# Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients – The European MelSkinTox study

J.-M. L'orphelin, J. Cassecuel, L. Kandolf, C. Harwood, P. Tookey, M. Junejo, Sarah Hogan, C. Lebbé, Z. Appalla, T.-m. Kränke, et al.

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## To cite this version:

J.-M. L'orphelin, J. Cassecuel, L. Kandolf, C. Harwood, P. Tookey, et al., Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients – The European MelSkinTox study. Journal of the European Academy of Dermatology and Venereology, 2023, 10.1111/jdv.19112. inserm-04067755

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https://inserm.hal.science/inserm-04067755

Submitted on 13 Apr 2023

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ORIGINAL ARTICLE

# Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients—The European MelSkinTox study

J.-M. L'Orphelin<fnref n="1" /> ID | J. Cassecuel<fnref n="2" /> | L. Kandolf<fnref n="3" /> | C. A. Harwood<fnref n="4" /> | P. Tookey<fnref n="4" /> |

M. H. Junejo<fnref n="4" /> ID | S. Hogan<fnref n="4" /> | C. Lebbé<fnref n="5" /> | Z. Appalla<fnref n="6" /> ID | T.-M. Kränke<fnref n="7" /> |

G. Pellacani<fnref n="8" /> ID | D. Cerasuolo<fnref n="9" /> | B. Dujovic<fnref n="3" /> | V. Del Marmol<fnref n="10" /> | A. Forschner<fnref n="11" /> |

C. Garbe<fnref n="11" /> ID | V. Bataille<fnref n="12" /> | J. M. Ressler<fnref n="13" /> ID | P. Sollena<fnref n="14" /> | A. Dompmartin<fnref n="1" /> |

K. Peris<fnref n="14" />,<fnref n="15" /> ID | B. Dreno<fnref n="2" /> ID | And European Association of Dermato-Oncology

Correspondence

J.-M. L'Orphelin, Department of Dermatology,
Caen-Normandie University Hospital, Caen,
France.

Email: lorphelin-jm@chu-caen.fr

B. Dreno, Nantes Université, Nantes – Angers
INSERM, Immunology and New Concepts in
ImmunoTherapy, INCIT, UMR 1302, Nantes
F-44000, France.

Email: brigitte.dreno@atlanmed.fr

K. Peris, Department of Medical Science,
Dermatology, Fondazione Policlinico
Universitario A. Gemelli – IRCCS, Largo a
Gemelli 8, Rome 00168, Italy.

Email: ketty.peris@unicatt.it

Abstract

**Background:** Checkpoint inhibitors provide an effective approach for the melanoma treatment. They prolong lymphocyte effects, which explains the cytotoxicity underlying immune-related adverse events (IrAEs). Cutaneous IrAEs affect nearly 40% of PD-1i and 50% of CTLA4i-treated patients. Severe cutaneous irAE do not often occur but could be life-threatening and may persist despite treatment discontinuation.

**Methods:** We aimed to investigate cutaneous IrAEs in a cohort of patients treated with ICI across Europe in an effort to characterize the reactions in a real-world, phase IV, post-marketing study using a follow-up questionnaire.

Data since November 2016 until March 2021 were obtained from the Melskintox database, a European multicentric biobank dedicated to the follow-up of melanoma and cutaneous adverse events, supported by EADO. The dermatoses reported were pooled into four categories: inflammatory dermatosis, bullous diseases, drug-related eruptions and pigmentary diseases.

**Results:** Inflammatory benign dermatoses (n=63) represented the most common group of reactions (52.5%), followed by drug-related eruptions (n=24, 20%),

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

© 2023 The Authors. *Journal of the European Academy of Dermatology and Venereology* published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

<footnote n="1">¹Department of Dermatology, Caen-Normandie University Hospital, Caen, France</footnote>

<footnote n="2">²Nantes Université, Nantes – Angers INSERM, Immunology and New Concepts in ImmunoTherapy, INCIT, UMR 1302, Nantes, France</footnote>

<footnote n="3">³Department of Dermatology, Medical Faculty Military Medical Academy, Belgrade, Serbia</footnote>

<footnote n="4">⁴Department of Dermatology, Second Floor, South Tower, Royal London Hospital, Barts Health NHS Trust Whitechapel, E1 1 BB and Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London, UK</footnote>

<footnote n="5">⁵Department of Dermatology, APHP Hôpital Saint Louis, Paris, France</footnote>

<footnote n="6">⁶Second Department of Dermatology, Aristotle University of Thessaloniki, Thessaloniki, Greece</footnote>

<footnote n="7">⁷Department of Dermatology, Medical University of Graz, Graz, Austria</footnote>

<footnote n="8">⁸Department of Dermatology, University of Modena and Reggio Emilia via del Pozzo 71, Modena, Italy</footnote>

<footnote n="9">⁹Biostatistics and Clinical Research Unit, Caen-Normandy University Hospital, Caen, France</footnote>

<footnote n="10">¹⁰Department of Dermatology – Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium</footnote>

<footnote n="11">¹¹Department of Dermatology, Eberhard Karls University, Tuebingen, Germany</footnote>

<footnote n="12">¹²Department of Dermatology, Hemel Hempstead Hospital NHS, London, UK</footnote>

<footnote n="13">¹³Department of Dermatology, Medical University of Vienna, Vienna, Austria</footnote>

<footnote n="14">¹⁴Department of Medical Science, Dermatology, Fondazione Policlinico Universitario A. Gemelli – IRCCS, Rome, Italy</footnote>

<footnote n="15">¹⁵Department of Dermatology, Catholic University of Rome, Rome, Italy</footnote>
pigmentary diseases (n=23, 19.2%) and bullous diseases (n=10, 8.3%). Grade II (n=41, 34.2%) are represented by bullous pemphigoid, eczema, hypodermitis, lichenoid eruption, maculopapular rash, pruritus, psoriasis-like rash, urticarial erup- tion and vitiligo. Grade III (n=18, 15.0%) are represented by bullous pemphigoid, lichenoid eruption and rashes. Grade IV (n=2, 1.7%) is only represented by bullous disease. Most cutaneous IrAEs led to immunotherapy continuation (n=95, 88.0%). CR is associated with more severe the cutaneous irAEs. We report an average time- to-onset of 208 days and some late-onset events.

**Conclusion:** Our study has characterized the clinical spectrum of cutaneous irAEs, their timing and severity and their relationship with tumour response. Grade I–II cutaneous IrAE are easily managed allowing ongoing anticancer treatment. Severe late-onset cutaneous irAE are not uncommon. A dermatological follow-up helps mit-igate the risk of life-threatening adverse events. These findings highlight the impor-tance of oncodermatological involvement in management of patients with melanoma receiving immunotherapy.

