ORIGINAL

ARTICLES

Cutaneous adverse events (AEs) of anti-programmed

cell death (PD)-1 therapy in patients with metastatic
melanoma: A single-institution cohort
Shelley Ji Eun Hwang, MBBS (Hons),a,e Giuliana Carlos, MBBS,a,e Deepal Wakade, MD,a,e
Karen Byth, PhD,b,e Benjamin Y. Kong, MBBS,c Shaun Chou, MBBS,d Matteo S. Carlino, MBBS, FRACP,c,e,f
Richard Kefford, MBBS, PhD, FRACP,c,f and Pablo Fernandez-Penas, MD, PhD, FACDa,e
Sydney, Australia
Background: Anti-programmed cell death (PD)-1 therapy is emerging as the backbone of new standard of
care immunotherapy for metastatic melanoma. Immune-related cutaneous events are observed in these
patients.
Objective: We sought to describe cutaneous adverse events observed in patients with metastatic melanoma
on anti-PD-1 therapy.
Methods: We reviewed the clinical and histologic information of all patients treated with single-agent
anti-PD-1 therapy for metastatic melanoma at Westmead Hospital, Sydney, Australia, from May 2012 to
February 2015.
Results: Of the 82 patients included in the study, 34 had dermatology assessments. Forty (49%) developed
a form of anti-PD-1-associated cutaneous adverse events. In all, 17% developed lichenoid reactions and
eczema, and 15% developed vitiligo. An estimated 25% of patients were expected to develop their first
lichenoid reactions within 8.3 months, and eczema and vitiligo within 10.3 months of therapy. These
adverse events tend to appear together in patients on anti-PD-1 therapy.
Limitations: The study was from a single center and clinical information was reviewed retrospectively in
patients not referred to dermatology.
Conclusion: Anti-PD-1 therapy is associated with the development of immune-related cutaneous events.
Lichenoid reactions, eczema, and vitiligo are the 3 most prevalent lesions observed in our population.
There is a tendency for lichenoid reactions and eczema to occur with vitiligo. ( J Am Acad Dermatol
2016;74:455-61.)
Key words: anti-programmed cell death-1; eczema; immune reaction; immunotherapy; lichenoid reaction;
metastatic melanoma; vitiligo.

o date, metastatic melanoma imposes a significant therapeutic challenge to clinicians,

because of poor response rates, severe
toxicities, and short response duration.1,2

Programmed cell death (PD)-1 is an immune

checkpoint receptor that is expressed by activated
T cells, which, when activated by its ligand, downregulates T-cell activation to avoid autoimmunity

From the Department of Dermatology,a Research and Education

Network,b Crown Princess Mary Cancer Center,c and Tissue
Pathology and Diagnostic Oncology,d Westmead Hospital;
Sydney Medical School, University of Sydneye; and Melanoma
Institute Australia.f
Funding sources: None.
Dr Carlino is an advisory board member for Merck and BMS. Dr
Kefford is an advisory board member for Merck, BMS, GSK,
Roche, and Amgen. Drs Hwang, Carlos, Wakade, Byth, Kong,
Chou, and Fernandez-Penas have no conflicts of interest to
declare.

Presented orally at the 2015 Australasian Society for Dermatology

Research Meeting, in Adelaide, Australia, on May 16, 2015.
Accepted for publication October 15, 2015.
Reprint requests: Shelley Ji Eun Hwang, MBBS (Hons), Westmead
Hospital, Hawkesbury Road, Westmead NSW 2145, Sydney,
Australia. E-mail: shelley.hwang@hotmail.com.
Published online January 12, 2016.
0190-9622/$36.00
2015 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2015.10.029

