Conditions: Triple Negative Breast Neoplasms
Keywords: M7824 Bintrafusp alfa Programmed death-ligand 1 Transforming growth factor-β (TGF-β) Breast Cancer MS200647
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The main purpose of this study was to evaluate bintrafusp alfa monotherapy in participants with triple negative breast cancer (TNBC) who express high levels of HMGA2 as determined by a centralized reverse transcriptase-polymerase chain reaction (RT-PCR) test.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Bintrafusp alfa
Intervention descriptions: intervention 1: Participants received an intravenous infusion of 1200 milligrams (mg) bintrafusp alfa once every 2 weeks until confirmed disease progression, unacceptable toxicity, study withdrawal or death.

Protocol document:
Prot_000.pdf: 
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Version Number
Type
Version Date
1.0
Original Protocol
11-Jul-2019
2.0
Global Amendment
06-Jul-2021
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Section # and Name
Description of Change
Brief Rationale
Title Page
Revised “Amendment Number” row
Removed “Medical Responsible” field
Removed “Protocol Version”,
“Replaces Version”, “Approval Date”, 
and "Medical Monitor Contact 
Information” rows 
To be consistent with current Sponsor 
protocol template (Version 15)
1.3 Schedule of Activities
!
Text updated to clarify limited 
disease history information to be 
collected at prescreening 
!
Text is updated to clarify 
Intervention Period window of 
±3 days is not applicable for 
tumor evaluations
To clarify study procedures.
2.3 Benefit/Risk 
Assessment
Text updated to address risk 
reclassification
The risk reclassification was based on in-
depth analysis of a pooled safety dataset 
of N = 765 participants who received 
bintrafusp alfa monotherapy at 1200 mg 
Q2W.
5. Study Population
Appendix 2
Edits related to informed consent 
procedure
To be consistent with current Sponsor 
protocol template (Version 15)
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Section # and Name
Description of Change
Brief Rationale
6.9 Management of 
Adverse Events of 
Special Interest 
Appendix 4
Risk reclassification has been done 
and the list of events has been 
updated accordingly
The risk reclassification was based on in-
depth analysis of a pooled safety dataset 
of N = 765 participants who received 
bintrafusp alfa monotherapy at 1200 mg 
Q2W as reflected in Investigator’s 
Brochure, V7.0.
6.9.1 Infusion-related 
Reactions Including 
Hypersensitivity
Infusion-related reactions are 
reclassified from “important identified 
risk” to “identified risk” for bintrafusp 
alfa
6.9.1, Table 5. Treatment 
Modification of Bintrafusp 
alfa for Symptoms of 
Infusion Related 
Reactions Including 
Immediate 
Hypersensitivity
Additional details of treatment 
modifications for severe or life-
threatening reactions have been 
added.
6.9.2 Immune-related 
Adverse Events
Risk reclassification has been done 
and the list of events has been 
updated accordingly
6.9.3. TGF-β Inhibition 
Mediated Skin Reactions
Skin Adverse Events have been 
renamed as TGF-β Inhibition 
Mediated Skin Reactions
6.9.4 Anemia
Term “treatment-related anemia 
events” has been revised to “anemia” 
and reclassified from “important 
potential risk” to “important identified 
risk” for bintrafusp alfa
6.9.5 Bleeding Events
Bleeding events are reclassified from 
“potential risk” to “important identified 
risk” for bintrafusp alfa
6.9.6.1 Impaired Wound 
Healing
The risk name “Alterations in Wound 
Healing or Repair of Tissue Damage” 
has been changed to “Impaired 
Wound Healing”
7.3 Lost to Follow-up
Edits are done related to Lost to 
Follow-up information
To be consistent with current Sponsor 
protocol template (Version 15)
8.1 Efficacy Assessments 
and Procedures
Text has been updated to suggest 
caution in diagnosis of disease 
progression based solely on nodal 
enlargement within 8 weeks of 
coronavirus vaccination.
To clarify study procedures.
Note: Minor changes have been performed throughout the protocol to address consistency pertaining to major 
changes made in the protocol or to add further clarity and precision.
- Confidential –
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2021 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Endpoints (Outcome Measures)
Primary
!
To evaluate clinical efficacy of bintrafusp alfa in 
participants with TNBC with high HMGA2 
expression, based on ORR
!
Confirmed objective response according to RECIST 1.1 
assessed by an IRC
Secondary
!
To evaluate clinical efficacy of bintrafusp alfa 
based on DOR
!
DOR according to RECIST 1.1 assessed by an IRC
!
To evaluate clinical efficacy of bintrafusp alfa 
based on DRR
!
Durable response of at least 6 months assessed by an 
IRC
!
To evaluate clinical efficacy based on PFS
!
PFS according to RECIST 1.1 assessed by an IRC
!
To evaluate ORR, DOR, DRR, and PFS by 
Investigator read
!
Objective response, DOR, DRR, and PFS according to 
RECIST 1.1 as assessed by the Investigator 
!
To evaluate clinical efficacy based on OS
!
OS
!
To evaluate clinical safety of bintrafusp alfa
!
Occurrence of TEAEs and treatment-related AEs 
including AEs of special interest
!
To characterize the PK profile of bintrafusp alfa
!
The concentration observed immediately at the end of 
infusion (CEOI) of bintrafusp alfa
!
The concentration observed immediately before next 
dosing (corresponding to predose or trough 
concentration [Ctrough] for multiple dosing) of bintrafusp 
alfa
!
To characterize the immunogenicity of 
bintrafusp alfa
!
Immunogenicity of bintrafusp alfa as measured by ADA 
assay from Screening through Safety Follow-up Visit up 
to 28 days after last treatment
ADA=antidrug antibody, AE=adverse event, DOR=duration of response, DRR=durable response rate, 
HMGA2=High Mobility Group AT-Hook 2, IRC=Independent Review Committee, ORR=objective response rate, 
OS=overall survival, PFS=progression-free survival, PK=pharmacokinetic, RECIST 1.1=Response Evaluation 
Criteria in Solid Tumors Version 1.1, TEAE=Treatment-emergent adverse event, TNBC=Triple negative breast 
cancer.
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DOR=duration of response, DRR=durable response rate, HMGA2=High Mobility Group AT-Hook 2, IV=intravenous, 
N=number of participants, OS=overall survival, PFS=progression-free survival, Q2W=every 2 weeks.

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Triple negative breast cancer
HMGA2 expressing
N=29 
Bintrafusp alfa 
1200 mg 
IV, Q2W,
Up to 24 months
Primary endpoint: 
Objective response
Key secondary 
endpoints:
Safety, DOR, DRR, PFS 
and OS
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6FKHGXOHRI$FWLYLWLHV
Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Administrative Procedures
Written 
informed 
consent
Xa
X
Screening tests 
performed as part 
of routine care prior 
to informed 
consent signed will 
be accepted if they 
are within 28-day 
Screening window 
(see Section 5.4).
a: Prescreening 
ICF will be used to 
determine the main 
study eligibility 
criteria ahead of 
full Screening 
procedures (see 
Section 4.1).
Inclusion/
exclusion 
criteria/
Enrollment (if 
eligible)
X
X
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Demographic 
data
X
Xb
See Appendix 2.
b: Demographic 
data collected 
during 
Prescreening 
should be verified 
and updated (if 
indicated) at 
Screening Visit.
Medical history 
Xc
X
See Appendix 2.
c: Part of the 
Disease History 
should be collected 
during 
Prescreening. The  
remaining Disease 
History and the full 
Medical History 
should be collected 
only if the 
participant passes 
prescreening.
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Prior
anticancer 
drug/radio
therapy 
/procedures for 
baseline visit
X
Xd
Prior anticancer 
procedures and 
therapies should at 
least include prior 
therapy, prior 
diagnosis of pre-
malignant lesions 
and treatments, 
surgical resection 
and recurrence, 
and details on 
anticancer 
treatments, 
treatment duration, 
and treatment 
responses.
d: Prior therapy 
collected during 
Prescreening 
should be verified 
and updated (if 
indicated) at 
Screening Visit.
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Documentation 
of concomitant 
medication 
and 
procedures
X
X
X
X
X
X
X
X
X
X
Q2W
X
X
Xe
Xe
e: The 12-week 
Safety Follow-up 
and Long-term 
Follow-up may be 
conducted via 
telephone calls or 
patient chart 
reviews as 
necessary unless 
there is medical 
necessity requiring.
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
Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Tumor Biopsies/Archival Tissue Collection
Tumor tissue 
collectionf
X
Xf
Xf
Xf
See Section 8.8.
Archival or fresh 
tumor tissue during 
Prescreening 
period is required 
for HMGA2 testing
(see Section 4.1
and 8.8).
f: Optional fresh 
biopsies during 
Screening, at W3 
and End-of-
Treatment Visit 
(excluding bone 
biopsies) may be 
tested for 
 
 
biomarkers (see 
Section 8.8).
Tissue from 
unscheduled 
procedures may 
also be submitted.
Bintrafusp alfa Drug Administration
Bintrafusp alfa
administration
X
X
X
X
X
X
X
X
X
Q2W
See Section 4.1 for 
treatment duration.
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Safety Assessments
Documentation 
of AEs
Xg
X
X
X
X
X
X
X
X
X
X
Q2W
X
X
Xh
Xh
See Section 8.3
and Appendix 4 for 
definition of AE 
reporting period 
and follow-up.
g: During 
Prescreening, only 
AEs associated 
with study 
procedures should 
be recorded.
h: The 12-week 
Safety Follow-up 
and Long-term 
Follow-up may be 
conducted via 
telephone calls or 
patient chart 
reviews as 
necessary unless 
there is medical 
necessity requiring 
a clinical visit.
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Physical 
examination
X
X
X
X
X
X
X
X
X
X
Q2W
X
X
Complete PE to be 
performed at 
Screening; 
subsequent 
focused 
examinations to be 
performed as 
described in 
Section 8.2.1.
Skin 
assessment
X
X
X
Q6W
X
X
See Section Error! R
eference source 
not found. for skin 
assessment.
Vital signs
X
X
X
X
X
X
X
X
X
X
Q2W
X
X
Including weight 
and height (height 
at Screening only).
See Section 8.2.2.
ECOG PS
X
X
X
X
X
X
X
X
X
X
Q2W
X
X
12-lead ECG
X
12-lead ECG will be repeated if clinically indicated
See Section 8.2.3.
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Laboratory Assessments
Virology 
serology
(HIV)
As clinically indicated in participants with a history of HIV infection
HIV testing is not 
mandatory. Any 
HIV history should 
be indicated in 
medical history. If a 
test is performed at 
any point in 
Screening or while 
on study, a site 
must consent the 
participant for HIV 
testing as per local 
standard guidance
(see Inclusion 
Criteria 9).
Virology 
serology (HBV 
and HCV)
X
As clinically indicated in participants with a history of HBV or HCV infection
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Hematology
X
X
X
X
X
X
X
X
Q4W
X
X
See Appendix 6 for 
details on blood 
tests. Samples 
must also be drawn 
prior to study 
intervention 
administration and 
results of selected 
laboratory tests 
(see Appendix 6) 
must be reviewed 
within 3 days prior 
to dosing.
Biochemistry
X
X
X
X
X
X
X
X
Q4W
X
X
Biochemistry is 
listed in Appendix
6. Samples must 
be drawn prior to
study intervention 
administration and 
results of selected 
laboratory tests 
(see Appendix 6) 
must be reviewed 
within 3 days prior 
to dosing.
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
Urinalysis
X
As clinically indicated
Routine urinalysis 
at the Screening 
Visit. If the 
urinalysis is 
abnormal, then a 
culture should be
performed.
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
β-hCG 
pregnancy test
X
X
X
X
X
X
Q4W
X
Xi
β-hCG should be 
determined from 
serum at Screening 
and from a urine or 
serum sample 
thereafter. Results 
of the most recent 
pregnancy test 
should be available 
prior to dosing of 
study intervention. 
If a confirmation of 
a participant’s 
postmenopausal 
status is 
necessary, FSH 
and estradiol tests 
will be performed 
at Screening.
i: Participants may 
go to local 
laboratory to 
perform pregnancy 
test. Clinical visit is 
not required. 
T4 and TSH
X
X
X
Q6W
X
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
+Tumor Assessments
Tumor 
evaluation
/staging (CT 
scan/MRI/other 
established 
methods) 
X
X
X
Q8W 
up to 
12 
months, 
then 
Q12W
Xj
See Section 8.1.
j: For participants 
discontinuing 
treatment due to 
reason other than 
PD, perform tumor 
evaluation Q8W 
until 12 months
(e.g.W49), then 
Q12W until 
confirmed PD or 
study 
discontinuation.
The window for 
tumor evaluation is 
± 7 days. The 
Intervention Period 
window of 
(± 3 days) is not 
applicable for 
tumor evaluations.
Subsequent 
anticancer 
therapy (any 
line)
X
X
X
Survival 
follow-up
X
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Assessments 
& Procedures
Pre
scree
ning
Scree
ning
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28
to 
Treat
ment 
Assign
ment
V1
V2
V3
V4
V5
V6
V7
V8
V9
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks)
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
W15
W17
D1
D15 D29 D43 D57
D71
D85
D99
D113
PK, ADA and Biomarker 
PK and ADA 
sampling
See Table 2 for PK and ADA sampling times
Whole blood
for pharmaco-
genetics
X
Whole blood 
sample for 
participants who 
provide separate 
informed consent.
This sample can be 
collected at any 
other visit if missed 
in this visit.
Liquid biopsy 
(plasma)
X
X
X
Q12W 
X
Liquid biopsy 
(plasma) for 
genetic profiling 
including TMB 
analysis will be 
collected within 
2 hours prior to 
study intervention 
infusion as 
scheduled.
ADA=antidrug antibody, AE=adverse events, β-hCG=β-human chorionic gonadotropin, CT=computed tomography, D=Day, ECG=electrocardiogram, 
ECOG PS=Eastern Cooperative Oncology Group performance status, FSH=follicle-stimulating hormone, HBV=hepatitis B virus, HCV=hepatitis C virus, 
HIV=Human immunodeficiency virus, HMGA2=High Mobility Group AT-Hook 2, ICF= informed consent form, MRI=magnetic resonance imaging, PD=progressive
disease, PE=physical examination, PK=pharmacokinetics, Q2W=every 2 weeks; Q4W=every 4 weeks, Q6W=every 6 weeks, Q8W=every 8 weeks, Q12W=every 
12 weeks, T4=free thyroxine, TMB= Tumor mutational burden, TSH=thyroid-stimulating hormone, V=visit, W=Week.
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Bintrafusp 
alfa 
Measure
Screening /
Baseline 
Assessments
Intervention Period
(± 3 days)
End-of-
Treatment
Visit
Safety Follow-up Visit
Notes
Day -28 to 
First 
Treatment
V1
V2
V3
V4
V7
Until 
Progression 
Pre/End 
Infusion
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
Up to 28 
Days 
(± 5 days) 
After Last 
Treatment
12 Weeks 
(± 2 weeks) 
After Last 
Treatment
W1
W3
W5
W7
W13
D1
Pre/End 
Infusion
D15
Pre/End 
Infusion
D29
Pre/End 
Infusion
D43
Pre/End 
Infusion
D85
Pre/End 
Infusion
Blood 
sample for 
PK
X/X
X/-
X/X
X/-
X/-
X/-
Q6W up 
to/including 
W25, then 
Q12W
X
X
Samples for PK analysis to 
be taken before (pre) infusion 
(as close to the start of the 
infusion as possible), 
immediately after the 
completion of infusion (as 
close to the completion as 
possible but no later than 
30 minutes post end of 
infusion). The predose 
sample should still be drawn 
even if dosing is ultimately 
deferred at the study visit. 