INTRODUCTION

Cutaneous melanoma develops from pigment-containing
cells known as melanocytes¹ and represents nearly 2%–3%
of all cancers²; it is a highly aggressive cancer but has been
shown to be highly responsive to immunotherapy, especially
immune checkpoints inhibitors (ICI).³

Immune checkpoints regulate the outcome of lympho-
cyte engagement with antigen-presenting cells and tumour
cells.⁴ They downmodulate the intensity of the adaptive im-
mune response, thus providing a new gold standard in the
treatment of metastatic melanoma.³,⁵

PD-1 inhibits the proliferation of immune cells that
downmodulate effector functions⁶,⁷ and promotes self-
tolerance.¹ Engagement of PD-1 by PD-L1 leads to the
inhibition of T cell receptor-mediated lymphocyte prolifer-
ation and cytokine secretion,⁸ and consequently increased
tolerance.

Checkpoint inhibitors (ICI) such as ipilimumab (CTLA-4 inhibitor) or nivolumab or pembrolizumab (PD-1 inhibitors) provide an effective approach⁹ for the melanoma treatment preventing cancer cells from evading immune detection and then enabling their destruction.¹⁰

Immune-related adverse events and cutaneous adverse events

Treatment by ICI prolong lymphocyte effects, which ex-
plains the cytotoxicity underlying irAE. The irAE are
graded according to the Common Terminology Criteria for
Adverse Events (CTCAE). The CTCAE displays grades I
(asymptomatic or mild symptoms) through 5 (death related
to AE) with unique clinical descriptions of severity for each
AE. Nearly 70% of patients receiving ICI will experience an
irAE and of those nearly 10% will experience severe irAE
(grade III–IV).<sup>11,12</sup> The occurrence of severe irAE may be
as high as 55%–60% with combination immunotherapies.<sup>13</sup>

These may have varying phenotypes and may involve mul-
tiple organs, including the skin. Most adverse events occur
during or after the first cycle of treatment at a median time
of 40 days¹⁴ and include gastrointestinal, rash, hyperglycae-
mia, thyroiditis, hepatitis and musculoskeletal disorders.¹⁵

Cutaneous IrAEs in ICI-treated patients with metastatic
melanoma affect nearly 40% of PD-1i and 50% of CTLA4i-
treated patients.¹¹,¹² Severe cutaneous irAE do not often
occur and are reported in under 3% of patients¹³; however,
these irAE may be life-threatening and may persist despite
treatment discontinuation.¹⁶ Pruritus, eczema and vitiligo
are the most frequent skin manifestations reported with ICI
use, across all cancers.

Recently, the EADV task force ‘Dermatology for cancer patients’ has edited phenotype-specific treatment recommendations for cutaneous irAEs including levels of evidence and grades of recommendation.¹⁷

Rationale and aim of the study

Cutaneous IrAE are probably underestimated and diagno-
sis is often delayed because of a lack of recognition. If di-
agnosed early, cutaneous irAE—particularly lower intensity
grade I–II reactions—may be managed without interrup-
tion of anti-cancer treatment. ICI may result in severe grade
III–IV cutaneous manifestations in the absence of previous
skin pathology and rapid diagnosis is crucial. Recognition
and management of all grade cutaneous IrAE is important,
as this may facilitate continuation of ICI for anti-cancer
treatment.¹³

The clinical presentations of cutaneous IrAE are diverse
and our knowledge of their clinical course, pathophysiology
and impact on disease course is poorly understood.

We aimed to investigate cutaneous adverse events in a co-
hort of patients treated with ICI across Europe in an effort
to characterize the reactions in a real-world, phase IV, post-
marketing study using a follow-up questionnaire.
MATERIALS AND METHODS

Data on patients with advanced melanoma since November 2016 until March 2021 were obtained from the Melskintox database, a European multicentric biobank dedicated to the follow-up of melanoma patients and cutaneous adverse events, supported by the European Association of Dermato Oncology (EADO). The study complies with the ethical standards resulting from the Declaration of Helsinki. An information sheet was given to each patient to collect their consent to the study, and none of them refused to participate.

The Melskintox database gathers data from 21 partic-
ipating centres in different European countries (France
*n* = 39, United Kingdom *n* = 21, Italy *n* = 20, Serbia *n* = 17,
Austria *n* = 15, Greece *n* = 4, Belgium *n* = 2 and Germany
*n* = 2) represented by different dermatological unit
all around Europe as Nantes (n=33), Rome Catholic
University (n = 19), Belgrade (n = 17), London NHS (n = 16),
Vienna (n = 13), Paris APHP (n = 6), London (n = 5), Athens
(n = 4), Brussel (n = 2), Graz (n = 2), Tuebingen (n = 2) and
Modena (n = 1).

The inclusion criteria were as follows:

* Patients with unresectable stage IV melanoma

* Patients treated with anti-PD-1 or combination therapy

* Patients who experienced cutaneous irAE with the ad-
  ministered immunotherapy.

We only included patients in whom the drug was started for clinical indication in real life experience. Atezolizumab, cemiplimab and avelumab delivered in melanoma clinical trials (n = 10/130) have been excluded. Patients who received intravenous anti-PD-1 or a combination of PD-1 and anti-CTLA4 or anti-LAG3 were selected and the type, occurrence of cutaneous adverse events were analysed thanks a questionnaire. All cutaneous adverse events have been registered.

It is a prospective study for which a questionnaire was
filled in to characterize the dermatosis and follow its evolu-
tion. Data were collected by an oncodermatologist at onset of
the cutaneous adverse event (i.e. at inclusion of patients) and
at 3, 6 and 12 months after the onset. Templates are given in
*Appendix 1*.

The cutaneous adverse events reported were pooled into
four categories as follows:

*   *Benign inflammatory dermatosis:* psoriasis vulgaris; inverse psoriasis; pruritus; sarcoidosis cutis; lichen planus; urticarial eruption; acneiform rash; photosensitive eruption; xosis; lichenoid eruption; folliculitis; prurigo; eczema; eczema; palmoplantar hyperkeratosis

*   *Bullous diseases:* Steven–Johnson–Lyell syndrome/toxic epidermal necrolysis; bullous pemphigoid

*   Drug-related maculopapular rashes: maculopapular erup-
    tion; morbilliform rash; papulomatous rash

* Pigmentary diseases: vitiligo.

Grades III and IV cutaneous IrAEs were pooled in the
analysis.

Skin biopsies were not routinely performed since clinical
presentation was considered sufficient for diagnosis in most
cases.

The primary endpoint of our study was to describe and characterize cutaneous adverse events induced by check point inhibitors, type and delay of appearance. In a second time, we studied tumoral response regarding type and grades of cutaneous irAEs. Each delay of appearance of cutaneous irAEs was studied regarding sub-types of dermatitis to determine if some sub-types of dermatitis have special issue and need special follow-up.

Statistical analysis

Baseline characteristics are presented as n (%) for categorical
data.