455

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456 Hwang et al

MARCH 2016

and create immune tolerance.3,4 Tumor cell PD

body skin examination. Sixteen segmented full-body
ligand-1 expression leads to T-cell exhaustion.2
photographs were taken at the initial visits.
Subsequently, patients were reviewed at 3- to 6-week
Anti-PD-1 immunotherapy, such as nivolumab and
intervals. A complete skin check was conducted at
pembrolizumab, block the interaction between PD-1
each visit and new lesions were identified, photoand PD ligand-1, stimulating T-cell responses.2,3
graphed, and biopsied/excised when clinically
These immunotherapies have demonstrated
indicated.
improved survival in patients with metastatic melaDermatology team review
noma.5-8 Both agents have
did not occur in all patients
recently been Food and
CAPSULE SUMMARY
for a number of reasons
Drug Administration (FDA)
including patients being in
approved and are now
Little is known about cutaneous adverse
terminal phases of their diswidely used in clinical
events associated with anti-programmed
eases, patients refusal, and
practice.2,9-12
cell death-1 therapy.
management of minor skin
As anti-PD-1 therapy is
Anti-programmed cell death-1 therapy is
toxicities by the treating
comparatively new,13 there
associated with the progressive
medical oncology service.
is a lack of detailed literature
development of lichenoid reactions,
The final diagnoses of
on
anti-PD-1-associated
eczema, and vitiligo.
lesions were based on the
cutaneous adverse events
clinical evaluation and sup(AEs). A recent study reThese immune-related adverse events
ported by histopathology
ported commonly observed
tend to appear together in patients on
findings. The biopsied lecutaneous
AEs
include
anti-programmed cell death-1 therapy.
sions were processed and
maculopapular
eruption,
reviewed by pathologists
pruritus, and hypopigmentain the Department of Tissue Pathology, Institute of
tion.14 Often clinical trials report skin toxicities via
Clinical Pathology, and Medical Research, Westmead
global terms such as rash or pruritus according to
Hospital, Sydney, Australia. The tissue samples with
Common Terminology Criteria for AEs.15,16 Although
diagnosis of uncertainty were further evaluated by a
anti-PD-1 is known to induce less severe toxicities
dermatologist (P. F-P.), a pathologist (S. C.), and
compared with anti-cytotoxic T-lymphocytedermatology research associates (S. H., G. C., D. W.);
associated protein 4 (CTLA-4),3,11,13,17 grade 3/4
and the final diagnosis was derived by consensus.
drug-mediated toxicities are still observed in 9% of
patients, limiting the drug use.17
We herein describe the cutaneous AEs observed
Statistical analysis
in patients with metastatic melanoma treated with
Statistical analysis was conducted using software
anti-PD-1 antibodies.
(SPSS, Version 22, IBM Corp, Armonk, NY). All
analyses were exploratory and 2-tailed tests with a
METHODS
significance level of 5% were used throughout.
Patient selection and evaluation
Kaplan-Meier survival curves were used to illustrate
This is a prospective and retrospective observathe distribution of time from commencement of
tional study of patients with unresectable stage IIIC/
treatment to onset of each cutaneous AEs. Log rank
IV metastatic melanoma treated with pembrolizutests and Cox regression were used to test for
mab or nivolumab at or above the FDA-approved
association between gender and age, and the
dose of each agent, as part of clinical trials or
distribution of time from commencement of
receiving drugs on compassionate grounds from a
treatment to onset of each lesion type. A x 2 test
pharmaceutical company, between May 1, 2012, and
was used to test for within-patient association among
February 1, 2015, at Westmead Hospital, Sydney,
the occurrence of lichenoid reactions, eczema, and
Australia. Patients with previous exposure to
vitiligo immune-related AEs.
ipilimumab were included if their interval between
ipilimumab and anti-PD-1 therapy was greater than
28 days. The study was approved by the Westmead
RESULTS
Hospital Human Research Ethics Committees (HREC
Demographics
LNR/13/WMEAD/418).
Of the 82 eligible patients, 34 were assessed by the
Patients demographics and clinical information
dermatology team. Medical records were reviewed
including cutaneous AEs associated with antifor all patients not referred for dermatology review to
PD-1 therapy were prospectively collected. All
identify any cutaneous AEs observed and treated by
patients referred to dermatology underwent fullthe oncology team.
d

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Hwang et al 457

VOLUME 74, NUMBER 3

Abbreviations used:

Table I. Number of patients who developed a skin

lesion

AE:
BRAFI:
FDA:
PD:
SCC:

Cutaneous adverse reactions

adverse event
BRAF inhibitor
Food and Drug Administration
programmed cell death
squamous cell carcinoma

Of 82 patients, 51 were male (62%). The median

age of patients was 61 years (range 19-88 years). The
median number of months on treatment was
5.7 months (interquartile range 2.7-12.4 months).
Five patients were on nivolumab and 77 patients
were on pembrolizumab. In all, 51 patients had
previous treatment with ipilimumab. There was no
statistically significant difference in the distribution
of the time to first new skin lesion by previous
ipilimumab exposure (log rank test P = .789), by
gender (log rank test P = .487), or by age (Cox
regression P = .085). Seven patients had previous
treatment with interferon.
Forty patients (49%) developed new cutaneous
AEs after the anti-PD-1 therapy. The most frequent
lesions were lichenoid reaction (n = 14, 17%),
eczema (n = 14, 17%), and vitiligo (n = 12, 15%).
Other commonly observed lesions include actinic
keratosis (n = 11, 13%), seborrheic keratosis (n = 11,
13%), pruritus (n = 9, 11%), infection (n = 7, 9%),
folliculitis (n = 5, 6%), squamous cell carcinoma
(SCC) (n = 5, 6%), and new nevus (n = 5, 6%). Less
commonly observed lesions include cutaneous
metastatic melanoma (n = 3, 4%), basal cell
carcinoma (n = 2, 2%), and bullous pemphigoid
(n = 2, 2%). Other rarely observed lesions are
included in Table I.
Lichenoid reaction
Of 14 patients (7 male) who developed lichenoid
reactions, 1 also developed oral lichenoid lesions.
Eight patients had previous ipilimumab exposure.
There was no statistically significant association
between the distribution of time from commencement of treatment to first lichenoid reaction and
previous ipilimumab exposure (log rank test
P = .851), gender (log rank test P = .431), or age
(Cox regression P = .648).
The median age of patients who did and did
not developed lichenoid reaction was 62.5 years
(interquartile range 58-72 years) and 60 years
(interquartile range 53-69.5 years), respectively.
Clinically, lichenoid reactions presented as
multiple discrete, erythematous, and sometimes
violaceous, and varied from minimally scaly papules
to plaques. These predominantly appeared on the

Actinic keratosis
Basal cell carcinoma
Bullous pemphigoid
Eczema
Folliculitis
Hypopigmented nevus
Infections (tinea/herpes zoster/cellulitis)
Pruritus
Lichenoid reaction
Primary melanoma
Cutaneous metastatic melanoma
New nevus
Seborrheic keratosis
Squamous cell carcinoma
Vitiligo
None
Others in 15 patients (18.3%)
Sebopsoriasis
Acute generalized exanthematous
pustulosis
Photosensitivity
Solar lentigo
Cyst
Wound
Keratosis pilaris
Skin tag
Rosacea
Psoriasis
Hemangioma
Livedo reticularis
Unidentified abdominal rash*

No. of patients,
n = 82

11
2
2
14
5
1
7
9
14
1
3
5
11
5
12
42

(13.4%)
(2.4%)
(2.4%)
(17.1%)
(6.1%)
(1.2%)
(8.5%)
(11.0%)
(17.1%)
(1.2%)
(3.7%)
(6.1%)
(13.4%)
(6.1%)
(14.6%)
(51.2%)
1
1
1
2
1
1
1
1
1
1
2
1
1

Data represented as n (%).

*Not reviewed by dermatology, reviewed by oncology.

chest and back. Typically mucous membranes were

spared. However, in 1 patient, the lesions presented
as multiple crusted and annular vesicles affecting
lower limbs and trunk.
Sixteen biopsy specimens were obtained from 10
patients. Histologically, the interface and lichenoid
inflammation had quite variable appearance in
different biopsy specimens, including different
lesions from the same patient in some cases. The
lichenoid inflammation was florid and well
developed in 9 biopsy specimens from 7 patients.
Only 3 biopsy specimens showed hyperkeratosis,
irregular acanthosis, and hypergranulosis, and at
least 1 of these features was absent in all the other
biopsy specimens. Two of these 3 biopsy specimens
resembled lichen planus whereas the third biopsy
specimen had patchier lichenoid inflammation
despite having all 3 features. Features not typical of