The exact time of each draw 
must be recorded. 
Blood 
sample for 
ADA
X/-
X/-
X/-
X/-
X/-
X/-
Q6W up 
to/including 
W25, then 
Q12W
X
X
Predose ADA samples to be 
collected prior to study 
intervention infusions. The 
exact time of each draw must 
be recorded.
ADA=antidrug antibody, D=day, PK=pharmacokinetics, Q6W=every 6 weeks, Q12W=every 12 weeks, V=visit, W=Week.
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Objectives
Endpoints (Outcome Measures)
Primary
!
To evaluate clinical efficacy of bintrafusp alfa in 
participants with TNBC with high HMGA2 
expression, based on ORR
!
Confirmed objective response according to RECIST 1.1 
assessed by an IRC
Secondary
!
To evaluate clinical efficacy of bintrafusp alfa 
based on DOR
!
DOR according to RECIST 1.1 assessed by an IRC
!
To evaluate clinical efficacy of bintrafusp alfa 
based on DRR
!
Durable response of at least 6 months assessed by an 
IRC
!
To evaluate clinical efficacy based on PFS
!
PFS according to RECIST 1.1 assessed by an IRC
!
To evaluate ORR, DOR, DRR, and PFS by 
Investigator read
!
Objective response, DOR, DRR, and PFS according to 
RECIST 1.1 as assessed by the Investigator 
!
To evaluate clinical efficacy based on OS
!
OS
!
To evaluate clinical safety of bintrafusp alfa
!
Occurrence of TEAEs and treatment-related AEs 
including AEs of special interest
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Objectives
Endpoints (Outcome Measures)
!
To characterize the PK profile of bintrafusp alfa
!
The concentration observed immediately at the end of 
infusion (CEOI) of bintrafusp alfa
!
The concentration observed immediately before next 
dosing (corresponding to predose or trough 
concentration [Ctrough] for multiple dosing) of bintrafusp 
alfa
!
To characterize the immunogenicity of 
bintrafusp alfa
!
Immunogenicity of bintrafusp alfa as measured by ADA 
assay from Screening through Safety Follow-up Visit up 
to 28 days after last treatment
 
 
 
 
 
 
 
 
ADA=antidrug antibody, AE=adverse event, DOR=duration of response, DRR=durable response rate,
HMGA2=High Mobility Group AT-Hook 2, ir=immune-related, IRC=Independent Review Committee,
ORR=Objective response rate, OS=overall survival, PD-L1=programmed death-ligand 1, PFS=progression-free 
survival, PK=pharmacokinetic, RECIST 1.1=Response Evaluation Criteria in Solid Tumors Version 1.1, 
TEAE=Treatment-emergent adverse event, TMB=tumor mutational burden, TNBC=triple negative breast cancer. 
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NCI-CTCAE v5.0 Grade
Treatment Modification 
Grade 1 – mild
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Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
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Increase monitoring of vital signs as medically 
indicated as long as participants are deemed 
medically stable by the attending Investigator.
Grade 2 – moderate
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Therapy or infusion interruption indicated but if 
responds promptly to symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for ∀24 hours.
!
Stop the infusion of the study intervention caused 
IRR.
!
Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator. 
!
If symptoms resolve quickly or decrease to Grade 1, 
resume infusion at 50% of original rate with close 
monitoring of any worsening, otherwise dosing held 
until resolution of symptoms with mandated 
premedication for the next scheduled visit. 
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modification guidelines accordingly.
Grade 3 or Grade 4 – severe or life-threatening
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Grade 3: Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.
!
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
!
Stop the infusion of study intervention caused IRR 
immediately and disconnect infusion tubing from the 
participant with additional appropriate medical 
measures and closely monitor until deemed 
medically stable by the attending Investigator. 
Hospitalization and/or close monitoring is 
recommended.
!
Administration of glucocorticoids may be required.
!
Restart the medication taking out the drug that is the 
cause of IRRs from the next scheduled visit.
IRR=infusion-related reaction, IV=intravenous, NCI-CTCAE=National Cancer Institute Common Terminology 
Criteria for Adverse Events, NSAID=nonsteroidal anti-inflammatory drug. 
Once the bintrafusp alfa infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain 
decreased for all subsequent infusions. For Grade 3 or 4 IRRs, bintrafusp alfa discontinuation is mandated. 
For all types and grades of infusion reactions, details about drug physical constitution, method of preparation, and 
infusion must be recorded.
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Baseline Anemia Evaluation (Prior to Transfusion, if feasible)
CBC with differential (e.g., Hgb, hematocrit, MCV, reticulocytes counts, ANC).
Peripheral blood smear for cell morphological assessment.
Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, and other chemistries, if indicated:
1.
Coagulation factors (PT, PTT, INR)
2.
Urinalysis including culture
3.
Iron panel (TIBC, ferritin, Fe)
4.
Serum folate, B12 values
5.
TSH/hormonal panel
6.
Fecal-occult blood testing
7.
Erythropoietin
Further Recommendation Based on Suspected Etiology (in Addition to Baseline Anemia Testing)
Unknown etiology, suspect 
possible hemolysis
Coombs test, fibrinogen, haptoglobin, d-dimer.
Consider hematology consultation.
Consider blood transfusion at clinical discretion.
Unknown etiology, suspect 
possible bleeding
Consider blood transfusion at clinical discretion.
Consider surgical/interventional radiology consultation.
Consider imaging, as clinically indicated (e.g., FAST scan, CT scan, MRI, angiography).
Consider endoscopy (upper/lower). 
Unknown etiology despite 
above work-up
Hematology consultation.
Consider bone marrow aspiration/morphologic evaluation.
ANC=absolute neutrophil count, CBC=complete blood count, CT=computed tomography, FAST=Focused assessment 
with sonography for trauma, Fe=iron, Hgb=hemoglobin, INR=international normalized ratio, LDH=lactate 
dehydrogenase, LFT=liver function test, MCV=mean corpuscular volume, MRI=magnetic resonance imaging, 
PT=prothrombin time, PTT=partial thromboplastin time, TIBC=total iron binding capacity, TSH=thyroid-stimulating 
hormone.
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Screening (SCR)
All participants, who provided informed consent, regardless of the participant’s study 
intervention status in the study.
Safety (SAF)
All participants, who were administered at least 1 infusion of bintrafusp alfa.
Full analysis Set 
(FAS)
All participants, who were administered at least 1 infusion of bintrafusp alfa.
Pharmacokinetic 
(PK)
All participants who complete at least 1 infusion of bintrafusp alfa, and who provide at least 
1 sample with a measurable concentration of bintrafusp alfa.
Immunogenicity
All participants who were administered at least 1 infusion of bintrafusp alfa and have at 
least one valid ADA result.
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Endpoint
Statistical Analysis Methods
Primary
Confirmed objective 
response according to 
RECIST 1.1 assessed by 
an IRC
The ORR will be determined as the proportion of participants with a confirmed 
objective response of PR or CR. Confirmation of the response according to 
RECIST 1.1 will be required no sooner than 4 weeks after the initial documentation of 
CR or PR.
The 95% CI for the ORR will be calculated using the Clopper-Pearson method.
Key Secondary
DOR assessed by an 
IRC
DOR is defined as the time from first documentation of a confirmed objective 
response (CR or PR) according to RECIST1.1 to the date of first documentation of 
objective response of disease progression (PD) or death due to any cause whichever 
occurs first. The censoring rules for DOR are as described below for PFS.
Kaplan-Meier estimates will be provided;
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Endpoint
Statistical Analysis Methods
Median DOR and the 95% CI for the median will be calculated according to 
Brookmeyer and Crowley (Brookmeyer 1982);
Swimmer plots will be provided.
Durable response 
assessed by an IRC
A durable response is defined as an objective response (CR or PR) according to 
RECIST 1.1, determined by an IRC, with a duration of at least 6 months. Participants 
for whom the DOR is censored will be treated as failures (successes) in the analysis 
of durable response if the censored DOR is before (at least) 6 months. 
The DRR is defined as the percentage of participants with durable response. The 
95% CI for the DRR will be calculated using the Clopper-Pearson method.
PFS according to 
RECIST 1.1 assessed by 
an IRC
PFS according to RECIST 1.1, is defined as the time from first administration of study 
intervention until date of the first documentation of PD or death due to any cause in 
the absence of documented PD, whichever occurs first.
PFS data will be censored on the date of the last adequate tumor assessment for 
participants who do not have an event (PD or death), for participants who start new 
anticancer treatment prior to an event, or for participants with an event after 2 or more 
missing tumor assessments. Participants who do not have a baseline tumor 
assessment or who do not have any post-baseline tumor assessments will be 
censored on the date of first administration of study intervention unless death 
occurred on or before the time of the second planned tumor assessment, in which 
case the death will be considered an event.
Kaplan-Meier estimates will be provided;
Median PFS and the 95% CI for the median will be calculated according to 
Brookmeyer and Crowley (Brookmeyer 1982).
Overall survival 
Overall survival is defined as the time from first administration of study intervention to 
the date of death due to any cause. Participants last known to be alive will be 
censored at date of last contact.
Kaplan-Meier estimates will be provided;
Median OS and the 95% CI for the median will be calculated according to 
Brookmeyer and Crowley (Brookmeyer 1982).
Confirmed Objective 
response, DOR, DRR, 
and PFS according to 
RECIST 1.1 assessed by 
Investigator
Definition and analyses to be performed on the efficacy endpoints as assessed by 
Investigator will be similar to the endpoints as assessed by the Investigator, see 
above.
CI= confidence interval, CR=complete response, DOR=duration of response, DRR=durable response rate,
IRC=Independent Review Committee, ORR=objective response rate, OS=overall survival, PD=progressive 
disease, PFS= progression-free survival, PR=partial response, RECIST 1.1=Response Evaluation Criteria in Solid 
Tumors Version 1.1.
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Endpoint
Statistical Analysis Methods
Primary
Not applicable
Secondary
Occurrence of TEAEs 
and treatment-related 
AEs
The safety endpoints will be tabulated using descriptive statistics.
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Participants will be analyzed according to the actual treatment they receive.
!
The safety endpoints will be analyzed using descriptive statistics.
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The incidence of TEAEs, SAEs, treatment-related AEs, AESIs, and irAEs will be 
summarized by preferred term and system organ class for each treatment arm, 
and described in terms of severity and relationship to treatment.
!
The worst on-treatment grades for chemistry and hematology laboratory results 
will be summarized.
!
Shifts in toxicity grading from Baseline to highest grade during the on-treatment 
period will be displayed. 
!
For laboratory tests without an NCI-CTCAE grade definition results will be 
presented categorically (e.g., below, within, or above normal limits). 
Further details of safety analyses (including AEs, clinical laboratory assessments, 
vital signs, physical examination, ECG parameters, and ECOG PS) will be provided in 
the IAP.
AE=adverse event, AESI=adverse event of special interest, ECG=electrocardiogram, ECOG PS=Eastern 
Cooperative Oncology Group performance status, IAP=Integrated Analysis Plan, irAE=immune-related adverse 
event, NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events, SAE=serious 
adverse event, TEAE=treatment-emergent adverse event.
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1.0 Skin Toxicities
1.1 Rash/inﬂammatory dermatitis
Deﬁnition: Erythema multiforme minor (a targetoid reaction in the skin and mucous membranes usually triggered 
by infections, such as herpes simplex viruses, but can be associated with an immune-related drug eruption and if 
progresses to erythema multiforme major, it and can be a harbinger of SCAR, such as SJS), lichenoid (resembling 
the ﬂat-topped, polygonal, and sometimes scaly or hypertrophic lesions of lichen-planus), eczematous 
(inﬂammatory dermatitis characterized by pruritic, erythematous, scaly, or crusted papules or plaques on the skin, 
which is vulnerable to superinfection, psoriasiform [resembling the well-demarcated, erythematous, and scaly 
papules and plaques of psoriasis], morbilliform [a nonpustular, nonbullous measles-like exanthematous rash of the 
skin often referred to as “maculopapular” and without systemic symptoms or laboratory abnormalities, excluding 
occasional isolated peripheral eosinophilia], palmoplantar erythrodysesthesia [hand-foot syndrome; redness, 
numbness, burning, itching, and superﬁcial desquamation of the palms and soles], neutrophilic dermatoses [e.g, 
Sweet syndrome], and others)
Diagnostic work-up
Pertinent history and physical examination
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition 
linked to another systemic disease or unrelated primary skin disorder
If needed, a biologic checkup, including a blood cell count and liver and kidney tests
Directed serologic studies if an autoimmune condition is suspected, such as lupus or dermatomyositis: a screening 
antinuclear antibody test, SS-A/Anti-Ro, SS-B/Anti-La if predominantly photodistributed/photosensitivity, 
antihistone, double-stranded DNA, and other relevant serologies. Consider expanding serologic studies or 
diagnostic work-up if other autoimmune conditions are considered based on signs, symptoms Skin biopsy
Consider clinical monitoring with use of serial clinical photography
Review full list of patient medications to rule out other drug-induced cause for photosensitivity
Grading
Management
Grading according to CTCAE is a challenge for skin. 
Instead, severity may be based on BSA, tolerability, 
morbidity, and duration
G1: Symptoms do not affect the quality of life or 
controlled with topical regimen and/or oral antipruritic
Continue ICPi
Treat with topical emollients and/or mild-moderate 
potency topical corticosteroids
Counsel patients to avoid skin irritants and sun 
exposure
G2: Inﬂammatory reaction that affects quality of life and 
requires intervention based on diagnosis
Consider holding ICPi and monitor weekly for 
improvement. If not resolved, interrupt treatment until 
skin AE has reverted to Grade 1
Consider initiating prednisone (or equivalent) at dosing 
1 mg/kg, tapering over at least 4 weeks
In addition, treat with topical emollients, oral 
antihistamines, and medium- to high-potency topical 
corticosteroids
G3: As G2 but with failure to respond to indicated 
interventions for a G2 dermatitis
Hold ICPi therapy and consult with dermatology to 
determine appropriateness of resuming
Treat with topical emollients, oral antihistamines, and 
high-potency topical corticosteroids
Initiate (methyl)prednisolone (or equivalent) 1-2 mg/kg, 
tapering over at least 4 weeks
G4: All severe rashes unmanageable with prior 
interventions and intolerable
Permanently discontinue ICPi
Systemic corticosteroids: IV (methyl)prednisolone (or 
equivalent) dosed at 1-2 mg/kg with slow tapering when 
the toxicity resolves
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1.0 Skin Toxicities
Monitor closely for progression to severe cutaneous 
adverse reaction
Should admit patient immediately with direct oncology 
involvement and with an urgent consult by dermatology
1.2 Bullous dermatoses
Deﬁnition: Including bullous pemphigoid or other autoimmune bullous dermatoses, bullous drug reaction
Diagnostic work-up
Physical examination
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition 
linked to another systemic disease
If needed, a biologic checkup, including a blood cell count, liver, and kidney tests; consider serum antibody tests to 
rule out bullous pemphigoid or, under the guidance of dermatology, sending patient serum for indirect 
immunoﬂuorescent testing to rule out other autoimmune blistering diseases
Referral to dermatology for blisters that are not explained by infectious or transient other causes (e.g, herpes 
simplex, herpes zoster, bullous impetigo, bullous insect bite, friction or pressure blister)
Consider skin biopsy (both hematoxylin and eosin evaluation of lesional skin and direct immunoﬂuorescence 
evaluation of perilesional skin)
Grading
Management
G1: Asymptomatic, blisters covering < 10% BSA and no 
associated erythema
If blisters are < 10% BSA, asymptomatic, and 
noninﬂammatory (such as the case with friction blisters 
or pressure blisters), cessation of ICPi is not necessary, 
and only observation and/or local wound care is 
warranted.