The associations of response to treatment and of tumour grade with sex, type of lesion and treatment strategy were evaluated in two sequential bivariate analyses by the chi-squared test with simulated *p*-value. The value of *p* was computed by Monte Carlo simulation when the chi-square test conditions for validity were not met.

The associations between the grade (independent vari-
able) and the response to treatment at 3rd and 6th month
assessments (dependent variable) were evaluated by two
multinomial logistic regression models and odds ratios
(ORs) and corresponding 95% intervals were calculated.
Considering the sample size and the relatively high number
of classes of grade and response variables, no adjustment
variable was included in the final model.

All analyses were realized on R (version 4.2.1) and Rstudio
(2022.07.1).

RESULTS

A total of 120 patients were recruited across the centres between November 2016 and March 2021: Nantes (n = 33, 27.5%), Rome Catholic University (n = 19, 15.8%), Belgrade (n = 17, 14.2%), London NHS (n = 16, 13.3%), Vienna (n = 13, 10.8%), Paris APHP (n = 6, 5.0%), London (n = 5, 4.2%), Athens (n = 4, 3.3%), Brussel (n = 2, 1.7%), Graz (n = 2, 1.7%), Tuebingen (n = 2, 1.7%) and Modena (n = 1, 0.8%).

Immunotherapies included PD-1i (pembrolizumab n = 52, 43.3%, nivolumab n = 43, 35.9%) or CTLA-4i (ipilimumab n = 2, 1.7%) or combination of immunotherapies (nivolumab + ipilimumab n = 20, 16.7% and nivolumab+relatlimab n = 3, 2.5%). There was no statistical difference between all these immunotherapies.

Male:female ratio was 2.75 (88/32) that is, 73.3% of males
of 120 cases.

Inflammatory benign dermatoses (n = 63) represented the
most common group of reactions (52.5%), followed by drug-
related maculopapular rashes (n = 24, 20.0%), pigmentary
diseases (n=23, 19.2%) and bullous diseases (n=10, 8.3%). The diversity of cutaneous events under immunotherapy is represented in Figures 1 and 2.

Of the 120 cases, 49.2% (n=59), 34.2% (n=41), 15.0% (n=18) and 1.7% (n=2) were grade I, grade II, grade III and grade IV cutaneous adverse events, respectively. Grade II (n=41, 34.2%) were represented by bullous pemphigoid, eczema, hypodermitis, lichenoid eruption, maculopapular rash, pruritus, psoriasis-like rash, urticarial eruption and vitiligo. Grade III (n=18, 15.0%) were represented by bullous pemphigoid, dry skin, lichenoid eruption, maculopapular rash, morbilliform rash and psoriasis-like rash. Grade IV (n=2, 1.7%) was only represented by bullous disease.

Most cutaneous IrAEs led to immunotherapy continuation (n=95, 88.0%). The first tumour assessment 3 months after cutaneous event reported partial response (PR, n=39, 34.2%), followed by stable disease (SD, n=36, 31.6%), progression (PD, n=25, 21.9%) and complete response (CR, n=14, 12.3%).

Grades III–IV were significantly associated with partial response (PR), stable disease (SD) and progressive disease (PD) at 3 and 6 months with all OR <1 which means making a non-complete response after immunotherapy is protective from severe cutaneous irAEs. These results were summarized in Table 1.

The effects of clinicopathological factors on tumour response to immunotherapy at 3 and 6 months and grade of cutaneous irAEs were assessed by bivariate analysis and are presented in Tables 2 and 3, respectively.

CR was numerically associated with more severe the cutaneous irAEs: the percentage of CR rose from 5.3% for

grade I irAEs to 12.8% for grade II and 31.6% for grade III/IV irAEs, *p*=0.100. These results were similar for the 6 months assessment.

The proportion of presentations with bullous disease increased with increasing irAE grade (1.7%, 12.2% and 20.0%, respectively, for grade I, grade II and grade III + IV), whereas vitiligo significantly decreased (30.5%, 9.8% and 5.0%, respectively, grade I, grade II and grade III + IV).

Treatment of cutaneous irAEs was summarized in Table 4.

We pooled all cutaneous irAEs into three categories according to time of onset after implementation of immunotherapy: late-onset events occurring 1 year or more; early events occurring less than 3 months; and medium-onset events occurring at >3 months to <1 year.

We found an average time-to-onset of 208 days that is, 7 months and mean time-to-onset of 140 days [0; 1222] i.e., 4.7 months [0; 40.7].

Late-onset events occurred in 25 cases (20.8%); early events in 44 (36.6%); and medium onset events in 51 (42.5%) cases.

There was no association between time-of-onset of cutaneous events and the tumour response to immunotherapy (*p*=0.522 at 3 months and *p*=0.5658 at 6 months) as shown in Table 5.

There was no association between the time-of-onset of cutaneous events and the type of cutaneous event (inflammatory benign dermatoses, pigmentary disease, bullous disease or drug-related maculopapular rash), *p*=0.128 (Table 6). Inflammatory diseases were more likely to appear early whereas vitiligo is more often a medium-onset event.

<figure><img src="image_5.png" /><figcaption>**FIGURE 1** Clinical pictures of skin adverse reaction to immunotherapies: (a, b, c) palmo-plantar lichenoid eruption; (d) maculopapular rash; (e) psoriasis-like palmar hyperkeratosis, courtesy of Dr. Ketty Peris.</figcaption></figure>
DISCUSSION

Our study confirms the diversity of cutaneous irAE and describe the way to manage these adverse events. Inflammatory diseases are more likely to appear early whereas vitiligo is more often a medium-onset event. Complete response is associated with severe cutaneous irAE.

Adverse events are commonly observed in melanoma patients treated with ICI, and almost 10%–20% of patients experience grade III–IV irAE.¹¹,¹² The most common adverse events are gastrointestinal or pulmonary.¹²,¹⁸ In our real-world study focused on cutaneous irAEs, we reported mainly 24 rashes most of which morbilliform rashes, 23 vitiligo, 19 psoriasiform, 15 lichenoid, 8 eczematous, 6 bullous, 6 urticarial eruptions and only 1 Steven–Johnson–Lyell syndrome/toxic epidermal necrolysis overlap syndrome.

We report a sex ratio of 2.7 (88/32, 73% of males), which is higher to Bottlaenderet et al.¹⁹ which reported 57.7% of males.

In cancer centres, ICI are commonly administrated by oncologists and metastatic melanoma treatment does not routinely involve dermatologists. Cutaneous irAEs may therefore not be systematically recognized and diagnosed. Rash is a widely misused term by oncologists which has a very precise definition in dermatology. Our data provide an argument to routinely involve organ specialists in oncological treatment: this would facilitate early diagnosis and

treatment of cutaneous irAEs, and continuation of ICI treatment.¹³ Consistent with this we show that low-grade cutaneous irAE are usually easily managed and patients are less likely to discontinue treatment.