458 Hwang et al

J AM ACAD DERMATOL

MARCH 2016

Fig 1. Estimated cumulative incidence of developing the first lichenoid reactions (A), eczema
(B), and vitiligo (C) by months since commencement of treatment. Tick marks represent
censored observations.

lichen planus such as parakeratosis were seen in 8

biopsy specimens, including the 2 biopsy specimens
that had some resemblance to lichen planus. There
were also small subepidermal blisters secondary to
the lichenoid inflammation in 2 biopsy specimens
from 1 patient taken at a different stage of treatment.
Five biopsy specimens had quite mild interface
dermatitis where the predominant pattern was either
lichenoid or basal vacuolar change. These 5 biopsy
specimens also lacked chronic epidermal changes
except for mild acanthosis in 1 biopsy specimen. In
addition, dermal eosinophils were identified in 6
biopsy specimens from 5 patients.
As shown in Fig 1, the incidence of developing
lichenoid reaction increases at an approximately
constant rate after commencement of treatment.
A quarter of patients (cumulative incidence rate
25%, SE 6.4%) are expected to develop their first
lichenoid reaction within 8.3 months of commencing
treatment, with one third of patients (cumulative
incidence rate 33%, SE 8.3%) estimated to develop
their first lichenoid reaction within 14.0 months of
commencing treatment.
Eczema
Of 14 patients (8 male) who developed eczema, 7
had previous ipilimumab exposure. There was no
statistically significant association between the distribution of time from commencement of treatment
to first eczema and previous ipilimumab exposure
(log rank test P = .514), gender (log rank test
P = .968), or age (Cox regression P = .188).
The median age of patients who did and did not
develop eczema was 69.5 years (interquartile range
59.0-75.0 years) and 60 years (interquartile range
52.5-69.0 years), respectively.
Lesions appeared on multiple sites, most
commonly on the back and lower or upper limbs,
less frequently on the face, chest, and abdomen. The
clinical presentation varied from classic eczema
(ill-defined erythematous scaly lesions) to multiple

nummular plaques. The lesions were pruritic in most

cases.
As seen in Fig 1, the incidence of developing
eczema increases at an approximately constant rate
after commencement of treatment. A quarter of
patients (cumulative incidence rate 25%, SE 7.1%)
are expected to develop their first eczema within
10.3 months of commencing treatment and one third
of patients (cumulative incidence rate 33%, SE 9.1%)
are estimated to develop the first eczema within
13.8 months of commencing treatment, increasing
to an estimated 40% of patients (cumulative
incidence rate 40%, SE 11.2%) within 20.0 months
of commencing treatment.

Vitiligo
Of 12 patients (9 male) who developed vitiligo, 6
had previous ipilimumab exposure. There was no
statistically significant association between the
distribution of time from commencement of
treatment to first vitiligo and previous ipilimumab
exposure (log rank test P = .73), gender (log rank test
P = .066), or age (Cox regression P = .649).
The median age of patients who did and did
not develop vitiligo was 65.5 (interquartile range
57.5-69.5 years) and 60.0 years (interquartile range
53.0-70.0), respectively.
Lesions appeared on various areas of the body,
including arms, face, neck, trunk, chest, and
legs. The clinical presentation was typical (sharply
demarcated and depigmented white macules).
As shown in Fig 1, the incidence of developing
vitiligo increases at an approximately constant rate
after commencement of treatment. A quarter of
patients (cumulative incidence rate 25%, SE 7.3%)
are expected to develop their first vitiligo within
10.3 months of commencing treatment, increasing
to an estimated 40% of patients (cumulative
incidence rate 40%, SE 10%) within 13.8 months of
commencing treatment.

