GSK, Merck
KGaA, MSD, Roche, Novartis; Scientific Support: Bristol-Myers
Squibb.
 LH: Personal fees and advisory role: Bristol-Myers Squibb, MSD,
Roche, GSK, Novartis, Amgen; Travel grants: Bristol-Myers
Squibb, MSD; Grants: Novartis.
 JA: Speakers bureau and advisory boards: Bristol-Myers Squibb.
 OB: Travel grants, advisory board, speaker honoraria: Bristol-
Myers Squibb, NOXXON, Roche, Medac
 TKE: Personal fees from Bristol-Myers Squibb, Roche, Amgen,
Novartis.
 MOG: Consultancy fees from AstraZeneca, Amgen, Bayer Health
Care, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Pfizer,
Sanofi, and Teva; Grants from Novartis; Payment for lectures:
Bayer Health Care, Bristol-Myers Squibb, Hexal, Janssen-Cilag,
JenaPharm, Novartis, Pfizer, Pierre Fabre and Sanofi.
 VG: Honoraria: Bristol-Myers Squibb, Novartis, MSD, Pfizer,
Roche, Ipsen, Eisai.
 JL: Speaker fees: Bristol-Myers Squibb, Roche; Consultancy fees:
Janssen-Cilag, Roche.
 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49 45

Fig. 3. Overview of dosing schedules. Boxed are the approved dosing schedules for nivolumab (N) and Ipilimumab (I) mono as well as Nivolumab-Ipilimumab combination
regimen; also shown are the experimental combination regimen used in phase I/II trials for indications other than advanced melanoma.

 NR: Honoraria or consultation fees: Roche, Lilly, Novartis, MSD,
Bristol-Myers Squibb, Boehringer-Ingelheim, AstraZeneca, Pfizer.
 JKT: Speaker honoraria from MSD, Bristol-Myers Squibb, Roche,
Amgen, Almirall, Novartis; Consultancy fees from Bristol-Myers
Squibb and Roche, Support for scientific meetings: Bristol-
Myers Squibb.
 JT: Speakers bureau and advisory boards: Bristol-Myers Squibb,
MSD
 LZ: Consultant/advisory role: Roche, Bristol-Myers Squibb, MSD,
Novartis; Honoraria: Roche, Bristol-Myers Squibb, MSD, Novar-
tis, Merck KGaA, GSK; Support for scientific meetings: Bristol-
Myers Squibb, MSD, Novartis, Amgen.
46 J.C. Hassel et al. / Cancer Treatment Reviews 57 (2017) 36–49

Table 3
Recommendations for routine laboratory testing ICB mono versus combination regimen (Nivolumab 1 m/kg + Ipilimumab 3 mg/kg).

Immune Checkpoint Blockade (ICB) mono Combined ICB

* **
Laboratory test Prior therapy Prior cycle (i.e. q2/3 w) Prior therapy* Weekly (‘between cycles’) Prior cycle***
Blood count
Differential blood count x x x x x

Clinical chemistry
Electrolytes (Na, K, Ca) x x x x x
Creatinine x x x x x
CK x x x x x
Blood urea nitrogen (x) (x) (x) (x)
Bilirubin x x x (x) x
Liver transaminases (AST, ALT, GGT) x x x x x
LDH x (x) x x
Lipase x x x x
C-reactive protein (x) (x) (x) (x)
Glucosea (x) (x) (x) (x)
TSHb x x x (x) x
Free Triiodothyronine & Thyroxine x (x) x (x) x
Cortisol (x) (x) (x) (x)
Serologic tests
Hepatitis A/B/C (x) (x)
Cytomegalovirus (x) (x)
HIV (x) (x)
Epstein-Barr virus (x) (x)

Legend: x: test recommended.

(x): test optional x or (x): additional (recommended/optional) test proposed for combined ICB (or change in ‘relevance’ (optional ? recommended)).
Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CK, Creatinine kinase, GGT, gamma-glutamyl transferase; LDH, lactate deydrogenase; TSH, thyroid-
stimulating hormone.
a
Glucose should be preferably measured by a blood test but might be also measured by urine analysis (urine test strips) for screening of elevated glucose concentrations.
b
If TSH is elevated or decreased under therapy or a thyroid dysfunction or hypophysitis is suspected, fT3, fT4 and cortisol should be measured. Baseline measurement of fT3
and fT4 should be considered.
*
Prior therapy = baseline.
**
Prior cycle: might be every 2nd week (i.e. for nivolumab mono regimen), or every 3rd week (for ipilimumab mono regimens).
***
Prior cycle: i.e. ‘‘3 weekly” prior to nivolumab + ipilimumab administration; in these weeks, the laboratory examination include the ‘‘weekly” examinations.

 RG: Honoraria: GSK, Roche, Bristol-Myers Squibb, MSD, Novar- References

tis, Pfizer, Janssen, Amgen, Merck KGaA, Boehringer Ingelheim,
Almirall Hermal, Pierre Fabre; Consultancy or advisory roles:
GSK, Bristol-Myers Squibb, Roche, Novartis, Almirall Hermal,
MSD, Amgen; Research funding: Novartis, Pfizer, Johnson &
Johnson; Travel & Accomodations: Roche, Bristol-Myers Squibb.
Acknowledgements
The authors vouch for the content of this publication, and
confirm that recommendations made by consensus are match-
ing their viewpoints. The corresponding author prepared the
initial draft of the manuscript with editorial and writing assis-
tance, and all authors contributed to the subsequent drafts. All
authors contributed to the content of the manuscript, the
drafted manuscript and approved the final version as well as
the submission.
Editorial assistance and medical writing was provided by
Dr Markus Hartmann from Ecc-Oncology, funded by Bristol-Myers
Squibb – Germany. Bristol-Myers Squibb did not influence the
content of the manuscript, nor did the authors receive financial
compensation for authoring this manuscript.
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