In the literature of the approval studies and in former literature, cutaneous irAEs were the most common side-effects of anti-PD-1 or anti-CTLA-4 up to 50% of the patients suffer from pruritus and rash with very few grade III-IV adverse skin reactions.²⁰⁻²² However, these cutaneous irAEs were poorly described. Previous real-life studies reported cutaneous irAE in of 8% to 49%.¹⁹,²³ The most common reactions in these two large series were eczematous eruptions (38% and 9.5%, respectively), and vitiligo (26% and 8.5%, respectively).¹⁹,²³ In our real-life study, we identified vitiligo in 19% (n=23) of cases and the prevalence of rashes (n=24, 20%) and eczemas (n=8, 6%), was similar. We found no difference in occurrence of cutaneous irAE between various ICI or combination treatment, whereas other studies reported that anti-CTLA4 therapy is associated with higher rates of cutaneous IrAE than anti-PD1 therapies.¹³ Our real-life study reports a different incidence rate of cutaneous irAEs from the one in literature of the approval studies. It highlights the importance of characterization and reporting of these reactions in a real-world, phase IV, post-marketing to make our scientific knowledge evolve with more hindsight.

Rates of grade III-IV cutaneous irAE have been reported in 1%–4% of patients receiving CTLA-4i²⁴ and 0.6% (n=3/496) of those receiving PD-1i immunotherapy.²³ Grade III–IV cutaneous irAE reached 0.6% (3/496) were represented by lichenoid skin reaction and Sweet syndrome in Hofmann study,²³ whereas Bottlaender et al.¹⁹ reported more severe or life-threatening grade cutaneous effects (around 2.6%, 5/189). We found around 15% (n=18) of grade III and 1.7% of grade IV cutaneous irAE. As we did, Bottlaenderet, Hofmann and Gault¹³ reported that higher grade cutaneous irAE lead to the interruption ICI therapy.

Our study suggests a positive association between high-grade cutaneous irAE and complete response to treatment as we reported 5.4%, 12.8% and 31.6% of complete response rates, respectively, with grades I, II and III–IV irAE. However, these elements must be considered with caution, because the longer the duration of drug use (correlating with longer OS), the greater the possibility of any adverse event, including severe IrAE, occurring. Given the mechanism of action of ICI, which promotes T-cell activation and enhances T-cell activity, it is plausible that immune-related irAE are

<figure><img src="image_6.png" /><figcaption>FIGURE 2 Clinical pictures of skin adverse reaction to immunotherapies: (a) relapse and worsening of previous psoriasis; (b) lichenoid nail distrophy and vitiligo-like eruption; (c) neutrophilic sweet-like eruption; (d) pyoderma gangrenosum, courtesy of Dr. Ketty Peris.</figcaption></figure>