When symptomatic bullae or erosions, which are 
deroofed vesicles or bullae, are observed on the skin or 
mucosal surfaces, the cutaneous irAE is by deﬁnition 
considered at least G2
See G2 management recommendations
G2: Blistering that affects quality of life and requires 
intervention based on diagnosis not meeting criteria for 
Grade > 2
Blisters covering 10%-30% BSA
Hold ICPi therapy and consult with dermatology for 
work-up and to determine appropriateness of resuming
Attention given to general local wound care, which 
includes plain petrolatum ointment and bandages or 
plain petrolatum ointment gauze and bandage over any 
open erosions, which are left over on the skin after the 
blister has popped or if the roof of the blister easily 
sloughs off
Counsel patients to avoid skin irritants and 
overexposure to sun, wear protective clothing, use 
sunscreens
Work-up for autoimmune bullous disease as above
Initiate Class 1 high-potency topical corticosteroid (e.g, 
clobetasol, betamethasone or equivalent) and reassess 
every 3 days for progression or improvement
Low threshold to initiate treatment with prednisone (or 
equivalent) at 0.5-1 mg/kg dosing and taper over at 
least 4 weeks
Monitor patients with G2 irAEs closely for progression 
to involvement of greater BSA and/or mucous 
membrane involvement. Consider following patients 
closely using serial photography
Primer on monitoring for complicated cutaneous 
adverse drug reactions:
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1.0 Skin Toxicities
Review of systems: Skin pain (like a sunburn), fevers, 
malaise, myalgias, arthralgias, abdominal pain, ocular 
discomfort or photophobia, sores or discomfort in the 
nares, sores or discomfort in the oropharynx, 
odynophagia, hoarseness, dysuria, sores or discomfort 
in the vaginal area for women or involving the meatus 
of the penis for men, sores in the perianal area, or pain 
with bowel movements
Physical examination: Include vital signs and a full skin 
examination speciﬁcally evaluating all skin surfaces 
and mucous membranes (eyes, nares, oropharynx, 
genitals, and perianal area). Assess for 
lymphadenopathy, facial or distal extremity swelling 
(may be signs of DIHS/DRESS). Assess for pustules or 
blisters or erosions in addition to areas of “dusky 
erythema,” which may feel painful to palpation. To 
assess for a positive Nikolsky sign, place a gloved 
ﬁnger tangentially over erythematous skin and apply 
friction parallel to the skin surface. Nikolsky sign is 
positive if this results in detached or sloughing 
epidermis demonstrating poor attachment of the 
epidermis to the dermis, which is the case in some 
autoimmune disorders (eg, pemphigus) and SJS/TEN
G3: Skin sloughing covering > 30% BSA with 
associated pain and limiting self-care ADL
Hold ICPi therapy and consult with dermatology to 
determine appropriateness of resuming
Administer IV (methyl)prednisolone (or equivalent) 1-2 
mg/kg, tapering over at least 4 weeks
If bullous pemphigoid is diagnosed, it may be possible 
to avoid long-term use of systemic corticosteroids and 
treat with rituximab, as an alternative approach to 
treating the irAE
Seek infectious disease consultation if patient might 
have secondary cellulitis or if patient has other infection 
risk factors, such as neutropenia, etc.
G4: Blisters covering > 30% BSA with associated ﬂuid 
or electrolyte abnormalities
Permanently discontinue ICPi
Admit patient immediately and place under supervision 
of a dermatologist
Administer IV (methyl)prednisolone (or equivalent) 1-2 
mg/kg with tapering over at least 4 weeks when the 
toxicity resolves
If bullous pemphigoid is diagnosed, it may be possible 
to avoid long-term use of systemic corticosteroids and 
treat with rituximab as an alternative approach to 
treating the irAE
Seek infectious disease consultation if patient might 
have secondary cellulitis or if patient has other infection 
risk factors, such as neutropenia, etc
1.3 SCARs, including SJS, TEN, acute generalized exanthematous pustulosis, and DRESS/DIHS
Deﬁnition: Severe changes in either structure or functions of skin, the appendages or the mucous membranes due 
to a drug
Diagnostic work-up
Total body skin examination with attention to examining all mucous membranes as well as complete review of 
systems
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin condition 
linked to another systemic disease
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1.0 Skin Toxicities
A biologic checkup, including a CBC with differential test, and liver and kidney function tests, including urinalysis, 
in addition to the blood work; if the patient is febrile, blood cultures should be considered as well
Skin biopsies to assess for full-thickness epidermal necrosis, as is seen in SJS/TEN, as well as other possible 
etiologies like paraneoplastic pemphigus or other autoimmune blistering dermatoses or other drug reactions, such 
as acute generalized exanthematous pustulosis
Consider following patients closely using serial clinical photography
If mucous membrane involvement or blistering is observed on the skin, consider early admission to a burn center 
for further monitoring and management Primer on monitoring for complicated cutaneous adverse drug reactions:
Review of systems: Skin pain (like a sunburn), fevers, malaise, myalgias, arthralgias, abdominal pain, ocular 
discomfort or photophobia, sores or discomfort in the nares, sores or discomfort in the oropharynx, odynophagia, 
hoarseness, dysuria, sores or discomfort in the vaginal area for women or involving the meatus of the penis for 
men, sores in the perianal area, or pain with bowel movements
Physical examination: Include vital signs and a full skin examination speciﬁcally evaluating all skin surfaces and 
mucous membranes (eyes, nares, oropharynx, genitals, and perianal area). Assess for lymphadenopathy, facial or 
distal extremity swelling (may be signs of DIHS/DRESS). Assess for pustules or blisters or erosions in addition to 
areas of “dusky erythema”, which may feel painful to palpation. To assess for a positive Nikolsky sign, place a 
gloved ﬁnger tangentially over erythematous skin and apply friction parallel to the skin surface. Nikolsky sign is 
positive if this results in detached or sloughing epidermis demonstrating poor attachment of the epidermis to the 
dermis, which is the case in some autoimmune disorders (e.g, pemphigus) and SJS/TEN
Grading
Management
All Grades
In cases of suspected SJS or any mucous membrane 
involvement, discontinue ICPi treatment and monitor 
closely for improvement, regardless of grade
G1: NA
For SCARs, there is no G1 category; if lower BSA is 
involved with bullae or erosions, there should remain a 
high concern that this reaction will progress to G3 or G4
G2: Morbilliform (“maculopapular”) exanthem covering 
10%-30% BSA with systemic symptoms, 
lymphadenopathy, or facial swelling
Hold ICPi and monitor patients closely every 3 days 
with G2 irAEs for progression to involvement of greater 
BSA and/or mucous membrane involvement
Consider following patients closely using serial 
photography
Initiate therapy with topical emollients, oral
antihistamines, and medium- to high-strength topical 
corticosteroids
Consider initiation of prednisone (or equivalent) 0.5-1 
mg/kg tapered over at least 4 weeks
G3: Skin sloughing covering < 10% BSA with mucosal 
involvement associated signs (e.g, erythema, purpura, 
epidermal detachment, mucous membrane 
detachment)
Hold ICPi therapy and consult with dermatology
Treat skin with topical emollients and other petrolatum 
emollients, oral antihistamines, and high-strength 
topical corticosteroids; dimethicone may also be offered 
as an alternative to petrolatum
Administer IV (methyl)prednisolone (or equivalent) 0.5-
1 mg/kg and convert to oral corticosteroids on 
response, wean over at least 4 weeks
Admit to burn and/or consult wound services with 
attention to supportive care, including ﬂuid and 
electrolyte balance, minimizing insensible water losses, 
and preventing infection
Given the immune mechanism of action of these 
medicines, use of immune suppression is warranted 
and should be offered
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1.0 Skin Toxicities
For mucous membrane involvement of SJS or TEN, 
appropriate consulting services should be offered to 
guide management in preventing sequelae from 
scarring (e.g, ophthalmology; ear, nose, and throat; 
urology; gynecology; etc, as appropriate)
G4: Skin erythema and blistering/sloughing covering 
 10% to > 30% BSA with associated signs (e.g, 
erythema, purpura, epidermal detachment, mucous 
membrane detachment) and/or systemic symptoms and 
concerning associated blood work abnormalities (e.g, 
liver function test elevations in the setting of 
DRESS/DIHS)
Permanently discontinue ICPi
Admit patient immediately to a burn unit or ICU with 
consulted dermatology and wound care services
Consider further consultations based on management 
of mucosal surfaces
(e.g, ophthalmology; urology; gynecology; ear, nose, 
and throat surgery; etc) Initiate IV (methyl)prednisolone 
(or equivalent) 1-2 mg/kg, tapering when toxicity 
resolves to normal
IVIG or cyclosporine may also be considered in severe 
or corticosteroid-unresponsive cases
Consider pain/palliative consultation and/or admission 
in patients presenting with DRESS manifestations
Additional considerations: The usual prohibition of corticosteroids for SJS is not relevant here, as the underlying 
mechanism is a T-cell immunodirected toxicity
Adequate suppression is necessary with corticosteroids or other agents and may be prolonged in cases of 
DRESS/DIHS
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate
Abbreviations: ADL, activities of daily living; AE, adverse event; BSA, body surface area; CBC, complete blood count; 
CTCAE, Common Terminology Criteria for Adverse Events; DIHS, drug-induced hypersensitivity syndrome; DRESS, 
drug reaction with eosinophilia and systemic symptoms; G, Grade; ICPi, immune checkpoint inhibitor; ICU, intensive 
care unit; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; NA, not 
applicable; SCAR, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal 
necrolysis.
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2.0 GI Toxicities
2.1 Colitis
Deﬁnition: A disorder characterized by inﬂammation of the colon
Diagnostic work-up
G2
Work-up of blood (CBC, comprehensive metabolic panel, TSH, ESR, CRP), stool (culture, Clostridium difficile, 
parasite, CMV or other viral etiology, ova and parasite) should be performed
Consider testing for lactoferrin (for patient stratiﬁcation to determine who needs more urgent endoscopy) and 
calprotectin (to follow-up on disease activity)
Screening laboratories (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients to start inﬂiximab 
should be routinely done in patients at high risk for those infections and appropriately selected patients based on 
infectious disease expert’s evaluation
Imaging (e.g, CT scan of abdomen and pelvis and GI endoscopy with biopsy) should be considered as there is 
evidence showing that the presence of ulceration in the colon can predict a corticosteroid-refractory course, which 
may require early inﬂiximab
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating 
endoscopy for disease monitoring can be considered when clinically indicated and when planning to resume 
therapy
G3-4
All the work-up listed for G2 (blood, stool, imaging, and scope with biopsy) should be completed immediately
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating 
endoscopy for disease monitoring should only be considered when clinically indicated and when planning to 
resume ICPi
Grading (based on CTCAE for diarrhea, as most often 
used clinically)
Management
All patients
Counsel all patients to be aware of and inform their 
health care provider immediately if they experience:
Abdominal pain, nausea, cramping, blood or mucus in 
stool or changes in bowel habits, fever, abdominal 
distention, obstipation, constipation
For G2 or higher, consider permanently discontinuing 
CTLA-4 agents and may restart PD-1, PD-L1 agents if 
patient can recover to G1 or less; concurrent 
immunosuppressant maintenance therapy should be 
considered only if clinically indicated in individual cases
G1: Increase of fewer than four stools per day over 
baseline; mild increase in ostomy output compared with 
baseline
Continue ICPi; alternatively, ICPi may be held 
temporarily and resumed if toxicity does not exceed
G1
Monitor for dehydration and recommend dietary 
changes Facilitate expedited phone contact with 
patient/caregiver May obtain gastroenterology consult 
for prolonged G1 cases
G2: Increase of four to six stools per day over baseline; 
moderate increase in ostomy output compared with 
baseline
Should hold ICPi temporarily until patient’s symptoms 
recover to G1; can consider permanently
discontinuing CTLA-4 agents and may restart PD-1, 
PD-L1 agents if patient can recover to G1 or less
Concurrent immunosuppressant maintenance therapy 
(10 mg prednisone equivalent dose) may be offered 
only if clinically indicated in individual cases
May also include supportive care with medications such 
as Imodium if infection has been ruled out
Should consult with gastroenterology for G2 or higher
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Administer corticosteroids, unless diarrhea is transient, 
starting with initial dose of 1 mg/kg/day prednisone or 
equivalent
When symptoms improve to G1 or less, taper 
corticosteroids over at least 4-6 weeks before resuming 
treatment, although resuming treatment while on low-
dose corticosteroid may also be an option after an 
evaluation of the risks and beneﬁts
EGD/colonoscopy, endoscopy evaluation should be 
highly recommended for cases Grade  2 to stratify 
patients for early treatment with inﬂiximab based on the 
endoscopic ﬁndings and to determine the safety of 
resuming PD-1, PD-L1 therapy
Stool inﬂammatory markers can be considered 
(lactoferrin and calprotectin) in cases of G2 or higher to 
differentiate functional versus inﬂammatory diarrhea, 
and use calprotectin to monitor treatment response if 
provider prefers
Repeat colonoscopy is optional for cases of G2 or 
higher for disease activity monitoring to achieve 
complete remission, especially if there is a plan to 
resume ICPi
G3: Increase of seven or more stools per day over 
baseline, incontinence, hospitalization indicated, severe 
increase in ostomy output compared with baseline, 
limiting self-care ADL
Should consider permanently discontinuing CTLA-4 
agents and may restart PD-1, PD-L1 agents if patient 
can recover to G1 or less.