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Hwang et al 459

VOLUME 74, NUMBER 3

Table II. Difference between the observed

frequency and that expected if the 3 lesions of
interest (lichenoid reactions, eczema, vitiligo) occur
independently within patient

Lesion present

None
Lichenoid reaction only
Eczema only
Vitiligo only
Lichenoid 1 eczema only
Lichenoid 1 vitiligo only
Eczema 1 vitiligo only
All

Observed
frequency
(n = 82)

Expected
frequency if lesions
independent (n = 82)

55
7
6
3
2
3
4
2

48.3
9.9
9.9
8.2
2.0
1.7
1.7
0.3

Do these above AEs occur independently

within a patient?
Of 82 patients, 2 (2.4%) developed all 3 AEs
(lichenoid reaction, eczema, and vitiligo) and 9
(10.8%) developed combinations of these 3 AEs.
These values were above expected (Table II) and we
found that there is statistically significant association
among the presence of lichenoid reaction, eczema,
and vitiligo (x 2 20.4, df = 7, P = .005) (supplementary
document for calculation of expected frequencies
under null hypothesis of independence available at
http://www.jaad.org).
Squamous cell carcinoma
Five patients (4 male) developed SCC (6.1%).
The median age of patients who did and did not
develop SCC was 73 years (interquartile range
73-80 years) and 60 years (interquartile range
53-69 years), respectively. The difference in age
between these 2 groups was statistically significant
(P = .004).
One of 5 patients had previous ipilimumab;
2 patients had previous combination of BRAF
inhibitor (BRAFI) and mitogen-activated protein
kinase inhibitor, and 3 patients had no previous
BRAFI. There was no statistically significant
difference in the distribution of the time to first
SCC by previous BRAFI exposure (log rank test
P = .143).
Lesions mostly appeared on the photodamaged
areas including the face, chest, and arms.
One fifth of patients (cumulative incidence rate
20%, SE 9.7%) are expected to develop their first SCC
within 23.5 months of commencing treatment.

DISCUSSION
In our study, lichenoid reactions, eczema, and
vitiligo were the commonest and characteristic lesions.

All these lesions are mediated by lymphocyte damage

and we have grouped them as immune-related AEs.
Moreover, these 3 lesions demonstrated a statistically
significant tendency to appear in combination rather
than alone within a patient supporting this concept.
Vitiligo in particular appeared more commonly in
combination with lichenoid, eczema, or both than
would be expected if these lesions occurred
independently within patients.
The frequency of immune-related AEs in our
cohortelichenoid reactions (17%), eczema (17%),
and vitiligo (15%)eis consistent with current limited
literature where vitiligo and pruritus appeared in
10% to 20% of patients on anti-PD-1 therapy.13 In a
pembrolizumab phase-I clinical trial, patients
developed rash (20%), pruritus (24%), and vitiligo
(11%).18 We speculate whether the authors here
were referring to lichenoid reactions as rash and
eczema as pruritus. The frequency of vitiligo
(11%)18 was similar to our study cohort.
The incidence of each of the 3 most common
lesion types (lichenoid reaction, eczema, and
vitiligo) increased at an approximately constant
rate after commencement of treatment, reaching
25% of patients within 10.3 months for each type as
seen in Fig 1. We suggest that with great durable
tumor response to anti-PD-1,11,17-20 more patients
are expected to experience immune-related AEs
during their prolonged survival. As immunotherapies require reasonable time to induce immune
responses, both the tumor treatment response and
autoimmune AEs may take longer to appear
compared with cytotoxic or targeted therapies.2
Hence, long-term monitoring is warranted to
assess both treatment response and AEs in these
populations.
The prognostic value of using an immune-related
AE as a marker of treatment response is currently
unknown.13 It would be interesting to investigate the
possible relationship when a larger sample size is
available.
Histopathology of lichenoid reactions in several
patients demonstrated features resembling lichen
planus with hyperkeratosis and irregular acanthosis,
similar to a previous small case series.13 However,
the degrees of interface dermatitis and epidermal
changes are more variable in our cohort than what
has been described previously.
Moreover, approximately 33% of our study
population (n = 27/82) developed at least 1 of 3
immune-related AEs, which suggests potential
association between an anti-PD-1 therapy and
development of immune-related AEs. To date, the
presence of vitiligo21 and a case series on lichenoid
dermatitis observed with anti-PD-1 therapy use