<table><caption>TABLE 1 OR (95%CI) for immunotherapy response at first and second assessment after cutaneous event according to grade, with CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.</caption><thead><tr><th rowspan="2"></th><th colspan="2">3rd month assessment</th><th colspan="2">6th month assessment</th></tr><tr><th>Grade II</th><th>Grades III and IV</th><th>Grade II</th><th>Grade III and IV</th></tr></thead><tbody><tr><td>CR</td><td>Ref</td><td>Ref</td><td>Ref</td><td>Ref</td></tr><tr><td>PR</td><td>0.42 [0.08; 2.05]</td><td>0.12 [0.02; 0.68]</td><td>0.44 [0.10; 1.99]</td><td>0.11 [0.02; 0.60]</td></tr><tr><td>SD</td><td>0.47 [0.09; 2.3]</td><td>0.11 [0.02; 0.65]</td><td>0.57 [0.013; 2.58]</td><td>0.09 [0.02; 0.54]</td></tr><tr><td>PD</td><td>0.24 [0.04; 1.33]</td><td>0.13 [0.02; 0.78]</td><td>0.43 [0.09; 2.14]</td><td>0.18 [0.03; 0.93]</td></tr></tbody></table>
<table><caption>TABLE 2 Association of tumoral response at first and second assessment with tumour characteristics, bivariate, with irAEs: immune-related adverse events; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.</caption><thead><tr><th rowspan="2"></th><th colspan="4">Tumour response at 3 months</th><th colspan="4">Tumour response at 6 months</th></tr><tr><th>CR</th><th>PD</th><th>PR</th><th>SD</th><th>p</th><th>CR</th><th>PD</th><th>PR</th><th>SD</th><th>p</th></tr></thead><tbody><tr><td>n</td><td>14</td><td>25</td><td>39</td><td>36</td><td></td><td>16</td><td>24</td><td>35</td><td>34</td><td></td></tr><tr><td>Sex = male (%)</td><td>11 (78.6)</td><td>19 (76.0)</td><td>28 (71.8)</td><td>26 (72.2)</td><td>0.950</td><td>11 (68.8)</td><td>18 (75.0)</td><td>26 (74.3)</td><td>24 (70.6)</td><td>0.959</td></tr><tr><td>Type of cutaneous irAEs (%)</td><td></td><td></td><td></td><td></td><td>0.428</td><td></td><td></td><td></td><td></td><td>0.447</td></tr><tr><td>Inflammatory benign dermatosis</td><td>7 (50.0)</td><td>13 (52.0)</td><td>24 (61.5)</td><td>18 (50.0)</td><td></td><td>8 (50.0)</td><td>14 (58.3)</td><td>22 (62.9)</td><td>16 (47.1)</td><td></td></tr><tr><td>Bullous diseases</td><td>3 (21.4)</td><td>3 (12.0)</td><td>1 (2.6)</td><td>2 (5.6)</td><td></td><td>3 (18.8)</td><td>3 (12.5)</td><td>1 (2.9)</td><td>1 (2.9)</td><td></td></tr><tr><td>Pigmentary diseases</td><td>1 (7.1)</td><td>3 (12.0)</td><td>8 (20.5)</td><td>9 (25.0)</td><td></td><td>3 (18.8)</td><td>3 (12.5)</td><td>6 (17.1)</td><td>9 (26.5)</td><td></td></tr><tr><td>Drug-related maculopapular rashes</td><td>3 (21.4)</td><td>6 (24.0)</td><td>6 (15.4)</td><td>7 (19.4)</td><td></td><td>2 (12.5)</td><td>4 (16.7)</td><td>6 (17.1)</td><td>8 (23.5)</td><td></td></tr><tr><td>Treatment of cutaneous IrAES (%) y</td><td>11 (78.6)</td><td>21 (84.0)</td><td>25 (64.1)</td><td>25 (69.4)</td><td>0.334</td><td>12 (75.0)</td><td>19 (79.2)</td><td>24 (68.6)</td><td>23 (64.7)</td><td>0.651</td></tr><tr><td>Cutaneous irAES resolution (%)</td><td></td><td></td><td></td><td></td><td>0.288</td><td></td><td></td><td></td><td></td><td>0.682</td></tr><tr><td>Improvement</td><td>4 (36.4)</td><td>11 (55.0)</td><td>16 (72.7)</td><td>14 (56.00)</td><td></td><td>5 (45.5)</td><td>10 (52.6)</td><td>16 (69.6)</td><td>12 (54.5)</td><td></td></tr><tr><td>Progression</td><td>0 (0.0)</td><td>1 (5.0)</td><td>2 (9.1)</td><td>1 (4.0)</td><td></td><td>0 (0.0)</td><td>1 (5.3)</td><td>1 (4.3)</td><td>2 (9.1)</td><td></td></tr><tr><td>Resolved</td><td>7 (63.6)</td><td>8 (40.0)</td><td>4 (18.2)</td><td>11 (40.0)</td><td></td><td>6 (54.5)</td><td>8 (42.1)</td><td>6 (26.1)</td><td>8 (36.4)</td><td></td></tr><tr><td>Grades of event</td><td></td><td></td><td></td><td></td><td>0.100</td><td></td><td></td><td></td><td></td><td>0.065</td></tr><tr><td>Grade I</td><td>3 (21.4)</td><td>15 (60.0)</td><td>20 (51.3)</td><td>18 (50.0)</td><td></td><td>4 (25.0)</td><td>13 (54.2)</td><td>20 (57.1)</td><td>18 (52.9)</td><td></td></tr><tr><td>Grade II</td><td>5 (35.7)</td><td>6 (24.0)</td><td>14 (35.9)</td><td>14 (38.9)</td><td></td><td>5 (31.2)</td><td>7 (29.2)</td><td>11 (31.4)</td><td>13 (38.2)</td><td></td></tr><tr><td>Grade III or IV</td><td>6 (42.9)</td><td>4 (16.0)</td><td>5 (12.8)</td><td>4 (11.1)</td><td></td><td>7 (43.8)</td><td>4 (16.7)</td><td>4 (11.4)</td><td>3 (8.8)</td><td></td></tr><tr><td>Action taken on IT after cutaneous irAES (%)</td><td></td><td></td><td></td><td></td><td>0.651</td><td></td><td></td><td></td><td></td><td>0.107</td></tr><tr><td>Continuation</td><td>9 (90.0)</td><td>20 (87.0)</td><td>32 (86.5)</td><td>29 (87.9)</td><td></td><td>10 (83.3)</td><td>19 (86.4)</td><td>31 (91.2)</td><td>25 (83.3)</td><td></td></tr><tr><td>Discontinuation</td><td>1 (10.0)</td><td>2 (8.7)</td><td>2 (5.4)</td><td>3 (9.1)</td><td></td><td>2 (16.7)</td><td>3 (13.6)</td><td>1 (2.9)</td><td>2 (6.7)</td><td></td></tr><tr><td>Interruption</td><td>0 (0.0)</td><td>1 (4.3)</td><td>3 (8.1)</td><td>1 (3.0)</td><td></td><td>0 (0.0)</td><td>0 (0.0)</td><td>2 (5.9)</td><td>3 (10.0)</td><td></td></tr></tbody></table>
<table><caption>TABLE 3 Association between tumour grades and type of cutaneous event, and follow-up, bivariate, with CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.</caption><thead><tr><th></th><th>Grade I<br>n=59</th><th>Grade II<br>n=41</th><th>Grade III+IV<br>n=20</th><th>p</th></tr></thead><tbody><tr><td>Sex = Male (%)</td><td>46 (78.0)</td><td>27 (65.9)</td><td>15 (75.0)</td><td>0.397</td></tr><tr><td>Event (%)</td><td></td><td></td><td></td><td><strong>0.006</strong></td></tr><tr><td>Inflammatory benign dermatosis</td><td>28 (47.5)</td><td>26 (63.4)</td><td>9 (45.0)</td><td></td></tr><tr><td>Bullous diseases</td><td>1 (1.7)</td><td>5 (12.2)</td><td>4 (20.0)</td><td></td></tr><tr><td>Pigmentary diseases</td><td>18 (30.5)</td><td>4 (9.8)</td><td>1 (5.0)</td><td></td></tr><tr><td>Drug-related maculopapular rashes</td><td>12 (20.3)</td><td>6 (14.6)</td><td>6 (30.0)</td><td></td></tr><tr><td>Treatment of cutaneous IrAES (%)</td><td>34 (57.6)</td><td>32 (78.0)</td><td>18 (90.0)</td><td><strong>0.009</strong></td></tr><tr><td>Cutaneous irAES resolution (%)</td><td></td><td></td><td></td><td>0.103</td></tr><tr><td>Improvement</td><td>16 (50.0)</td><td>21 (70.0)</td><td>8 (47.1)</td><td></td></tr><tr><td>Progression</td><td>0 (0.0)</td><td>2 (6.7)</td><td>2 (11.8)</td><td></td></tr><tr><td>Resolved</td><td>16 (50.0)</td><td>7 (23.3)</td><td>7 (41.2)</td><td></td></tr><tr><td>Action taken on IT after cutaneous irAES (%)</td><td></td><td></td><td></td><td><strong>&lt;0.001</strong></td></tr><tr><td>Continuation</td><td>54 (94.7)</td><td>31 (91.2)</td><td>10 (58.8)</td><td></td></tr><tr><td>Discontinuation</td><td>2 (3.5)</td><td>2 (5.9)</td><td>4 (23.5)</td><td></td></tr><tr><td>Interruption</td><td>1 (1.8)</td><td>1 (2.9)</td><td>3 (17.6)</td><td></td></tr><tr><td>Response at 3M (%)</td><td></td><td></td><td></td><td>0.100</td></tr><tr><td>CR</td><td>3 (5.4)</td><td>5 (12.8)</td><td>6 (31.6)</td><td></td></tr><tr><td>PD</td><td>15 (26.8)</td><td>6 (15.4)</td><td>4 (21.1)</td><td></td></tr><tr><td>PR</td><td>20 (35.7)</td><td>14 (35.9)</td><td>5 (26.3)</td><td></td></tr><tr><td>SD</td><td>18 (32.2)</td><td>14 (35.9)</td><td>4 (21.1)</td><td></td></tr><tr><td>Response at 6M (%)</td><td></td><td></td><td></td><td>0.065</td></tr><tr><td>CR</td><td>4 (7.3)</td><td>5 (13.9)</td><td>7 (38.9)</td><td></td></tr><tr><td>PD</td><td>13 (23.6)</td><td>7 (19.4)</td><td>4 (22.2)</td><td></td></tr><tr><td>PR</td><td>20 (36.4)</td><td>11 (30.6)</td><td>4 (22.2)</td><td></td></tr><tr><td>SD</td><td>18 (32.7)</td><td>13 (36.1)</td><td>3 (16.7)</td><td></td></tr></tbody></table>

Bold values are significant when *p* < 0.05.

associated with better response of the tumour to ICI therapy. Vitiligo induced by ICI is a favourable prognostic factor in patients with melanoma.²⁵ This may be as a result of melanocyte destruction by autoreactive CD8⁺ T cells. Vitiligo is due to T cells infiltration, also involved in microenvironment of tumour, and explaining a better response to immunotherapy.²⁵ More broadly, it has been reported that any cutaneous irAE are significantly associated with a better overall survival,¹⁹ and we may assume, associated with enhanced response to immunotherapy.