Administer corticosteroids (initial dose of 1-2 mg/kg/d 
prednisone or equivalent)
Consider hospitalization or outpatient facility for patients 
with dehydration or electrolyte imbalance
If symptoms persist  3-5 days or recur after 
improvement, consider administering IV corticosteroid 
or noncorticosteroid (e.g, inﬂiximab)
Consider colonoscopy in cases where patients have 
been on immunosuppression and may be at risk for 
opportunistic infections as an independent cause for 
diarrhea (i.e, CMV colitis) and for those who are anti-
TNF or corticosteroid refractory
G4: Life-threatening consequences; urgent intervention 
indicated
Permanently discontinue treatment
Should admit patient when clinically indicated; patients 
managed as outpatients should be very closely 
monitored
Administer 1-2 mg/kg/d methylprednisolone or 
equivalent until symptoms improve to G1, and then start 
taper over 4-6 weeks
Consider early inﬂiximab 5-10 mg/kg if symptoms 
refractory to corticosteroid within 2-3 days Consider 
lower GI endoscopy if symptoms are refractory despite 
treatment or there is concern of new infections
Additional considerations
The use of vedolizumab may be considered in patients refractory to inﬂiximab and/or contraindicated to TNF-a 
blocker. The decision should be made on an individual basis from gastroenterology and oncology evaluation. This 
is based on case series showing promising results
Patients with hepatitis and irAE colitis are rare, and management should include permanently discontinuing ICPi 
and offering other immunosuppressant agents that work systemically for both conditions
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Currently, enteritis alone as the cause of diarrhea is uncommon and requires small bowel biopsy as the evaluation 
tool. It may be managed similar as colitis, including corticosteroid and/or inﬂiximab, etc
2.2 Hepatitis
Deﬁnition: A disorder characterized by a viral pathologic process involving the liver parenchyma
Diagnostic work-up
Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin prior to each infusion and/or weekly if G1 
liver function test elevations. No treatment is recommended for G1 liver function test abnormality
For G2 or higher:
Work-up for other causes of elevated liver enzymes should be tested, viral hepatitis, alcohol history, iron study, 
thromboembolic event, liver ultrasound, cross-sectional imaging for potential liver metastasis from primary 
malignancy. If suspicion for primary autoimmune hepatitis is high, can consider ANAs, antismooth muscle 
antibodies, antineutrophil cytoplasmic antibodies. If patients with elevated alkaline phosphatase alone, g-glutamyl 
transferase should be tested. For isolated elevation of transaminases, consider checking CK for other etiologies
Grading
Management
All patients
Counsel all patients to be aware of and inform their 
health care provider immediately if they experience:
Yellowing of skin or whites of the eyes Severe nausea 
or vomiting
Pain on the right side of the abdomen Drowsiness
Dark urine (tea colored)
Bleeding or bruising more easily than normal Feeling 
less hungry than usual
G1: Asymptomatic (AST or ALT > ULN to 3.0 x ULN 
and/or total bilirubin > ULN to 1.5 x ULN)
Continue ICPi with close monitoring; consider alternate 
etiologies
Monitor laboratories one to two times weekly
Manage with supportive care for symptom control
G2: Asymptomatic (AST or ALT > 3.0 to  5 x ULN 
and/or total bilirubin > 1.5 to  3 x ULN)
Hold ICPi temporarily and resume if recover to G1 or 
less on prednisone  10 mg/d
For Grade 2 hepatic toxicity with symptoms, may 
administer corticosteroid 0.5-1 mg/kg/d prednisone or 
equivalent if the abnormal elevation persists with 
signiﬁcant clinical symptoms in 3-5 days Increase 
frequency of monitoring to every 3 days
Inﬂiximab might not be the most appropriate treatment 
option in the situation of immune-mediated hepatitis 
given the potential risk of idiosyncratic liver failure 
(Note: No clear evidence shows the liver toxicity from 
inﬂiximab from other studies)
In follow-up, may resume ICPi treatment followed by 
taper only when symptoms improve to G1 or less and 
corticosteroid  10 mg/d; taper over at least 1 month
Patients should be advised to stop unnecessary 
medications and any known hepatotoxic drugs
G3: Symptomatic liver dysfunction, ﬁbrosis by biopsy, 
compensated cirrhosis, reactivation of chronic hepatitis 
(AST or ALT 5-20 x ULN and/or total bilirubin 3-10x3 
ULN)
Permanently discontinue ICPi
Immediately start corticosteroid 1-2 mg/kg 
methylprednisolone or equivalent
If corticosteroid refractory or no improvement after 3 
days, consider mycophenolate mofetil or azathioprine (if 
using azathioprine should test for thiopurine 
methyltransferase deﬁciency)
Laboratories at daily or every other day; consider 
inpatient monitoring for patients with AST/ALT > 8 x 
ULN and/or elevated TB 3 x ULN
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2.0 GI Toxicities
Increase frequency of monitoring to every 1-2 days
Inﬂiximab might not be the most appropriate treatment 
option in the situation of immune-mediated hepatitis 
given the potential risk of liver failure (Note: No clear 
evidence shows that the liver toxicity from inﬂiximab 
from other studies); alternatives include non–TNF-a 
agents as systemic immunosuppressants If no 
improvement is achieved with corticosteroids or for 
patients on combination therapy with a novel agent, 
with standard chemotherapy, or with targeted therapy, 
refer to hepatologist for further pathologic evaluation of 
hepatitis
Corticosteroid taper can be attempted around 4-6 
weeks; re-escalate if needed; optimal duration unclear
G4: Decompensated liver function (e.g, ascites, 
coagulopathy, encephalopathy, coma; AST or ALT > 20 
x ULN and/or total bilirubin > 10 x ULN)
Permanently discontinue ICPi
Administer 2 mg/kg/d methylprednisolone equivalents
If corticosteroid refractory or no improvement after 
3 days, consider mycophenolate mofetil
Monitor laboratories daily; consider inpatient monitoring
Avoid the use of inﬂiximab in the situation of 
immune-mediated hepatitis
Hepatology consult if no improvement was achieved 
with corticosteroid
Corticosteroid taper can be attempted around 4-6 
weeks when symptoms improve to G1 or less; re-
escalate if needed; optimal duration unclear
Consider transfer to tertiary care facility if necessary
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations is moderate.
Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, 
aspartate aminotransferase; CBC, complete blood count, CK, creatine kinase; CMV, cytomegalovirus; CRP, 
C-reactive protein; CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; CTLA-4, 
cytotoxic T-cell lymphocyte-associated antigen-4; EGD, esophagogastroduodenoscopy; ESR, erythrocyte 
sedimentation rate; G, Grade; GI, gastrointestinal; HIV, human immunodeficiency virus; ICPi, immune checkpoint 
inhibitor; irAE, immune-related adverse event; IV, intravenous; PD-1; programmed death 1; PD-L1, programmed 
death-ligand 1; TB, tuberculosis; TNF, tumor necrosis factor; TSH, thyroid-stimulating hormone; ULN, upper limit of 
normal.
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3.0 Lung Toxicities
3.1 Pneumonitis
Deﬁnition: Focal or diffuse inﬂammation of the lung parenchyma (typically identiﬁed on CT imaging)
No symptomatic, pathologic, or radiographic features are pathognomonic for pneumonitis
Diagnostic work-up
Should include the following: CXR, CT, pulse oximetry
For G2 or higher, may include the following infectious work-up: nasal swab, sputum culture and sensitivity, blood 
culture and sensitivity, urine culture and sensitivity
Grading
Management
G1: Asymptomatic, conﬁned to one lobe of the lung or 
< 25% of lung parenchyma, clinical or diagnostic 
observations only
Continue ICPi 
If clinically indicated. Monitor participants weekly or 
more frequently as needed with history, physical 
examination and pulse oximetry; may also offer CXR. 
May offer one repeat CT scan in 3-4 weeks; in patients 
who have had baseline testing, may offer a repeat 
spirometry/DLCO in 3-4 weeks 
If symptoms appear and/or changes in the physical 
exam are noted, treat as G2
G2: Symptomatic, involves more than one lobe of the 
lung or 25%-50% of lung parenchyma, medical 
intervention indicated, limiting instrumental ADL
Hold ICPi until resolution to G1 or less
Prednisone 1-2 mg/kg/d and taper by 5-10 mg/wk over 
4-6 weeks Consider bronchoscopy with BAL
Consider empirical antibiotics
Monitor every 3 days with history and physical 
examination and pulse oximetry, consider CXR; no 
clinical improvement after 48-72 hours of prednisone, 
treat as G3
G3: Severe symptoms, hospitalization required, 
involves all lung lobes or 50% of lung parenchyma, 
limiting self-care
ADL, oxygen indicated
G4: Life-threatening respiratory compromise, urgent 
intervention indicated (intubation)
Permanently discontinue ICPi
Empirical antibiotics; (methyl)prednisolone IV 1-2 
mg/kg/d; no improvement after 48 hours, may add 
inﬂiximab 5 mg/kg or mycophenolate mofetil IV 1 g 
twice a day or IVIG for 5 days or cyclophosphamide; 
taper corticosteroids over 4-6 weeks
Pulmonary and infectious disease consults if necessary
Bronchoscopy with BAL ± transbronchial biopsy
Patients should be hospitalized for further management
Additional considerations
GI and Pneumocystis prophylaxis with PPI and Bactrim may be offered to patients on prolonged corticosteroid use 
(> 12 weeks), according to institutional guidelines
Consider calcium and vitamin D supplementation with prolonged corticosteroid use
The role of prophylactic ﬂuconazole with prolonged corticosteroid use (> 12 weeks) remains unclear, and 
physicians should proceed according to institutional guidelines
Bronchoscopy + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ADL, activities of daily living; BAL, bronchoalveolar lavage; CT, computed tomography; CXR, chest 
X-ray; DLCO, diffusing capacity of lung for carbon monoxide; G, Grade; GI, gastrointestinal; ICPi, immune checkpoint 
inhibitor; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; PPI, proton pump 
inhibitor.
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4.0 Endocrine Toxicity
Counsel patients to inform their health care provider immediately if they experience any changes in their health 
since their last visit, especially any of the following:
Headaches that will not go away or unusual headache 
patterns
Vision changes
Rapid heartbeat
Increased sweating
Extreme tiredness or weakness
Muscle aches
Weight gain or weight loss
Dizziness or fainting
Feeling more hungry or thirsty than usual
Hair loss
Changes in mood or behavior, such as decreased sex 
drive, irritability, or forgetfulness Feeling cold
Constipation
Voice gets deeper
Urinating more often than usual
Nausea or vomiting
Abdominal pain
4.1 Thyroid
4.1.1 Primary hypothyroidism
Deﬁnition: Elevated TSH, normal or low FT4
Diagnostic work-up
TSH and FT4 every 4-6 weeks as part of routine clinical monitoring on therapy or for case detection in 
symptomatic patients
Grading
Management
G1: TSH < 10 mIU/L and asymptomatic
G2: Moderate symptoms; able to perform ADL; TSH 
persistently > 10 mIU/L
Should continue ICPi with close follow-up and 
monitoring of TSH, FT4 May hold ICPi until symptoms 
resolve to baseline
Consider endocrine consultation
Prescribe thyroid hormone supplementation in 
symptomatic patients with any degree of TSH elevation 
or in asymptomatic patients with TSH levels that persist 
> 10 mIU/L (measured 4 weeks apart)
Monitor TSH every 6-8 weeks while titrating hormone 
replacement to normal TSH FT4 can be used in the 
short term (2 weeks) to ensure adequacy of therapy in 
those with frank hypothyroidism where the FT4 was 
initially low
Once adequately treated, should monitor thyroid 
function (at least TSH) every 6 weeks while on active 
ICPi therapy or as needed for symptoms to ensure 
appropriate replacement; repeat testing annually or as 
indicated by symptoms once stable
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until symptoms resolve to baseline with 
appropriate supplementation
Endocrine consultation
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4.0 Endocrine Toxicity
May admit for IV therapy if signs of myxedema 
(bradycardia, hypothermia) Thyroid supplementation 
and reassessment as in G2
Additional considerations
For patients without risk factors, full replacement can be estimated with an ideal body weight–based dose of 
approximately 1.6 μg/kg/d
For elderly or fragile patients with multiple comorbidities, consider titrating up from low dose, starting at 25-50 mg
Extreme elevations of TSH can be seen in the recovery phase of thyroiditis and can be watched in asymptomatic 
patients to determine whether there is recovery to normal within 3-4 weeks
Under guidance of endocrinology, consider tapering hormone replacement and retesting in patients with a history 
of thyroiditis (initial thyrotoxic phase)
Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy is initiated 
4.1.2 Hyperthyroidism
Deﬁnition: Suppressed TSH and high normal or elevated FT4 and/or triiodothyronine
Diagnostic work-up
Monitor TSH, FT4 every 4-6 weeks from the start of therapy or as needed for case detection in symptomatic 
patients
Consider TSH receptor antibodies if there are clinical features and suspicion of Grave disease (e.g, 
ophthalmopathy)
Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch transition to hypothyroidism in 
patients with thyroiditis and hyperthyroidism
Grading
Management
G1: Asymptomatic or mild symptoms
Can continue ICPi with close follow-up and monitoring 
of TSH, FT4 every 2-3 weeks until it is clear whether 
there will be persistent hyperthyroidism (see below) or 
hypothyroidism (see 4.1.1)
Consider holding ICPi until symptoms return to baseline
Consider endocrine consultation
b-Blocker (e.g, atenolol, propranolol) for symptomatic 
relief
Hydration and supportive care
Corticosteroids are not usually required to shorten 
duration
For persistent hyperthyroidism (> 6 weeks) or clinical 
suspicion, work-up for Graves disease (TSI or TRAb) 
and consider thionamide (methimazole or PTU) Refer 
to endocrinology for Graves disease
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until symptoms resolve to baseline with 
appropriate therapy
Endocrine consultation
b-Blocker (e.g, atenolol, propranolol) for symptomatic 
relief
For severe symptoms or concern for thyroid storm, 
hospitalize patient and initiate prednisone 1-2 mg/kg/d 
or equivalent tapered over 1-2 weeks; consider also 
use of SSKI or thionamide (methimazole or PTU).
Additional considerations
Thyroiditis is transient and resolves in a couple of weeks to primary hypothyroidism or normal. Hypothyroidism can 
be treated as above. Graves disease is generally persistent and is due to increased thyroid hormone production 
that can be treated with antithyroid medical therapy. Physical examination ﬁndings of ophthalmopathy or thyroid 
bruit are diagnostic of Graves and should prompt early endocrine referral.
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4.0 Endocrine Toxicity
4.2 Adrenal – primary adrenal insufﬁciency
Deﬁnition: Adrenal gland failure leading to low morning cortisol, high morning ACTH, as well as hyponatremia and 
hyperkalemia with orthostasis and volume depletion due to loss of aldosterone
Diagnostic work-up for patients in whom adrenal 
insufﬁciency is suspected:
Evaluate ACTH (AM), cortisol level (AM)
Basic metabolic panel (Na, K, CO2, glucose)
Consider ACTH stimulation test for indeterminate 
results
If primary adrenal insufﬁciency (high ACTH, low 
cortisol) is found biochemically:
Evaluate for precipitating cause of crisis such as 
infection Perform an adrenal CT for 
metastasis/hemorrhage
Grading
Management
G1: Asymptomatic or mild symptoms
Consider holding ICPi until patient is stabilized on 
replacement hormone
Endocrine consultation
Replacement therapy with prednisone (5-10 mg daily) 
or hydrocortisone (10-20 mg orally every morning, 
5-10 mg orally in early afternoon)
May require ﬂudrocortisone (0.1 mg/d) for 
mineralocorticoid replacement in primary adrenal 
insufﬁciency
Titrate dose up or down as symptoms dictate
G2: Moderate symptoms, able to perform ADL
Consider holding ICPi until patient is stabilized on 
replacement hormone
Endocrine consultation
Initiate outpatient treatment at two to three times 
maintenance
(if prednisone, 20 mg daily; if hydrocortisone, 20-30 mg 
in the morning, and 10-20 mg in the afternoon) to 
manage acute symptoms.
Taper stress-dose corticosteroids down to maintenance 
doses over 5-10 days
Maintenance therapy as in G1.