460 Hwang et al

have been reported.13 Our study suggests that

approximately 25% of the patients on anti-PD-1
therapy would develop immune-related AEs during
the first 10 months of the treatment. As autoimmune
diseases are prevented by the PD-1 and PD ligand-1
pathways,22 we suspect that the immune-activating
mechanism of anti-PD-1 antibodies induce immune
response against native cellular systems, resulting in
immune-related AEs in patients on anti-PD-1
therapy.
Unlike dabrafenib and vemurafenib where most
SCCs appear early in the treatment period
(by 5.5 months in dabrafenib study) requiring
early-phase monitoring,23 immune-related AEs take
longer to develop, and the frequency increases with
increasing exposure to the treatment. Hence,
clinicians will need to provide long-term monitoring
for patients on anti-PD-1 therapy.
Compared with 20% of patients developing SCCs
on BRAFI,23 SCCs were only found in 6.1% in this
study. Although anti-PD-1 therapy is being trialled in
the treatment of metastatic head and neck SCC,24 the
rate of cutaneous SCC in our population is not lower
than expected.
Compared with the cutaneous AEs of single-agent
BRAFI and combination dabrafenib and trametinib,25 anti-PD-1 therapy has a completely different
AE profile because of its different mechanism
of action. Hence it could be considered an
alternate treatment option in patients who develop
severe AEs on BRAFI or combination dabrafenib and
trametinib.
As not all patients were reviewed by the
dermatology team, the prevalence of cutaneous
AEs may be underestimated in our population.
Conclusion
Clinicians need to be aware that immune-related
AEs such as lichenoid reaction, eczema, and vitiligo
are common among patients on anti-PD-1 therapy,
and they appear late in their treatment. Hence, we
recommend these patients have access to long-term
regular dermatology reviews.
Translational studies searching for predictive
biomarkers specific to anti-PD-1-associated lichenoid reactions may allow clinicians to use
these biomarkers to predict the likelihood of
developing immune-related AEs and the treatment
response.20,26
The authors acknowledge Dr Adam Cooper, Dr Arthur
Clements, Dr Marina Ali, Rupalben Patel, Dr Rachel
Anforth, Rebecca Hinshelwood, Joanna Jackson, Natalie
Byrne, Medhia Survery, Meenal Rai, Manuel Marquez,
Raymond Tangunan, Vicky Wegener, Andrea ForeroVelandia, Amie Cho, patients, and families.

J AM ACAD DERMATOL

MARCH 2016

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461.e1 Hwang et al

SUPPLEMENTARY METHODS
Statistical analysis
The longer patients stay on treatment, the more
likely they will develop an adverse event.
Because patients were on treatment for different
lengths of time, the method of analysis must
account for this differential follow-up. Patients
were either censored at the time of death, date of
anti-programmed cell death-1 cessation, oreif they
were still alive and on treatmenteat the cut-off date
for the study (February 2015). Kaplan-Meier survival
curves, Cox proportional hazards models, and log
rank tests are ways of analyzing survival data by
taking account of right-censored follow-up times.S1
Table II examines the joint distribution of the
occurrence of lichenoid reaction, eczema, and
vitiligo within a patient. Overall, 14 of 82 patients
developed lichenoid reaction, 14 of 82 developed
eczema, and 12 of 82 developed vitiligo. If these 3

J AM ACAD DERMATOL

MARCH 2016

lesions occurred independently within a patient,

then the probability of observing all 3 in a single
patient would be (14/82)*(14/82)*(12/82) = .00419.
Therefore, in the 82 patients, we would expect
82*0.00419 = 0.3 patients to display all 3 lesions. We
actually observed 2 patients with all 3 lesions.
In the same way, the expected number of patients
with vitiligo only is given by (12/82)*(1-14/82)*
(1-14/82)*82 = 8.2, which is many more than the 3
patients observed with only this lesion, and so on.
A x2 test of the difference between the observed
frequency and that expected if the 3 lesions of
interest (lichenoid reactions, eczema, vitiligo) occur
independently within a patient is used to test for an
association.
REFERENCE
S1. Armitage P, Berry G, Matthews J. Statistical methods in
medical research. 4th ed. Oxford: Blackwell Science; 2002.