Severe late-onset irAE have been described with a median onset time of 128 days for all organ-grade III–IV irAEs.²⁶ In our study, we report a median onset time of 208 days for all-grades cutaneous irAEs suggesting that appearance of cutaneous irAE could be delayed. Gault et al.¹³ reported a delay of appearance of 10 months for eczematous reactions and 50 days for psoriasis. It seems to be consistent with our study since we reported respectively 46.6% and 34.9% of inflammatory diseases which occur early (i.e. within the first 3 months of treatment) or medium-onset (i.e. after 3 months

and before 1 year). However, as we pooled all inflammatory cutaneous irAEs, we did not distinguish delay of appearance psoriasis from other inflammatory dermatosis.

We found that nearly 21% of cutaneous irAE were late-onset events appearing more than a year after immunotherapy initiation. Such late-onset irAEs may be difficult to formally impute as resulting from ICI, and are difficult to distinguish from coincidental dermatological disease.¹³ Drug-related rashes (20%) and bullous conditions (8.3%) are more likely to be life-threatening adverse effects and could appear more than 1 year after treatment initiation in patients with a long treatment duration.

It highlights the value of long-term dermatological follow-up after immunotherapy. Because the longer immunotherapy is administered, the higher the risk of a drug associated rash, the potential late-onset grade III–IV cutaneous irAEs encourages discontinuation of immunotherapy when oncological conditions permit.²⁶ It should be noted that discontinuation of immunotherapy must always be weighed against the risk of melanoma, since
<table><caption>TABLE 4 Description of treatment used to recover cutaneous irAEs regarding the type of cutaneous event.</caption><thead><tr><th></th><th>Inflammatory benign dermatosis</th><th>Bullous diseases</th><th>Pigmentary diseases</th><th>Drug-related maculopapular rashes</th></tr></thead><tbody><tr><td>No Treatment of cutaneous irAES received</td><td>11</td><td>0</td><td>20</td><td>5</td></tr><tr><td>Treatment of cutaneous irAES received</td><td>53</td><td>10</td><td>2</td><td>19</td></tr><tr><td>Topic steroids or TS + emollients</td><td>27 (8 bethametasone; 7 NS; 4 mometasone; 2 MPA; 2 clobetasol; 1 triamcinolone; 1 diflucortolone + emollient; 1 clobetasone + emollient)</td><td>2 (2 clobetasol)</td><td>0</td><td>7 (3 bethametasone; 2 NS; 1 diflucortolone; 1 mometasone)</td></tr><tr><td>Antihistamine</td><td>4 (1 chloropyramine; 1 desloratadine; 1 cetirizine; 1 desloratadine + hydroxyzine)</td><td>0</td><td>0</td><td>5 (2 desloratadine; 1 cetirizine; 1 chloropyramine; 1 cetirizine + desloratadine)</td></tr><tr><td>Topic steroids + antihistamine</td><td>4 (2 bethametasone + cetirizine; 1 clobetasol + chlorphenine + emollient; 1 TS NS + desloratadine + hydroxyzine)</td><td>0</td><td>1 (1 mometasone + cetirizine)</td><td>3 (2 bethametasone + desloratadine; 1 diflucortolone + desloratadine)</td></tr><tr><td>Antibiotics</td><td>2 (1 lymecycline + prednisone; 1 lymecycline + benzoyl peroxide)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Steroids</td><td>7 (2 methylprednisolone + bethametasone; 2 prednisolone + cetirizine + fexofenadine + hydroxyzine + clobetasol; 1 prednisolone + mometasone; 1 prednisolone; 1 prednisone)</td><td>5 (2 methylprednisolone; 1 prednisolone; 1 methylprednisolone + prednisolone + hydrocortisone; 1 prednisone + TS NS)</td><td>0</td><td>1 (1 methylprednisolone + clobetasol + prednisolone)</td></tr><tr><td>Immunosuppressive treatment</td><td>0</td><td>3 (1 rituximab + methylprednisolone; 1 methotrexate + prednisolone + doxycycline; 1 methotrexate + salazopryn + UVB therapy)</td><td>1 (1 tacrolimus)</td><td>1 (1 tacrolimus + prednisolone + bilastine)</td></tr><tr><td>Vitamin D + topic</td><td>3 (2 enstilar+emollient; 1 calcipotriol + bethametasone)</td><td>1 (1 Dovobet + emollient)</td><td>0</td><td>0</td></tr><tr><td>Retinoids</td><td>3 (1 acitretin + mometasone; 1 acitretin + daivobet; 1 keracutan + UVA therapy)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Other systemic treatment</td><td>1 (1 apremilast)</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Emollient</td><td>1</td><td>0</td><td>0</td><td>2</td></tr></tbody></table>

Note: Diprosone as betamethasone; Elocom as mometasone; Advantan as Methylprednisolone aceponate (MPA); Dermoval and Clarelux as Clobetasol; Nerisone as Diflucortolone; trimovate as clobetasone; Aerius as desloratadine; Atarax as hydroxyzine; eumovate and dermovate as clobetasol; Tetraalysal as lymecycline; cortacyl as prednisone; Eclaran as benzoyl peroxide.