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until patient is stabilized on replacement 
hormone
Endocrine consultation
See in clinic or, for after hours, make an emergency 
department referral for normal saline (at least 2 L) and 
IV stress-dose corticosteroids on presentation 
hydrocortisone 100 mg or dexamethasone 4 mg (if the 
diagnosis is not clear and stimulation testing will be 
needed)
Taper stress-dose corticosteroids down to maintenance 
doses over 7-14 days after discharge
Maintenance therapy as in G1
Additional considerations
Primary and secondary adrenal insufﬁciency can be distinguished by the relationship between ACTH and cortisol. 
If the ACTH is low with low cortisol, then management is as per 4.3.
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4.0 Endocrine Toxicity
Patients on corticosteroids for management of other conditions will have low morning cortisol as a result of 
iatrogenic, secondary adrenal insufﬁciency. ACTH will also be low in these patients. A diagnosis of adrenal 
insufﬁciency is challenging to make in these situations (see next section on hypophysitis).
Emergent therapy for someone with suspected adrenal insufﬁciency is best done with dexamethasone as a 
stimulation test can still be performed. If the diagnosis is already conﬁrmed, can use hydrocortisone 100 mg.
All patients need education on stress dosing and a medical alert bracelet for adrenal insufﬁciency to trigger stress-
dose corticosteroids by EMS.
Endocrine consultation prior to surgery or any procedure for stress-dose planning.
4.3 Pituitary - hypophysitis
Deﬁnition: Inﬂammation of the pituitary with varying effects on hormone function. Most commonly presenting with 
central adrenal insufﬁciency. May also have central hypothyroidism, diabetes insipidus, and hypogonadism. 
Diagnostic work-up
Diagnosis: Low ACTH with a low cortisol. Low or normal TSH with a low FT4. Hypernatremia and volume depletion 
with diabetes insipidus. Low testosterone or estradiol with low LH and FSH.
Testing:
Evaluate ACTH, cortisol (AM), TSH, FT4, electrolytes
Consider evaluating LH, FSH, and testosterone levels in males or estrogen in premenopausal females with fatigue, 
loss of libido, and mood changes Consider MRI of the brain with or without contrast with pituitary/sellar cuts in 
patients with multiple endocrine abnormalities ± new severe headaches or complaints of vision changes
Grading
Management
G1: Asymptomatic or mild symptoms
Consider holding ICPi until patient is stabilized on 
replacement hormones
Endocrine consultation
Hormonal supplementation as in G1
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until patient is stabilized on replacement 
hormones
Endocrine consultation
Hormonal supplementation as in G1
Consider initial pulse dose therapy with prednisone 1-2 
mg/kg oral daily (or equivalent) tapered over at least 
1-2 weeks
Additional considerations
Be aware of the need to start corticosteroids ﬁrst when planning hormone replacement therapy for multiple 
deﬁciencies
All patients need instruction on doubling doses for illness (stress dosing) and a medical alert bracelet for adrenal 
insufﬁciency to trigger stress-dose corticosteroids by EMS
Corticosteroid use can cause isolated central adrenal insufﬁciency
Work-up cannot be done with a simple AM cortisol in a patient on corticosteroids for other conditions
Laboratory conﬁrmation of adrenal insufﬁciency should not be attempted until treatment with corticosteroids for 
other disease is ready to be discontinued. For long-term exposure, consult endocrinology for recovery and 
weaning protocol using hydrocortisone.
4.4 Diabetes
Deﬁnition: T2DM is a combination of insulin resistance and insufﬁciency that may require oral or insulin therapy. It 
may be new onset or exacerbated during therapy for nonimmunologic reasons, such as corticosteroid exposure.
Autoimmune T1DM results from islet cell destruction and is often acute onset, with ketosis and an insulin 
requirement
Diagnostic work-up
Monitor patients for hyperglycemia or other signs and symptoms of new or worsening DM, including measuring 
glucose at baseline and with each treatment cycle during induction for 12 weeks, then every 3-6 weeks thereafter. 
To guide the work-up in new-onset hyperglycemia, clinicians should consider a patient’s medical background, 
exposure history, and risk factors for each subtype of DM.
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Laboratory evaluation in suspected T1DM should include testing for ketosis in urine and an assessment of the 
anion gap on a metabolic panel. Anti–glutamic acid decarboxylase, anti–islet cell, or anti–insulin antibodies are 
highly speciﬁc for autoimmune diabetes. Insulin and C-peptide levels can also assist in the diagnosis.
Grading
Management
G1: Asymptomatic or mild symptoms; fasting glucose 
value > ULN (160 mg/dL); fasting glucose value > ULN 
(8.9 mmol/L); no evidence of ketosis or laboratory 
evidence of T1DM
Can continue ICPi with close clinical follow-up and 
laboratory evaluation
May initiate oral therapy for those with new-onset T2DM
Screen for T1DM if appropriate, for example, acute 
onset with prior normal values or clinical concern for 
ketosis
G2: Moderate symptoms, able to perform ADL, fasting 
glucose value > 160-250 mg/dL; fasting glucose value 
> 8.9-13.9 mmol/L, ketosis or evidence of T1DM at any 
glucose level
May hold ICPi until glucose control is obtained
Titrate oral therapy or add insulin for worsening control 
in T2DM Should administer insulin for T1DM (or as 
default therapy if there is confusion about type)
Urgent endocrine consultation for any patient with 
T1DM; in the absence of endocrinology, internal 
medicine may sufﬁce
Consider admission for T1DM if early outpatient 
evaluation is not available or signs of ketoacidosis are 
present
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
G3: > 250-500 mg/dL (> 13.9-27.8 mmol/L)
G4: > 500 mg/dL (> 27.8 mmol/L)
Hold ICPi until glucose control is obtained on therapy 
with reduction of toxicity to G1 or less
Urgent endocrine consultation for all patients
Initiate insulin therapy for all patients
Admit for inpatient management: Concerns for 
developing DKA, Symptomatic patients regardless of 
diabetes type, New-onset T1DM unable to see 
endocrinology
Additional considerations
Insulin therapy can be used as the default in any case with hyperglycemia
Long-acting therapy alone is not usually sufﬁcient for T1DM, where half of daily requirements are usually given in 
divided doses as prandial coverage and half as long acting.
Insulin doses will be lower in T1DM because of preserved sensitivity (total daily requirement can be estimated at 
0.3-0.4 units/kg/d).
In T2DM, sliding-scale coverage with meals over a few days provides data to estimate a patient’s daily 
requirements and can be used to more rapidly titrate basal needs.
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ACTH, adrenocorticotropic hormone; ADL, activities of daily living; CT, computed tomography; DKA, 
diabetic ketoacidosis; DM, diabetes mellitus; EMS, emergency medical services; FSH, follicle-stimulating hormone; 
FT4, free thyroxine; G, Grade; ICPi, immune checkpoint inhibitor; irAE, immune-related adverse event; 
IV,intravenous; LH, luteinizing hormone; MRI, magnetic resonance imaging; PTU, propylthiouracil; SSKI, potassium 
iodide; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TRAb, thyroid-stimulating hormone receptor 
antibody; TSH, thyroid-stimulating hormone; TSI, thyroid-stimulating immunoglobulin; ULN, upper limit of normal.
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5.0 Musculoskeletal Toxicities
5.1 Inﬂammatory arthritis
Deﬁnition: A disorder characterized by inﬂammation of the joints
Clinical symptoms: Joint pain accompanied by joint swelling; inﬂammatory symptoms, such as stiffness after 
inactivity or in the morning, lasting > 30 minutes to 1 hour; improvement of symptoms with NSAIDs or 
corticosteroids but not with opioids or other pain medications may also be suggestive of inﬂammatory arthritis.
Diagnostic work-up
G1
Complete rheumatologic history and examination of all peripheral joints for tenderness, swelling, and range of 
motion; examination of the spine Consider plain x-ray/imaging to exclude metastases and evaluate joint damage 
(erosions), if appropriate
Consider autoimmune blood panel including ANA, RF, and anti-CCP, and anti-inﬂammatory markers (ESR and 
CRP) if symptoms persist; if symptoms are suggestive of reactive arthritis or affect the spine, consider HLA B27 
testing
G2
Complete history and examination as above; laboratory tests as above
Consider US ± MRI of affected joints if clinically indicated (e.g, persistent arthritis unresponsive to treatment, 
suspicion for differential diagnoses such as metastatic lesions or septic arthritis)
Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms of arthralgia persist 
> 4 weeks
G3-4
As for G2
Seek rheumatologist advice and review
Monitoring: Patients with inﬂammatory arthritis should be monitored with serial rheumatologic examinations, 
including inﬂammatory markers, every 4-6 weeks after treatment is instituted.
Grading
Management
All Grades
Clinicians should follow reports of new joint pain to 
determine whether inﬂammatory arthritis is present; 
question whether symptom new since receiving ICPi
G1: Mild pain with inﬂammation, erythema, or joint 
swelling
Continue ICPi
Initiate analgesia with acetaminophen and/or NSAIDs
G2: Moderate pain associated with signs of 
inﬂammation, erythema, or joint swelling, limiting 
instrumental ADL
Hold ICPi and resume upon symptom control and on 
prednisone  10 mg/d 
Escalate analgesia and consider higher doses of 
NSAIDS as needed
If inadequately controlled, initiate prednisone or 
prednisolone 10-20 mg/d or equivalent for 4-6 weeks
If improvement, slow taper according to response 
during the next 4-6 weeks; if no improvement after initial 
4-6 weeks, treat as G3
If unable to lower corticosteroid dose to < 10 mg/d after 
3 months, consider DMARD
Consider intra-articular corticosteroid injections for large 
joints
Referral to rheumatology
G3-4: Severe pain associated with signs of 
inﬂammation, erythema, or joint swelling; irreversible 
joint damage; disabling; limiting self-care ADL
For G3: Hold ICPi temporarily and may resume in 
consultation with rheumatology, if recover to G1 or less
For G4: permanently discontinue ICPi
Initiate oral prednisone 0.5-1 mg/kg
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5.0 Musculoskeletal Toxicities
If failure of improvement after 4 weeks or worsening in 
meantime, consider synthetic or biologic DMARD
Synthetic: methotrexate, leﬂunomide
Biologic: consider anticytokine therapy such as TNF-a 
or IL-6 receptor inhibitors. (Note: As caution, IL-6 
inhibition can cause intestinal perforation; while this is 
extremely rare, it should not be used in patients with 
colitis.) Test for viral hepatitis B, C, and latent/active TB 
test prior to DMARD treatment
Referral to rheumatology.
Additional considerations
Early recognition is critical to avoid erosive joint damage.
Corticosteroids can be used as part of initial therapy in inﬂammatory arthritis, but due to likely prolonged treatment 
requirements, physicians should consider starting corticosteroid-sparing agents earlier than one would with other 
irAEs
Oligoarthritis can be treated early on with intra-articular corticosteroids; consider early referral.
Consider PCP prophylaxis for patients treated with high dose of corticosteroids for 12 weeks, as per local 
guidelines.
5.2 Myositis
Deﬁnition: A disorder characterized by muscle inﬂammation with weakness and elevated muscle enzymes (CK). 
Muscle pain can be present in severe cases. Can be life-threatening if respiratory muscles or myocardium are 
involved
Diagnostic work-up
Complete rheumatologic and neurologic history regarding differential diagnosis; rheumatologic and neurologic 
examination, including muscle strength; and examination of the skin for ﬁndings suggestive of dermatomyositis. 
Muscle weakness is more typical of myositis than pain. Consider preexisting conditions that can cause similar 
symptoms.
Blood testing to evaluate muscle inﬂammation
CK, transaminases (AST, ALT), LDH, and aldolase can also be elevated
Troponin to evaluate myocardial involvement and other cardiac testing, such as echocardiogram, as needed
Inﬂammatory markers (ESR and CRP)
Consider EMG, imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain and overlap with 
neurologic syndromes, such as myasthenia gravis, is suspected
Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as myasthenia gravis 
Monitoring: CK, ESR, CRP
G1: Complete examination and laboratory work-up as above
G2: Complete history and examination as above; autoimmune myositis blood panel; EMG, MRI of affected joints
Early referral to a rheumatologist or neurologist
G3-4: As for G2
Urgent referral to a rheumatologist or neurologist
Grading
Management
G1: Mild weakness with or without pain
Continue ICPi
If CK is elevated and patient has muscle weakness, 
may offer oral corticosteroids, and treat as G2
Offer analgesia with acetaminophen or NSAIDs if there 
are no contraindications
G2: Moderate weakness with or without pain, limiting 
age-appropriate instrumental ADL
Hold ICPi temporarily and may resume upon symptom 
control, if CK is normal and prednisone dose 10 mg; if 
worsens, treat as per G3
NSAIDs as needed
Referral to rheumatologist or neurologist
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If CK is elevated three times or more), initiate 
prednisone or equivalent at 0.5-1 mg/kg
May require permanent discontinuation of ICPi in most 
patients with G2 symptoms and objective ﬁndings 
(elevated enzymes, abnormal EMG, abnormal muscle 
MRI or biopsy)
G3-4: Severe weakness with or without pain, limiting 
self-care ADL
For G3: Hold ICPi until G1 or less and permanently 
discontinue if any evidence of myocardial involvement
For G4: permanently discontinue ICPi
Consider hospitalization for severe weakness
Referral to rheumatologist or neurologist
Initiate prednisone 1 mg/kg or equivalent. Consider 1-2 
mg/kg of methylprednisolone IV or higher-dose bolus if 
severe compromise (weakness severely limiting 
mobility, cardiac, respiratory, dysphagia) 
Consider plasmapheresis
Consider IVIG therapy
Consider other immunosuppressant therapy, such as 
methotrexate, azathioprine, or mycophenolate mofetil, if 
symptoms and CK levels do not improve or worsen 
after 4-6 weeks; rituximab is used in primary myositis 
but caution is advised given its long biologic duration
In case of management with rituximab, ICPi treatment 
should be discontinued
Additional considerations: Caution is advised with rechallenging
5.3 Polymyalgia-like syndrome
Deﬁnition: Characterized by marked pain and stiffness in proximal upper and/or lower extremities and no signs of 
true muscle inﬂammation such as CK elevation or EMG ﬁndings of myositis. No true muscle weakness, difﬁculty in 
active motion related to pain
Diagnostic work-up
G1
Complete rheumatologic history regarding differential diagnosis and examination of all joints and skin
Check for symptoms of temporal arteritis, such as headache or visual disturbances; refer to ophthalmologist if 
present, and consider temporal artery biopsy ANA, RF, anti-CCP
CK to evaluate differential diagnosis of myositis
Inﬂammatory markers (ESR, CRP)
Monitoring: ESR, CRP
G2: Complete history and examination as above; autoimmune tests as required for differential diagnosis; early 
referral to a rheumatologist
G3-4: As for G2; see rheumatologist advice and review
Grading
Management
G1: Mild stiffness and pain
Continue ICPi
Initiate analgesia with acetaminophen and/or NSAIDs if 
there are no contraindications
G2: Moderate stiffness and pain, limiting age-
appropriate instrumental ADL
Consider holding ICPi and resuming upon symptom 
control, prednisolone < 10 mg; if worsens, treat as per 
G3
Initiate prednisone 20 mg/d or equivalent; if symptoms 
improve, start to taper dose after 3-4 weeks
If no improvement or need for higher dosages after 4 
weeks, escalate to G3 Consider referral to 
rheumatology
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G3-4: Severe stiffness and pain, limiting self-care ADL
For G3: Hold ICPi and may resume, in consultation with 
rheumatology, if recover to G1 or less; however, note 
that cases of toxicity returning upon rechallenge have 
been reported. ICPi should be permanently 
discontinued in such cases
For G4: permanently discontinue ICPi
Referral to rheumatology
Should initiate prednisone 20 mg/d or equivalent. If no 
improvement or need for higher dosages for prolonged 
time, may offer a corticosteroid-sparing agent such as 
methotrexate or IL-6 inhibition with tocilizumab
(Note: As caution, IL-6 inhibition can cause intestinal 
perforation; while this is extremely rare, it should not be 
used in patients with colitis or GI metastases). Consider 
admission for pain control
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibodies; AST, 
aspartate aminotransferase; CCP, citrullinated protein antibody; CK, creatine kinase; CRP, C-reactive protein; 
DMARD, disease-modifying antirheumatic drug; EMG, electromyography; ESR, erythrocyte sedimentation rate; G, 
Grade; GI, gastrointestinal; HLA, human leukocyte antigen; ICPi, immune checkpoint inhibitor; IL, interleukin; irAE, 
immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; 
MRI, magnetic resonance imaging, NSAID, nonsteroidal anti-inﬂammatory drug; PCP, Pneumocystis pneumonia; RF, 
rheumatoid factor; TB, tuberculosis; TNF, tumor necrosis factor; US, ultrasound.
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6.0 Renal Toxicities
Nephritis and renal dysfunction: diagnosis and monitoring
For any suspected immune-mediated adverse reactions, exclude other causes
Monitor patients for elevated serum creatinine prior to every dose
Routine urinalysis is not necessary, other than to rule out UTIs, etc; nephrology may consider further
If no potential alternative cause of AKI identiﬁed, then one should forego biopsy and proceed directly with 
immunosuppressive therapy Swift treatment of autoimmune component important
6.1 Nephritis
Deﬁnition: Inﬂammation of the kidney affecting the structure
Grading
Management
G1: Creatinine level increase 
> ULN - 1.5 x ULN 
Consider temporarily holding ICPi, pending 
consideration of potential alternative etiologies (recent 
IV contrast, medications, ﬂuid status) and baseline renal 
function. A change that is still < 1.5 ULN could be 
meaningful
G2: Creatinine 
> 1.5 - 3.0 x baseline; > 1.5 - 3.0 x ULN 
Hold ICPi 
Consult nephrology
Evaluate for other causes (recent IV contrast, 
medications, ﬂuid status, etc); if other etiologies ruled 
out, administer 0.5-1 mg/kg/d prednisone equivalents
If worsening or no improvement: 1 to 2 mg/kg/d 
prednisone equivalents and permanently discontinue 
treatment
If improved to G1 or less, taper corticosteroids over 4-6 
weeks If no recurrence of chronic renal insufﬁciency, 
discuss resumption of ICPi with patient after taking into 
account the risks and beneﬁts.
G3: Creatinine 
> 3.0 x baseline; > 3.0 - 6.0 x ULN 
Permanently discontinue ICPi
G4: Life-threatening consequences; dialysis indicated; 
> 6.0 x ULN 
Permanently discontinue ICPi
Consult nephrology
Evaluate for other causes (recent IV contrast, 
medications, ﬂuid status, etc)
Administer corticosteroids (initial dose of 1-2 mg/kg/d 
prednisone or equivalent)
Additional considerations
Monitor creatinine weekly
Reﬂex kidney biopsy should be discouraged until corticosteroid treatment has been attempted
6.2 Symptomatic nephritis: follow-up
Grading
Management
G1
Improved to baseline, resume routine creatinine 
monitoring
G2
If improved to G1, taper corticosteroids over at least 
3 weeks before resuming treatment with routine 
creatinine monitoring If elevations persist > 7 days or 
worsen and no other cause found, treat as G3
G3
If improved to G1, taper corticosteroids over at least 
4 weeks 
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If elevations persist 3-5 days or worsen, consider 
additional immunosuppression (e.g, mycophenolate)
G4
If improved to G1, taper corticosteroids over at least 
4 weeks
If elevations persist 2-3 days or worsen, consider 
additional immunosuppression (e.g, mycophenolate)
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: AKI, acute kidney injury; G, Grade; ICPi, immune checkpoint inhibitor; irAE, immune-related adverse 
event; IV, intravenous; ULN, upper limit of normal; UTI, urinary tract infection.
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7.0 Nervous System Toxicities
7.1 Myasthenia gravis
Deﬁnition: Fatigable or ﬂuctuating muscle weakness, generally more proximal than distal. Frequently has ocular 
and/or bulbar involvement (ptosis, extraocular movement abnormalities resulting in double vision, dysphagia, 
dysarthria, facial muscle weakness). May have neck and/or respiratory muscle weakness. (Note: May occur with 
myositis and/or myocarditis). Respiratory symptoms may require evaluation to rule out pneumonitis, myocarditis. 
Miller Fisher variant of Guillain-Barré syndrome (ophthalmoparesis) and the oculobulbar myositis (ptosis, 
ophthalmoparesis, dysphagia, neck and respiratory weakness) with ICPi may have overlapping symptoms.
Diagnostic work-up
AChR and antistriated muscle antibodies in blood; if AChR antibodies are negative, consider muscle speciﬁc 
kinase and lipoprotein-related 4 antibodies in blood Pulmonary function assessment with NIF and VC
CPK, aldolase, ESR, CRP for possible concurrent myositis
Consider MRI of brain and/or spine, depending on symptoms to rule out CNS involvement by disease or alternate 
diagnosis
If respiratory insufﬁciency or elevated CPK, troponin T, perform cardiac examination with ECG and TTE for 
possible concomitant myocarditis
Neurologic consultation
Electrodiagnositic studies, including neuromuscular junction testing with repetitive stimulation and/or jitter studies, 
NCS to exclude neuropathy, and needle EMG to evaluate for myositis
Grading
Management
All grades
All grades warrant work-up and intervention given 
potential for progressive myasthenia gravis to lead to 
respiratory compromise
No G1
G2: Some symptoms interfering with ADL MGFA 
severity class 1 (ocular symptoms and ﬁndings only) 
and MGFA severity class 2 (mild generalized 
weakness)
Hold ICPi and may resume in G2 patients (MGFA 1 and 
2) only if symptoms resolve 
Should consult neurology
Pyridostigmine starting at 30 mg orally three times a 
day and gradually increase to maximum of 120 mg 
orally four times a day as tolerated and based on 
symptoms Administer corticosteroids (prednisone, 
1-1.5 mg/kg orally daily) if symptoms G2; wean based 
on symptom improvement
G3-4: Limiting self-care and aids warranted, weakness 
limiting walking, ANY dysphagia, facial weakness, 
respiratory muscle weakness, or rapidly progressive 
symptoms, or MGFA severity class 3-4 moderate to 
severe generalized weakness to myasthenic crisis
Permanently discontinue ICPi
Admit patient, may need ICU-level monitoring
Neurology consult
Continue corticosteroids and initiate IVIG 2 g/kg IV over 
5 days (0.4 g/kg/d) or plasmapheresis for 5 days
Frequent pulmonary function assessment
Daily neurologic review
Additional considerations
Avoid medications that can worsen myasthenia: β-blockers, IV magnesium, ﬂuoroquinolones, aminoglycosides, 
and macrolides Initially a 5-day course of plasmapheresis or a 2 g/kg course of IVIG over 5 days
1-2 mg/kg methylprednisolone daily, wean based on symptom improvement
Pyridostigmine, wean based on improvement
ICPi-associated myasthenia gravis may be monophasic, and additional corticosteroid-sparing agents may not be 
required
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7.2 Guillain-Barré syndrome
Deﬁnition: Progressive, most often symmetrical muscle weakness with absent or reduced deep tendon reﬂexes. 
Often starts with sensory symptoms/neuropathic pain localized to lower back and thighs. May involve extremities 
(typically ascending weakness but not always), facial, respiratory, and bulbar and oculomotor nerves. May have 
dysregulation of autonomic nerves.
Diagnostic work-up
Neurologic consultation
MRI of spine with or without contrast (rule out compressive lesion and evaluate for nerve root 
enhancement/thickening)
Lumbar puncture: CSF typically has elevated protein and often elevated WBCs; even though this is not typically 
seen in classic Guillain-Barré syndrome, cytology should be sent with any CSF sample from a patient with cancer.
Serum antibody tests for Guillain-Barré syndrome variants (GQ1b for Miller Fisher variant a/w ataxia and 
ophthalmoplegia) Electrodiagnostic studies to evaluate polyneuropathy
Pulmonary function testing (NIF/VC)
Frequent neurochecks
Grading
Management
All grades
Warrant work-up and intervention given potential for 
progressive Guillain-Barré syndrome to lead to 
respiratory compromise
Note: There is no G1 toxicity
G1: Mild, none
NA
G2: Moderate, some interference with ADL, symptoms 
concerning to patient
Discontinue ICPi
G3-4: Severe, limiting self-care and aids warranted, 
weakness, limiting walking, ANY dysphagia, facial 
weakness, respiratory muscle weakness, or rapidly 
progressive symptoms
Permanently discontinue ICPi. 
Admission to inpatient unit with capability of rapid 
transfer to ICU-level monitoring Start IVIG (0.4 g/kg/d 
for 5 days for a total dose of 2 g/kg) or plasmapheresis. 
Corticosteroids are usually not recommended for 
idiopathic Guillain-Barré syndrome; however, in 
ICPi-related forms, a trial is reasonable 
(methylprednisolone 2-4 mg/kg/d), followed by slow 
corticosteroid taper
Pulse corticosteroid dosing (methylprednisolone 1 g/d 
for 5 days) may also be considered for G3-4 along with 
IVIG or plasmapheresis
Frequent neurochecks and pulmonary function 
monitoring
Monitor for concurrent autonomic dysfunction
Nonopioid management of neuropathic pain
Treatment of constipation/ileus
Additional considerations
Slow prednisone taper after corticosteroid pulse plus IVIG or plasmapheresis May require repeat IVIG courses
Caution with rechallenging for severe cases
7.3 Peripheral neuropathy
Deﬁnition: Can present as asymmetric or symmetric sensory, motor, or sensory motor deﬁcit. Focal 
mononeuropathies, including cranial neuropathies (e.g, facial neuropathies/Bell palsy) may be present. Numbness 
and paresthesias may be painful or painless. Hypo- or areﬂexia or sensory ataxia may be present.
Diagnostic work-up
G1
Screen for reversible neuropathy causes: diabetic screen, B12, folate, TSH, HIV, consider serum protein 
electrophoresis, and other vasculitic and autoimmune screen Neurologic consultation
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7.0 Nervous System Toxicities
Consider MRI of spine with or without contrast
G2: in addition to above
MRI spine advised/MRI of brain if cranial nerve Consider EMG/NCS
Consider neurology consultation
G3-4: go to Guillain-Barré syndrome algorithm
Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient. Note: Any cranial nerve 
problem should be managed as moderate
Low threshold to hold ICPi and monitor symptoms for a 
week If to continue, monitor very closely for any 
symptom progression
G2: Moderate, some interference with ADL, symptoms 
concerning to patient (i.e, pain but no weakness or gait 
limitation)
Hold ICPi and resume once return to G1
Initial observation OR initiate prednisone 0.5-1 mg/kg (if 
progressing from mild)
Neurontin, pregabalin, or duloxetine for pain
G3-4: Severe, limiting self-care and aids warranted, 
weakness limiting walking or respiratory problems (i.e, 
leg weakness, foot drop, rapidly ascending sensory 
changes) Severe may be Guillain-Barré syndrome and 
should be managed as such
Permanently discontinue ICPi
Admit patient
Neurologic consultation
Initiate IV methylprednisolone 2-4 mg/kg and proceed 
as per Guillain-Barré syndrome management
7.4 Autonomic neuropathy
Deﬁnition: Nerves that control involuntary bodily functions are damaged. This may affect blood pressure, 
temperature control, digestion, bladder function, and sexual function. A case of severe enteric neuropathy with 
ICPi has been reported. Can present with GI difﬁculties such as new severe constipation, nausea, urinary 
problems, sexual difﬁculties, sweating abnormalities, sluggish pupil reaction, and orthostatic hypertension.
Diagnostic work-up
An evaluation by neurologist or relevant specialist, depending on organ system, with testing that may include
Screening for other causes of autonomic dysfunction: diabetic screen, adrenal insufﬁciency, HIV, paraproteinemia, 
amyloidosis, botulism; consider chronic diseases such as Parkinson and other autoimmune screening
AM orthostatic vitals
Consider electrodiagnostic studies to evaluate for concurrent polyneuropathy
Consider paraneoplastic Lambert-Eaton myasthenic syndrome, antineutrophil cytoplasmic antibodies, and 
ganglionic AChR antibody testing
Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient
Low threshold to hold ICPi and monitor symptoms for a 
week; if to continue, monitor very closely for any 
symptom progression
G2: Moderate, some interference with ADL, symptoms 
concerning to patient
Hold ICPi and resume once return to G1
Initial observation OR initiate prednisone 0.5-1 mg/kg (if 
progressing from mild)
Neurologic consultation
G3-4: Severe, limiting self-care and aids warranted
Permanently discontinue ICPi
Admit patient
Initiate methylprednisolone 1 g daily for 3 days followed 
by oral corticosteroid taper Neurologic consultation
7.5 Aseptic meningitis
Deﬁnition: may present with headache, photophobia, and neck stiffness; often afebrile but may be febrile. There 
may be nausea/vomiting. Mental status should be normal (distinguishes from encephalitis).
Diagnostic work-up
MRI of brain with or without contrast + pituitary protocol
AM cortisol, ACTH to rule out adrenal insufﬁciency
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Consider lumbar puncture: measure opening pressure; check cell count and protein glucose; and perform Gram 
stain, culture, PCR for HSV, and other viral PCRs depending on suspicion, cytology
May see elevated WBC count with normal glucose, normal culture, and Gram stain; may see reactive lymphocytes 
or histiocytes on cytology
Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient. Note: Any cranial nerve 
problem should be managed as moderate.
G2: Moderate, some interference with ADL, symptoms 
concerning to patient (i.e, pain but no weakness or gait 
limitation)
G3-4: Severe, limiting self-care and aids warranted
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts, consider 
empirical antiviral (IV acyclovir) and antibacterial 
therapy until CSF results Once bacterial and viral 
infection are negative, may closely monitor off 
corticosteroids or consider oral prednisone 0.5-1 mg/kg 
or IV methylprednisolone 1 mg/kg if moderate/severe 
symptoms
7.6 Encephalitis
Deﬁnition: As for aseptic meningitis, need to exclude infectious causes, especially viral (i.e, HSV).
Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of consciousness, 
focal weakness, speech abnormality 
Diagnostic work-up
Neurologic consultation
MRI of brain with or without contrast may reveal T2/ﬂuid-attenuated inversion recovery changes typical of what is 
seen in autoimmune encephalopathies or limbic encephalitis or may be normal
Lumbar puncture: check cell count and protein glucose and perform Gram stain, culture, PCR for HSV and other 
viral PCRs depending on suspicion, cytology, oligoclonal bands, autoimmune encephalopathy, and paraneoplastic 
panels.