Abbreviations: NS, non-stipulated; TS, Topic steroids.
<table><caption>TABLE 5 Association of delay of appearance of cutaneous irAEs with tumoral response, with CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.</caption><thead><tr><th rowspan="2"></th><th colspan="2">Early-onset event</th><th colspan="2">Medium-onset event</th><th colspan="2">Late-onset event</th><th rowspan="2">p</th></tr><tr><th>At 3 M n (%)</th><th>At 6 M n (%)</th><th>At 3 M n (%)</th><th>At 6 M n (%)</th><th>At 3 M n (%)</th><th>At 6 M n (%)</th></tr></thead><tbody><tr><td>CR</td><td>5 (11.4)</td><td>5 (11.6)</td><td>8 (16.7)</td><td>9 (19.6)</td><td>1 (4.5)</td><td>2 (10.0)</td><td>0.522</td></tr><tr><td>PD</td><td>12 (27.3)</td><td>12 (27.9)</td><td>10 (20.8)</td><td>10 (21.7)</td><td>3 (13.6)</td><td>2 (10.0)</td><td>at 3 M</td></tr><tr><td>PR</td><td>16 (36.4)</td><td>14 (32.6)</td><td>15 (31.3)</td><td>14 (30.4)</td><td>8 (36.4)</td><td>7 (35.0)</td><td>0.5658</td></tr><tr><td>SD</td><td>11 (25.0)</td><td>12 (27.9)</td><td>15 (31.3)</td><td>13 (28.3)</td><td>10 (45.5)</td><td>9 (45.0)</td><td>at 6 M</td></tr></tbody></table>

<table><caption>TABLE 6 Association of delay of appearance of cutaneous irAEs with type of cutaneous irAEs.</caption><thead><tr><th></th><th>Early-onset event n (%)</th><th>Medium-onset event n (%)</th><th>Late-onset event n (%)</th><th>p</th></tr></thead><tbody><tr><td>Inflammatory benign dermatosis (n = 62)</td><td>29 (65.9)</td><td>22 (43.1)</td><td>12 (48.0)</td><td>0.12</td></tr><tr><td>Bullous diseases (n = 7)</td><td>2 (4.55)</td><td>6 (11.8)</td><td>2 (8.0)</td><td></td></tr><tr><td>Pigmentary diseases (n = 23)</td><td>3 (6.82)</td><td>13 (25.9)</td><td>7 (28.0)</td><td></td></tr><tr><td>Drug-related maculopapular rashes (n = 19)</td><td>10 (22.7)</td><td>10 (19.6)</td><td>4 (16.0)</td><td></td></tr></tbody></table>

Bold values are significant when *p* < 0.05.

the risk of grade III-IV cutaneous toxicity is more often smaller than risk of death of stage III-IV melanoma. It suggests increased monitoring even after immunotherapy is discontinued.

## CONCLUSIONS

In conclusion, our European multi-centre prospective cohort of patients with melanoma has characterized the clinical spectrum of cutaneous irAEs, their timing and severity and their relationship with tumour response. We show that grade I-II cutaneous IrAE are easily managed allowing ongoing anti-cancer treatment and avoid potential progression to grade III-IV irAE that may lead to treatment discontinuation.

We reported late-onset events which means cutaneous side effects may appear a long time after the immunotherapy has been stopped or a long time after its initiation. When the cutaneous irAEs occurs at a later stage than the discontinuation of the immunotherapy, it is not easy to distinguish between a cutaneous side effect and a dermatosis with another aetiology.

This pleads for a reinforced dermatological follow-up, either by an oncodermatologist, or via a care pathway where the oncologist is linked with a dermatologist. These findings highlight the importance of specialist oncodermatological involvement in management of patients with melanoma receiving immunotherapy.

## ACKNOWLEDGEMENTS

To the EADO task force, and the melskintox network and all dermatologists all around Europe involved in Melskintox.

## FUNDING INFORMATION

No financial support.

## CONFLICT OF INTEREST STATEMENT

The authors have no conflicts of interest to declare.

## DATA AVAILABILITY STATEMENT

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request or from the Melskintox data scientist in charge: julie.cassecuel@chu-nantes.fr.

## ETHICAL STATEMENT

The study complies with the ethical standards resulting from the Declaration of Helsinki. An information sheet was given to each patient to collect their non-opposition to the study, and none of them was opposed to it. The patients in this manuscript have given written informed consent to the publication of their case details.

## ORCID

J.-M. L'Orphelin https://orcid.org/0000-0002-5680-7888

M. H. Junejo https://orcid.org/0000-0003-2458-9991

Z. Appalla https://orcid.org/0000-0002-9255-8196

G. Pellacani https://orcid.org/0000-0002-7222-2951

C. Garbe https://orcid.org/0000-0001-8530-780X

J. M. Ressler https://orcid.org/0000-0001-8602-0878

K. Peris https://orcid.org/0000-0003-1957-6600

B. Dreno https://orcid.org/0000-0001-5574-5825

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20. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-26.

21. Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book. 2015;76-83.

22. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J Clin Oncol off J Am Soc Clin Oncol. 2015;33(18):2092-9.

23. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer Oxf Engl 1990. 2016;60:190-209.

24. Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PloS One. 2013;8(1):e53745.

25. Fukuda K. Networks of CD8+ T cell response activation in melanoma and vitiligo. Front Immunol. 2022;13:866703.

26. L'Orphelin JM, Varey E, Khammari A, Dreno B, Dompmartin A. Severe late-onset grade III-IV adverse events under immunotherapy: a retrospective study of 79 cases. Cancer. 2021;13(19):4928.

**How to cite this article:** L'Orphelin J-M, Cassecuel J, Kandolf L, Harwood CA, Tookey P, Junejo MH, et al. And European Association of Dermato-Oncology. Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients—The European MelSkinTox study. J Eur Acad Dermatol Venereol. 2023;00:1-16. https://doi.org/10.1111/jdv.19112
# APPENDIX 1

## Templates of formula

### MEL SKINTOX: Cutaneous rash induced by check point inhibitors
INCLUDING GRADE I-II-III-IV

#### Initial report

Date ___/___/___

Center No. ___

Patient code number ___

Year of birth: ___

Sex ___ M

___ F

<table><thead><tr><th rowspan="2">Previous anti cancer<br>treatment<br>(name of the drug)</th><th rowspan="2">Treatment<br>start date</th><th rowspan="2">Treatment<br>dose</th><th rowspan="2">Treatment<br>schedule<br>dose</th><th rowspan="2">Treatment<br>end date</th><th colspan="2">Cutaneous or<br>other AE related<br>to treatment</th><th colspan="5">If YES CTCAE grade *</th></tr><tr><th>Yes</th><th>No</th><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th></tr></thead><tbody><tr><td></td><td></td><td></td><td></td><td></td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr></tbody></table>

<figure><img src="image_7.png" /></figure>

<table><thead><tr><th rowspan="2">Current anti cancer<br>treatment<br>(name of the drug)</th><th rowspan="2">Treatment<br>start date</th><th rowspan="2">Treatment<br>dose</th><th rowspan="2">Treatment<br>schedule<br>dose</th><th rowspan="2">Treatment<br>end date</th><th colspan="2">AE other than<br>skin related to<br>treatment</th><th colspan="5">If YES CTCAE grade *</th></tr><tr><th>Yes</th><th>No</th><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th></tr></thead><tbody><tr><td></td><td></td><td></td><td></td><td></td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr></tbody></table>

*AE should be classified according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0 or new VS when published)

<figure><img src="image_8.png" /></figure>

### 1. Does the patient have a medical history of:

* Autoimmune disease ☐ NO ☐ YES ☐ Unknown if yes, what type? ___

* EBV infection ☐ NO ☐ YES ☐ Unknown

* HIV infection ☐ NO ☐ YES ☐ Unknown

* HSV6 infection ☐ NO ☐ YES ☐ Unknown

* Previous skin disease (except melanoma) ☐ NO ☐ YES ☐ Unknown if yes, what type? ___