May see elevated WBC count with lymphocytic predominance and/or elevated protein
EEG to evaluate for subclinical seizures
Blood: metabolic, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including TPO and 
thyroglobulin Rule out concurrent anemia/thrombocytopenia, which can present with severe headaches and 
confusion
Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient. Note: Any cranial nerve 
problem should be managed as moderate.
G2: Moderate, some interference with ADL, symptoms 
concerning to patient (i.e, pain but no weakness or gait 
limitation)
G3-4: Severe, limiting self-care and aids warranted
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts
As above for aseptic meningitis suggest concurrent IV 
acyclovir until PCR results obtained and negative
Trial of methylprednisolone 1-2 mg/kg
If severe or progressing symptoms or oligoclonal bands 
present, consider pulse corticosteroids 
methylprednisolone 1 g IV daily for 3-5 days plus IVIG 2 
g/kg over 5 days If positive for autoimmune 
encephalopathy antibody and limited or no 
improvement, consider rituximab or plasmapheresis in 
consultation with neurology.
7.7 Transverse myelitis
Deﬁnition: Acute or subacute weakness or sensory changes bilateral, often with increased deep tendon reﬂexes
Diagnostic work-up
Neurologic consultation
MRI of spine (with thin axial cuts through the region of suspected abnormality) and MRI of brain
Lumbar puncture: cell count, protein, glucose, oligoclonal bands, viral PCRs, cytology, onconeural antibodies 
Blood: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG
Evaluation for urinary retention, constipation
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Grading
Management
G1: Mild, no interference with function and symptoms 
not concerning to patient. Note: Any cranial nerve 
problem should be managed as moderate.
G2: Moderate, some interference with ADL, symptoms 
concerning to patient (i.e, pain but no weakness or gait 
limitation)
G3-4: Severe, limiting self-care and aids warranted
Permanently discontinue ICPi
Methylprednisolone 2 mg/kg
Strongly consider higher doses of 1 g/d for 3-5 days 
Strongly consider IVIG
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: AChR, acetylcholine receptor; ACTH, adrenocorticotropic hormone; ADL, activities of daily living; ANA, 
antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; CBC, complete blood count; CNS, central nervous 
system; CPK, creatine phosphokinase; CRP, C-reactive protein; CSF, cerebrospinal fluid; ECG, electrocardiogram; 
EEG, electroencephalogram; EMG, electromyography; ESR, erythrocyte sedimentation rate; G, Grade; GI, 
gastrointestinal; HIV, human immunodeficiency virus; HSV, herpes simplex virus; ICPi, immune checkpoint inhibitor; 
ICU, intensive care unit; IgG, immunoglobulin G; irAE, immune-related adverse event; IV, intravenous; IVIG, 
intravenous immunoglobulin; MGFA, Myasthenia Gravis Foundation of America; MRI, magnetic resonance imaging; 
NA, not applicable; NCS, nerve conduction study; NIF, negative inspiratory force; PCR, polymerase chain reaction; 
RPR, rapid plasma reagin, TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone; TTE, transthoracic 
echocardiogram; VC, vital capacity; WBC, white blood cell.
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8.0 Hematologic Toxicities
8.1 Autoimmune hemolytic anemia
Deﬁnition: A condition in which RBCs are destroyed and removed from the blood stream before their normal 
lifespan is over. Symptoms include weakness, paleness, jaundice, dark-colored urine, fever, inability to do physical 
activity, and heart murmur.
Diagnostic work-up
History and physical examination (with special consideration of history of new drugs and insect, spider, or snake 
bites)
Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral smear; LDH, 
haptoglobin, bilirubin, reticulocyte count, free Hgb DIC panel, which could include PTNIR infectious causes
Autoimmune serology
Paroxysmal nocturnal hemoglobinuria screening
Direct and indirect bilirubin; LDH; direct agglutinin test; and if no obvious cause, bone marrow analysis, cytogenetic 
analysis to evaluate for myelodysplastic syndromes
Evaluation for viral/bacterial (mycoplasma, etc) causes of hemolysis studies
Protein electrophoresis, cryoglobulin analysis
Work-up for bone marrow failure syndrome if refractory, including B12, folate, copper, parvovirus, FE, thyroid, 
infection
Glucose-6-phosphate dehydrogenase
Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, 
quinine/quinidine, ﬂudarabine, ciproﬂoxacin, lorazepam, diclofenac, etc)
Assessment of methemoglobinemia
Grading
Management
G1: Hgb < LLN to 10.0 g/dL; < LLN to 6.2 mmol/L; < 
LLN to 100 g/L
Continue ICPi with close clinical follow-up and 
laboratory evaluation
G2: Hgb < 10.0 to 8.0 g/dL; < 6.2 to 4.9mmol/L; < 100 
to 80 g/L
Hold ICPi and strongly consider permanent 
discontinuation
Administer 0.5-1 mg/kg/d prednisone equivalents
G3: Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L; transfusion 
indicated
Permanently discontinue ICPi
Should use clinical judgment and consider admitting the 
patient
Hematology consult
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms/speed of development)
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently discontinue 
ICPi treatment
Consider RBC transfusion per existing guidelines; do 
not transfuse more than the minimum number of RBC
units necessary to relieve symptoms of anemia or to 
return a patient to a safe Hgb range (7-8 g/dL in stable, 
noncardiac inpatients)
Should offer patients supplementation with folic acid 1 
mg once daily
G4: Life-threatening consequences, urgent intervention 
indicated
Permanently discontinue ICPi
Admit patient
Hematology consult
IV prednisone corticosteroids 1-2 mg/kg/d
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If no improvement or if worsening while on 
corticosteroids or severe symptoms on presentation, 
initiate other immunosuppressive drugs, such as 
rituximab, IVIG, cyclosporin A, and mycophenolate 
mofetil
RBC transfusion per existing guidelines; discuss with 
blood bank team prior to transfusions that a patient with 
possible ICPi serious AE is in house.
Additional considerations: Monitor Hgb levels on a weekly basis until the corticosteroid tapering process is 
complete; thereafter, less-frequent testing is needed
8.2 Acquired TTP
Deﬁnition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic 
purpura, fever, renal abnormalities, and neurologic abnormalities, such as seizures, hemiplegia, and visual 
disturbances. It is an acute or subacute condition. 
Diagnostic work-up
History with speciﬁc questions related to drug exposure (e.g, chemotherapy, sirolimus, tacrolimus, opana ER 
antibiotics, quinine) Physical examination, peripheral smear
ADAMTS13 activity level and inhibitor titer
LDH, haptoglobin, reticulocyte count, bilirubin, urinalysis to rule out other causes
PT, activated PTT, ﬁbrinogen
Blood group and antibody screen, direct antiglobulin test, CMV serology
Consider CT/MRI brain, echocardiogram, ECG
Viral studies
Note: This disorder is usually associated with a severe drop in platelets and hemolysis/anemia precipitously
Grading
Management
All grades
The ﬁrst step in the management of TTP is a high index 
of suspicion for the diagnosis and timely recognition; 
hematology consult should immediately be called, as 
delay in identiﬁcation is associated with increased 
mortality/morbidity.
Initially, the patient should be stabilized and any critical 
organ dysfunction stabilized
G1: Evidence of RBC destruction (schistocytosis) 
without anemia, renal insufﬁciency, or 
thrombocytopenia clinically
G2: Evidence of RBC destruction (schistocytosis) 
without clinical consequence with G2 anemia and 
thrombocytopenia
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts, noting that 
there are currently no data to recommend restarting 
ICPi therapy Hematology consult
Administer 0.5-1 mg/kg/d prednisone
G3: Laboratory ﬁndings with clinical consequences (G3 
thrombocytopenia, anemia, renal insufﬁciency > 2)
G4: Life-threatening consequences (e.g, CNS 
hemorrhage or thrombosis/embolism or renal failure)
For G3: Hold ICPi and discuss resumption with patient 
only after taking into account the risks and beneﬁts, 
noting that there are currently no data to recommend 
restarting ICPi therapy
For G4: permanently discontinue ICPi
Hematology consult
In conjunction with hematology, initiate PEX according 
to existing guidelines with further PEX dependent on 
clinical progress
Administer methylprednisolone 1 g IV daily for 3 days, 
with the ﬁrst dose typically administered immediately 
after the ﬁrst PEX
May offer rituximab
In case of management with rituximab, ICPi treatment 
will be discontinued
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8.0 Hematologic Toxicities
8.3 Hemolytic uremic syndrome
Deﬁnition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, 
and severe thrombocytopenia. Signs and symptoms of hemolytic uremic syndrome can include:
Bloody diarrhea
Decreased urination or blood in the urine
Abdominal pain, vomiting, and occasionally fever
Pallor
Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability
Confusion or seizures
High blood pressure
Swelling of the face, hands, feet, or entire body
Diagnostic work-up
History and physical examination (special consideration for new history of high-risk drugs, hypertension, or cardiac 
causes) CBC with indices
Blood smear morphology. Note that the presence of schistocytes on smear is critical for diagnosis.
Serum creatinine
ADAMTS13 (to rule out TTP)
Homocysteine/methylmalonic acid
Complement testing C3, C4, CH50 (complement inhibitory antibodies for suspected familial)
Evaluate reticulocyte count and mean corpuscular volume
Evaluation of infectious cause, including screening for EBV, CMV, HHV6
Evaluation for nutritional causes of macrocytosis (B12 and folate)
Pancreatic enzymes
Evaluation for diarrheal causes, shiga toxin, Escherichia coli 0157, etc
Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia
Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, sirolimus, etc)
Evaluation for concurrent confusion
Grading
Management
G1-2: Evidence of RBC destruction (schistocytosis) 
without clinical consequences of anemia, 
thrombocytopenia Grade 2
G3: Laboratory ﬁndings with clinical consequences 
(e.g, renal insufﬁciency, petechiae)
G4: Life-threatening consequences (e.g, CNS 
thrombosis/ embolism or renal failure)
For G1 and G2: Continue ICPi with close clinical follow-
up and laboratory evaluation
Supportive care 
For G3 and G4: Permanently discontinue ICPi
Begin therapy with eculizumab therapy 900 mg weekly 
for four doses, 1,200 mg week 5, then 1,200 mg every 2 
weeks
Red blood transfusion according to existing guidelines
8.4 Aplastic anemia
Deﬁnition: Condition in which the body stops producing enough new blood cells 
Diagnostic work-up
History and physical examination (close attention to medications, exposure to radiation, toxins, recent viral 
infections) CBC, smear, reticulocyte count
Viral studies, including CMV, HHV6, EBV, parvovirus
Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, vitamin D
Serum LDH, renal function
Work-up for infectious causes
Identify marrow hypo/aplasia
Bone marrow biopsy and aspirate analysis
Peripheral blood analysis, including neutrophil count, proportion of GPI-negative cells by ﬂow for PNH
Flow cytometry to evaluate loss of GPI-anchored proteins
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Type and screen patient for transfusions and notify blood bank that all transfusions need to be irradiated and 
ﬁltered
Grading
Management
G1: Nonsevere, < 0.5 polymorphonuclear cells x 109/L 
hypocellular marrow, with marrow cellularity < 25%, 
peripheral platelet count > 20,000, reticulocyte count 
< 20,000
Hold ICPi and provide growth factor support and close 
clinical follow-up, and laboratory evaluation 
Supportive transfusions as per local guidelines
G2: Severe, hypocellular marrow < 25% and two of the 
following: ANC < 500, peripheral platelet < 20,000, and 
reticulocyte < 20,000
Hold ICPi and provide growth factor support and close 
clinical laboratory evaluations daily
Administer ATG + cyclosporine; HLA typing and 
evaluation for bone marrow transplantation if patient is 
candidate; all blood products should be irradiated and 
ﬁltered
Supportive care with granulocyte colony-stimulating 
factor may be added in addition
G3-4: Very severe, ANC > 200, platelet count > 20,000, 
reticulocyte count > 20,000, plus hypocellular marrow > 
25%
For G3: Hold ICPi and monitor weekly for improvement; 
if not resolved, discontinue treatment until AE has 
reverted to G1
For G4: permanently discontinue ICPi
Hematology consult, growth factor support
Horse ATG plus cyclosporine
If no response, repeat immunosuppression with rabbit 
ATG plus cyclosporine, cyclophosphamide
For refractory patients, consider eltrombopag plus 
supportive care
8.5 Lymphopenia
Deﬁnition: An abnormally low level of lymphocytes in PB; for adults, counts of < 1,500/mm3 
Diagnostic work-up
History and physical examination (special attention for lymphocyte-depleting therapy such as ﬂudarabine, ATG, 
corticosteroids, cytotoxic chemotherapy, radiation exposure, etc, as well as history of autoimmune disease, family
history of autoimmune disease) Evaluation of nutritional state as cause
Spleen size
CBC with differential, peripheral smear and reticulocyte counts
CXR for evaluation of presence of thymoma
Bacterial cultures and evaluation for infection (fungal, viral, bacterial speciﬁcally CMV/HIV)
Grading
Management
G1-2: 500-1,000 PB lymphocyte count
G3: 250-499 PB lymphocyte count
G4: < 250 PB lymphocyte count
Continue ICPi for G1 to G2
For G3 single laboratory values out of normal range 
without any clinical correlates, hold treatment until 
resolution to G1
For G4, for single laboratory values out of normal range 
without any clinical correlates, permanent treatment 
discontinuation is not required. Treatment should be 
held until the etiology is determined. Permanent 
treatment discontinuation will only be required, if 
lymphopenia is considered of immune-related in nature, 
no clear alternative explanation exists for the event, and 
grade 4 lymphopenia does not resolve within 14 days. If 
the event is not considered immune-related and 
resolves to G 1 restarting treatment may be 
considered.
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Check CBC weekly for monitoring, initiation of CMV 
screening Consider holding ICPi
Initiate Mycobacterium avium complex prophylaxis and 
Pneumocystis jirovecii prophylaxis, CMV screening. 
HIV/hepatitis screening if not already done
May consider EBV testing if evidence of 
lymphadenopathy/hepatitis, fevers, hemolysis 
consistent with lymphoproliferative disease. 
8.6 Immune thrombocytopenia
Deﬁnition: An autoimmune disorder characterized by immunologic destruction of otherwise normal platelets 
Diagnostic work-up
History and physical examination (special attention for lymphocyte-depleting therapy, such as ﬂudarabine, ATG, 
corticosteroids, cytotoxic therapy) Family history of autoimmunity or personal history of autoimmune disease
History of viral illness
CBC
Peripheral blood smear, reticulocyte count
Bone marrow evaluation only if abnormalities in the above test results and further investigation is necessary for a 
diagnosis
Patients with newly diagnosed immune thrombocytopenia should undergo testing for HIV, hepatitis C virus, 
hepatitis B virus, and Helicobacter pylori Direct antigen test should be checked to rule out concurrent Evan 
syndrome
Nutritional evaluation
Bone marrow evaluation if other cell lines affected and concern for aplastic anemia
Grading
Management
G1: Platelet count < 100/μL
G2: Platelet count < 75/μL
Continue ICPi with close clinical follow-up and 
laboratory evaluation
Hold ICPi but monitor for improvement; if not resolved, 
interrupt treatment until AE has reverted to G1
Administer prednisone 1 mg/kg/d (dosage range, 
0.5-2 mg/kg/d) orally for 2-4 weeks after which time this 
medication should be tapered over 4-6 weeks to the 
lowest effective dose IVIG may be used in conjunction 
with corticosteroids if a more-rapid increase in platelet 
count is required.