### Skin AE:

2. Date of onset: ___/___/___

CTCAE grade 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐

VERSION 4 10/MAY/2017
### 3. Aspect of cutaneous lesions related to drug eruption (please tick one or more box) with grading of cutaneous lesions according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0 or new V 5.0 when published)

<table><thead><tr><th rowspan="2"></th><th rowspan="2">NO</th><th rowspan="2">YES</th><th colspan="5">If YES CTCAE grade</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th></tr></thead><tbody><tr><td>Aspect of Steven-Johnson-Lyell</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Aspect of Sweet's syndrome</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Aspect of DRESS syndrome</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Aspect of erythema multiforme</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Vasculitis-like</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Bullous disease</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Lichenoid eruption</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Acneiform rash</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Urticarial eruption</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Psoriasis-like rash</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Erythema nodosum-like eruption</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Vitiligo</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Morbilliform rash</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><td>Other: Please provide a detailed dermatological description of the skin manifestation if you would like to point out any other specific aspect/sign/symptom:</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr></tbody></table>

4. Location: ☐ head/neck

☐ anterior trunk

☐ posterior trunk

☐ upper extremities

☐ lower extremities

5. Surface involved

☐ covering <10% BSA

☐ covering 10 - 30% BSA

☐ covering >30% BSA

6. Involvement of palms ☐ NO ☐ YES CTCAE grade 1☐ 2☐ 3☐ 4☐ 5☐
Soles ☐ NO ☐ YES CTCAE grade 1☐ 2☐ 3☐ 4☐ 5☐

7. Nail involvement: ☐ NO ☐ YES CTCAE grade 1☐ 2☐ 3☐ 4☐ 5☐

If yes, please provide a description of the nail abnormalities:

8. Hair involvement

Alopecia ☐ NO ☐ YES CTCAE grade 1☐ 2☐ 3☐ 4☐ 5☐

Modification of the structure or color of hair ☐ NO ☐ YES CTCAE grade 1☐ 2☐ 3☐ 4☐ 5☐

VERSION 4 10/MAY/2017
9. Mucosal involvement ☐ NO ☐ YES

<table><thead><tr><th rowspan="2"></th><th rowspan="2">NO</th><th rowspan="2">YES</th><th colspan="5">If YES CTCAE grade</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th></tr></thead><tbody><tr><th>Eye</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Mouth</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Genitalia</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Nose</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr></tbody></table>

10. Pruritus ☐ NO ☐ YES If yes: ☐ mild ☐ moderate ☐ severe
CTCAE grade 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐

11. Burning ☐ NO ☐ YES If yes: ☐ mild ☐ moderate ☐ severe
CTCAE grade 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐

12. Scaling/dryness ☐ NO ☐ YES If yes: ☐ mild ☐ moderate ☐ severe
CTCAE grade 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐

13. Photosensitivity ☐ NO ☐ YES If yes: ☐ mild ☐ moderate ☐ severe
CTCAE grade 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐

-- Location on sun-exposed areas (e.g. face, back of the hands):

-- Extension to sun protected area ☐ NO ☐ YES

Note: 
14. Photographic documentation ☐ NO ☐ YES if yes, specify the date: 
15. Associated Systemic symptoms

<table><thead><tr><th rowspan="2"></th><th rowspan="2">NO</th><th rowspan="2">YES</th><th colspan="5">If YES CTCAE grade</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th></tr></thead><tbody><tr><th>Fever</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Arthralgia</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Nausea</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Diarrhea</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Headache</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Others: please specify</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr></tbody></table>

16. Associated biological abnormalities

<table><thead><tr><th rowspan="2"></th><th rowspan="2">NO</th><th rowspan="2">YES</th><th colspan="5">If YES CTCAE grade</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>5</th></tr></thead><tbody><tr><th>Renal failure</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Elevation in aminotransferase</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Hyper eosinophilia</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Lymphopenia</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Thrombopenia</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr><tr><th>Others: please specify</th><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td><td>☐</td></tr></tbody></table>
MELSKINTOX: Cutaneous rash induced by check point inhibitors
INCLUDING GRADE I-II-III-IV
Follow-up at 3 months

Date ___/___/___

Center No.

Patient code number

Year of birth:

Sex ☐ M

☐ F

Cutaneous adverse event

Resolved?

☐ NO

☐ YES

If yes, date ___/___/___

With ☐

Without ☐ sequelae

If no, precise current grade ___

Impact on melanoma treatment:

Continuation

☐ NO

☐ YES

Discontinuation

☐ NO

☐ YES

Reduction

☐ NO

☐ YES

Interruption

☐ NO

☐ YES

Resumption after discontinuation

☐ NO

☐ YES

Is the patient still treated with immunotherapy

☐ NO

☐ YES

Is the patient still alive

☐ NO

☐ YES

Did the patient have any other cutaneous toxicity?

☐ NO

☐ YES

If yes, what type? ___

Please email the document to Nantes onco-dermatology department to julie.cassecuel@chu-nantes.fr

In case of medical discussion, you can send an email to ibtissam.moustaghfir@chu-nantes.fr

Brief follow-up forms will be sent at 6 and 12 months
# MELSKINTOX: Cutaneous rash induced by check point inhibitors
## INCLUDING GRADE I-II-III-IV
### Follow-up at 6 months

Date ___/___/___

Center No. ____________

Patient code number ____________

Year of birth: ___/___/___

Sex ☐ M

☐ F

Is the patient still treated with immunotherapy ____________

☐ NO

☐ YES

Is the patient still alive ____________

☐ NO

☐ YES

Did the patient have any other cutaneous toxicity? ____________

☐ NO

☐ YES

If yes, what type? ____________

Please email the document to Nantes onco-dermatology department to julie.cassecuel@chu-nantes.fr

In case of medical discussion, you can send an email to ibtissam.moustaghfir@chu-nantes.fr

Brief follow-up forms will be sent at 12 months

# MELSKINTOX: Cutaneous rash induced by check point inhibitors
## INCLUDING GRADE I-II-III-IV
### Follow-up at 12 months

Date ___/___/___

Center No. ____________

Patient code number ____________

Year of birth: ___/___/___

Sex ☐ M

☐ F

Is the patient still treated with immunotherapy ____________

☐ NO

☐ YES

Is the patient still alive ____________

☐ NO

☐ YES

Did the patient have any other cutaneous toxicity? ____________

☐ NO

☐ YES

If yes, what type? ____________

Please email the document to Nantes onco-dermatology department to julie.cassecuel@chu-nantes.fr

In case of medical discussion, you can send an email to lucie.peuvrel@chu-nantes.fr