G3: Platelet count < 50/μL
Hold ICPi but monitor for improvement; if not resolved, 
interrupt treatment until AE has reverted to G1
G4: Platelet count < 25/μL
Permanently discontinue ICPi
Hematology consult
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms)
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently discontinue 
treatment
IVIG used with corticosteroids when a more-rapid 
increase in platelet count is required
If IVIG is used, the dose should initially be 1 g/kg as a 
one-time dose. This dosage may be repeated if 
necessary
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If previous treatment with corticosteroids and/or IVIG 
unsuccessful, subsequent treatment may include 
rituximab, thrombopoietin receptor agonists, or more-
potent immunosuppression (From American Society of 
Hematology guideline on immune thrombocytopenia; 
consult for further details)
8.7 Acquired hemophilia
Deﬁnition: Disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation 
factors 
Diagnostic work-up
Full blood count to assess platelet number, ﬁbrinogen, PT, PTT, INR; the typical ﬁnding in patients with acquired 
hemophilia A is a prolonged activated PTT with a normal PT
MRI, CT, and ultrasonography may be indicated to localize, quantify, and serially monitor the location and 
response of bleeding Medication review to assess for alternative causes
Determination of Bethesda unit level of inhibitor
Grading
Management
G1: Mild, 5%-40% of normal factor activity in blood, 
0.05-0.4 IU/mL of whole blood
Hold ICPi and discuss resumption with patient only after 
taking into account the risks and beneﬁts
Administer 0.5-1 mg/kg/d prednisone
Transfusion support as required
Treatment of bleeding disorders with hematology 
consult
G2: Moderate, 1%-5% of normal factor activity in blood, 
0.01- 0.05 IU/mL of whole blood
Hematology consult
Administration of factor replacement (choice based on 
Bethesda unit of titer)
Administer 1 mg/kg/d prednisone ± rituximab (dose, 375 
mg/m2 weekly for 4 weeks) and/or cyclophosphamide 
(dose, 1-2 mg/kg/d); choice of rituximab v 
cyclophosphamide is patient speciﬁc and should be 
done with assistance of hematology consult; 
prednisone, rituximab, and cyclophosphamide should 
be given for at least 5 weeks
Factors should be provided to increase level during 
bleeding episodes, with choice of factor based on 
presence or absence of inhibitor
G3-4: Severe, < 1% of normal factor activity in blood, < 
0.01 IU/mL of whole blood
Permanently discontinue ICPi
Admit patient
Hematology consult
Administration of factor replacement, choice based on 
Bethesda unit level of inhibitor Bypassing agents may 
be used (factor VII, factor VIII inhibitor bypass activity); 
caution should be taken in the elderly and those with 
coronary artery disease
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms) ± rituximab (dose, 375 mg/m2 weekly for 
4 weeks) and/or cyclophosphamide (dose, 1-2 mg/kg/d).
Transfusion support as required for bleeding
If worsening or no improvement add cyclosporine or 
immunosuppression/immunoadsorption
Additional considerations: The American Heart Association requires specialist clinical and laboratory expertise. 
Consult and/or transfer to a specialist center is often appropriate. If consultation with or transfer to a hemophilia 
center is not immediately possible, then investigation and treatment should be initiated while a liaison is being 
established.
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All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: AE, adverse event; ANC, absolute neutrophil count; ATG, antithymocyte globulin; CBC, complete 
blood count; CMV, cytomegalovirus; CNS, central nervous system; CT, computed tomography; CXR, chest x-ray; 
DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus; ECG, electrocardiogram; ER, extended 
release; FE, ferritin; G, Grade; GPI, glycosylphosphatidylinositol; Hgb, hemoglobin; HHV6, human herpesvirus 6; HIV, 
human immunodeficiency virus; HLA, human leukocyte antigen; ICPi, immune checkpoint inhibitor; INR, international 
normalized ratio; irAE, immune-related adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; LDH, 
lactate dehydrogenase; LLN, lower limit of normal; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-
inﬂammatory drug; PB, peripheral blood; PEX, plasma ex-change; PNH, paroxysmal nocturnal hemoglobinuria; PT, 
prothrombin time; PTT, partial thromboplastin time; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.
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9.0 Cardiovascular Toxicities
9.1 Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and vasculitis
Deﬁnition: Signs and symptoms may include chest pain, arrhythmia, palpitations, peripheral edema, progressive or 
acute dyspnea, pleural effusion, fatigue
Diagnostic work-up
At baseline
ECG
Consider troponin, especially in patient treated with combination immune therapies Upon signs/symptoms 
(consider cardiology consult)
ECG
Troponin
BNP Echocardiogram CXR
Additional testing to be guided by cardiology and may include
Stress test
Cardiac catherization Cardiac MRI
Grading
Management
G1: Abnormal cardiac biomarker testing, including 
abnormal ECG
G2: Abnormal screening tests with mild symptoms
G3: Moderately abnormal testing or symptoms with mild 
activity
G4: Moderate to severe decompensation, IV medication 
or intervention required, life-threatening conditions
All grades warrant work-up and intervention given 
potential for cardiac compromise
Consider the following:
For G1: Hold ICPi
For G2, G3, and G4: Permanently discontinue ICPi
For G1-G4: High-dose corticosteroids (1-2 mg/kg of 
prednisone) initiated rapidly (oral or IV depending on 
symptoms)
Admit patient, cardiology consultation
Immediate transfer to a coronary care unit for patients 
with elevated troponin or conduction abnormalities
In patients without an immediate response to high-dose 
corticosteroids, consider early institution of cardiac 
transplant rejection doses of corticosteroids 
(methylprednisolone 1 g every day) and the addition of 
either mycophenolate, inﬂiximab, or antithymocyte 
globulin
Qualifying statement: Treatment recommendations are based on anecdotal evidence and the life-threatening 
nature of cardiovascular complications. The appropriateness of rechallenging remains unknown. Note that 
inﬂiximab has been associated with heart failure and is contraindicated at high doses in patients with moderate-
severe heart failure.
9.2 Venous thromboembolism
Deﬁnition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via 
the blood stream. Clinical signs and symptoms are variable and may include pain, swelling, increased skin vein 
visibility, erythema, and cyanosis accompanied by unexplained fever for DVT and dyspnea, pleuritic pain, cough, 
wheezing, or hemoptysis for PE
Diagnostic work-up
Evaluation of signs and symptoms of PE or DVT may include Clinical prediction rule to stratify patients with 
suspected venous thromboembolism Venous ultrasound for suspected DVT
CTPA for suspected PE
Can also consider D-dimer for low-risk patients based on risk stratiﬁcation by clinical prediction rule for DVT/PE 
when CT or Doppler are not available or appropriate Ventilation/perfusion scan is also an option when CTPA is not 
appropriate
Consider other testing, including ECG, CXR, BNP and troponin levels, and arterial blood gas
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Grading
Management
G1: Venous thrombosis (e.g, superﬁcial thrombosis)
Continue ICPi
Warm compress
Clinical surveillance
G2: Venous thrombosis (e.g, uncomplicated DVT), 
medical intervention indicated
G3: Thrombosis (e.g, uncomplicated PE [venous], 
nonembolic cardiac mural [arterial] thrombus), medical 
intervention indicated
Hold ICPi until AE reverts back to G1 or less. If reverts 
to G2, use benefit-risk assessment for ICPi continuation
Consider consult from cardiology or other relevant 
specialties
LMWH is suggested over VKA, dabigatran, rivaroxaban 
apixaban, or edoxaban for initial and long-term 
treatment
IV heparin is an acceptable alternative for initial use, 
and oral anticoagulants are acceptable for the long term
G4: Life-threatening (e.g, PE, cerebrovascular event, 
arterial insufﬁciency), hemodynamic or neurologic 
instability, urgent intervention indicated
Permanently discontinue ICPi
Admit patient and management according to CHEST, 
ACC, and/or AHA guidelines and with guidance from 
cardiology 
Respiratory and hemodynamic support
LMWH is suggested over VKA, dabigatran, rivaroxaban, 
apixaban, or edoxaban for initial and long-term 
treatment
IV heparin is an acceptable alternative for initial use, 
and oral anticoagulants are acceptable for the long term
Further clinical management as indicated based on 
symptoms
Additional considerations
While it may be impossible to determine the etiology of thromboembolic disease in patients with advanced cancer 
and the role, if any, that ICPi treatment plays, it is reasonable to remove the potential inciting agents given the 
severity and life-threatening potential of G4 complications. Clinicians are to use clinical judgment and take into 
account the risks and beneﬁts when deciding whether to discontinue ICPi treatment.
Anticoagulant therapy duration should continue for a minimum of 9-12 months to indeﬁnitely in the setting of active 
cancer unless patient is asymptomatic, doing well, or in remission.
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: BNP, brain natriuretic peptide; CT, computed tomography; CTPA, computed tomography pulmonary 
angiography; CXR, chest x-ray; DVT, deep vein thrombosis; ECG, electrocardiogram; G, Grade; ICPi, immune 
checkpoint inhibitor; irAE, immune-related adverse event; IV, intravenous; LMWH, low-molecular-weight heparin; 
MRI, magnetic resonance imaging; PE, pulmonary embolism; VKA, vitamin K agonist.
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10.0 Ocular Toxicities
Counsel all patients to inform their health care provider immediately if they experience any of the following ocular 
symptoms
Blurred vision
Change in color vision Photophobia
Distortion
Scotomas
Visual ﬁeld changes Double vision Tenderness
Pain with eye movement Eyelid swelling Proptosis
Evaluation, under the guidance of ophthalmology
Check vision in each eye separately
Color vision
Red reﬂex
Pupil size, shape, and reactivity
Fundoscopic examination
Inspection of anterior part of eye with penlight
Prior conditions
Exclude patients with history of active uveitis
History of recurrent uveitis requiring systemic immunosuppression or continuous local therapy
Additional considerations
Ocular irAEs are many times seen in the context of other organ irAEs
High level of clinical suspicion as symptoms may not always be associated with severity Best to treat after 
ophthalmologist eye examination
10.1 Uveitis/iritis
Deﬁnition: Inﬂammation of the middle layer of the eye Diagnostic work-up: as per above
Grading
Management
G1: Asymptomatic
Continue ICPi
Refer to ophthalmology within 1 week
Artiﬁcial tears
G2: Medical intervention required, anterior uveitis
Hold ICPi temporarily until after ophthalmology consult
Urgent ophthalmology referral
Topical corticosteroids, cycloplegic agents, systemic 
corticosteroids
May resume ICPi treatment once off systemic 
corticosteroids, which are purely indicated for ocular 
adverse effects or once corticosteroids for other 
concurrent systemic irAEs are reduced to  10 mg; 
continued topical/ocular corticosteroids are permitted 
when resuming therapy to manage and minimize local 
toxicity Re-treat after return to G1 or less
G3: Posterior or panuveitis
Permanently discontinue ICPi
Urgent ophthalmology referral.
Systemic corticosteroids and 
intravitreal/periocular/topical corticosteroids
G4: 20/200 or worse
Permanently discontinue ICPi
Emergent ophthalmology referral
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Systemic corticosteroids (IV prednisone 1-2 mg/kg or 
methylprednisolone 0.8-1.6 mg/kg) and 
intravitreal/periocular/topical corticosteroids per 
ophthalmologist opinion
Additional considerations: Consider use of inﬂiximab or other TNF-α blockers in cases that are severe and 
refractory to standard treatment
10.2 Episcleritis
Deﬁnition: Inﬂammatory condition affecting the episcleral tissue between the conjunctiva and the sclera that occurs 
in the absence of an infection Diagnostic work-up: As per 10.0
Grading
Management
G1: Asymptomatic
Continue ICPi
Refer to ophthalmology within 1 week
Artiﬁcial tears
G2: Vision 20/40 or better
Hold ICPi therapy temporarily until after ophthalmology 
consult
Urgent ophthalmology referral
Topical corticosteroids, cycloplegic agents, systemic 
corticosteroids
G3: Symptomatic and vision worse than 2/40
Permanently discontinue ICPi
Urgent ophthalmology referral.
Systemic corticosteroids and topical corticosteroids with 
cycloplegic agents
G4: 20/200 or worse
Permanently discontinue ICPi
Emergent ophthalmology referral.
Systemic corticosteroids and topical corticosteroids with 
cycloplegic agents
Additional considerations: Consider use of inﬂiximab or other TNF-α blockers in cases that are severe and 
refractory to standard treatment
10.3 Blepharitis
Deﬁnition: Inﬂammation of the eyelid that affects the eyelashes or tear production Diagnostic work-up: As per 10.0
Grading
Management
No formal grading system
Warm compresses and lubrication drops
Continue therapy unless persistent and serious
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
Abbreviations: ICPi, immune checkpoint inhibitor; G, Grade; irAE, immune-related adverse event; IV, intravenous, 
TNF, tumor necrosis factor.
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Laboratory 
Assessments
Parameters
Hematology
Platelet countd
Mean Corpuscular 
Volume (MCV)
White blood cell (WBC) 
Count with Differentiald:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Reticulocytes (%)
Mean corpuscular 
hemoglobin concentration 
(MCHC)
Hemoglobind
Mean corpuscular
hemoglobin (MCH)
Hematocrit
Activated partial 
thromboplastin time 
(aPTT)a
Red blood cell countd
Prothrombin timea
Absolute lymphocyte countd
International normalized
ratio (INR)a
Absolute neutrophil countd
Biochemistry
Blood Urea 
Nitrogen/Total 
urea
Potassium
Aspartate 
Aminotransferased
Bilirubin (total, 
indirect/direct)d
Creatinined
Sodium
Alanine 
Aminotransferased
Total Protein
Glucose
Calcium
Alkaline phosphatase
Tuberculin skin test, 
QuantiFERON-TB-Gold, 
or T-SPOT (if positive 
history of tuberculosis 
exposure)
Lipase
Chloride
Albumin
Lactate dehydrogenase 
(LDH)
C-reactive
protein
Amylase
Routine Urinalysis
Dipstick plus microscopic evaluation. Dipstick, including physical appearance, bilirubin, 
blood, color, glucose, ketones, leukocyte esterase, nitrite, pH, protein, specific gravity, 
urobilinogen, as locally available
Other Screening 
Tests
!
FSH and estradiol (as needed if not a WOCBP only)
!
Serum or highly sensitive urine β-hCG pregnancy test
!
Free T4 and TSH
!
Hepatitis Screeningb: Hepatitis B surface antigen; Hepatitis B core antibody and 
Hepatitis C antibody
!
HIV; HIV virus RNA, quantitative; and CD4 lymphocyte countc
a Coagulation parameters collected at baseline and as clinically indicated, thereafter (See Table 1).
b If hepatitis B surface antigen positive and hepatitis B core antibody positive, then reflex to quantitative HBV DNA 
(PCR); if hepatitis B core antibody positive alone, then reflex to quantitative hepatitis B DNA (PCR); if hepatitis C 
antibody positive, then reflex to quantitative hepatitis C RNA (PCR).
c Not required for all participants. Testing required for participants with known history of HIV. Participants must be 
adequately consented per local regulations for any HIV-related testing.
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Assessments
Parameters
d Results must be reviewed by the Investigator within 3 days prior to dosing. 
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