10.5826/dpc.1303a127
Introduction: Cutaneous immune-related adverse-events (cIRAEs), commonly seen in cancer patients receiving immune checkpoint inhibitors (ICI) are reported to be associated with better patient survival; however, they have seldom been studied in Indian population. Recent reports suggest racial differences in IRAEs and also in survival outcomes.
Objective: To study the various cIRAEs in Indian patients on ICI therapy and to analyze the association between cIRAEs and patient survival outcomes.
Methods: We conducted a retrospective cohort study of 86 cancer patients receiving immunotherapies in a tertiary care hospital in India and studied incidence, nature and grades of cutaneous immune-related adverse events and the association of cIRAEs with the patient survival outcomes.
Results: Eighty-six patients were included, of whom 16 patients (18.6%) developed cIRAEs, with pruritus (12.8%) and maculopapular eruption (8.1%) being the most common. Kaplan–Meier plot with log-rank test showed that patients developing any type of cIRAE had longer progression-free survival than those without (p=0.023) and a better objective-response-rate (50% vs 18.5%, p=0.008).
Conclusion: Most common cIRAEs in our study were pruritus and maculopapular rash. The incidence of cIRAEs was lower in our Indian cohort compared to that reported in Caucasian cohorts. Development of cutaneous immune-related adverse event in cancer patients on ICI was associated with a longer progression-free-survival and a better objective-response-rate. Thus, cIRAEs may serve as a surrogate marker for better patient outcomes.
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Wesley Jose
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Characterization and Prognostic Significance of Cutaneous Immune-Related Adverse Events in Indian Patients on Immune Checkpoint Inhibitor Therapy
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Original Article
2023-07-31
2022-09-08
2023-07-31
2023-08-24
e2023127
Dermatol Pract Concept
Introduction: Cutaneous immune-related adverse-events (cIRAEs), commonly seen in cancer patients receiving immune checkpoint inhibitors (ICI) are reported to be associated with better patient survival; however, they have seldom been studied in Indian population. Recent reports suggest racial differences in IRAEs and also in survival outcomes.
Objective: To study the various cIRAEs in Indian patients on ICI therapy and to analyze the association between cIRAEs and patient survival outcomes.
Methods: We conducted a retrospective cohort study of 86 cancer patients receiving immunotherapies in a tertiary care hospital in India and studied incidence, nature and grades of cutaneous immune-related adverse events and the association of cIRAEs with the patient survival outcomes.
Results: Eighty-six patients were included, of whom 16 patients (18.6%) developed cIRAEs, with pruritus (12.8%) and maculopapular eruption (8.1%) being the most common. Kaplan–Meier plot with log-rank test showed that patients developing any type of cIRAE had longer progression-free survival than those without (p=0.023) and a better objective-response-rate (50% vs 18.5%, p=0.008).
Conclusion: Most common cIRAEs in our study were pruritus and maculopapular rash. The incidence of cIRAEs was lower in our Indian cohort compared to that reported in Caucasian cohorts. Development of cutaneous immune-related adverse event in cancer patients on ICI was associated with a longer progression-free-survival and a better objective-response-rate. Thus, cIRAEs may serve as a surrogate marker for better patient outcomes.
Wesley Jose
2023/07/31
10.5826/dpc.1303a127
e2023127
Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences, Kochi, India
2160-9381
reactions
en
e2023127
Gault A, Anderson AE, Plummer R, et al. Cutaneous immune-related adverse events in patients with melanoma treated with checkpoint inhibitors. Br J Dermatol. 2021;185(2):263–271. DOI:10.1111/bjd.19750. PMID: 33393076.
Characterization and Prognostic Significance of Cutaneous Immune-Related Adverse Events in Indian Patients on Immune Checkpoint Inhibitor Therapy
https://dpcj.org/index.php/dpc/article/download/2824/2207
        Characterization and Prognostic Significance
       of Cutaneous Immune-Related Adverse Events
          in Indian Patients on Immune Checkpoint
                      Inhibitor Therapy
            Prasanna Duraisamy1, Vinitha Varghese Panicker1, Wesley Mannirathil Jose2


1 Department of Dermatology, Amrita Institute of Medical Sciences, Kochi, India
2 Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences, Kochi, India



Key words: immune checkpoint inhibitors, cutaneous immune related adverse events, reactions, immunotherapy
Citation: Duraisamy P, Panicker VV, Jose WM. Characterization and prognostic significance of cutaneous immune related adverse events
in Indian patients on immune checkpoint inhibitor therapy. Dermatol Pract Concept. 2023;13(3):e2023127. DOI: https://doi.org/10.5826/
dpc.1303a127
Accepted: December 15, 2022; Published: July 2023
Copyright: ©2023 Duraisamy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Vinitha V Panicker, Department of Dermatology, Amrita Institute of Medical Sciences, Ponnekara, Kochi.
Tel: 0484-2858590, 9847179964 Email: varghesevinitha@yahoo.com, vinithavpanicker@aims.amrita.edu




  ABSTRACT             Introduction: Cutaneous immune-related adverse-events (cIRAEs), commonly seen in cancer patients
                       receiving immune checkpoint inhibitors (ICI) are reported to be associated with better patient survival;
                       however, they have seldom been studied in Indian population. Recent reports suggest racial differences
                       in IRAEs and also in survival outcomes.
                       Objectives: To study the various cIRAEs in Indian patients on ICI therapy and to analyze the associ-
                       ation between cIRAEs and patient survival outcomes.
                       Methods: We conducted a retrospective cohort study of 86 cancer patients receiving immuno-
                       therapies in a tertiary care hospital in India and studied incidence, nature and grades of cutaneous
                       immune-related adverse events and the association of cIRAEs with the patient survival outcomes.
                       Results: Eighty-six patients were included, of whom 16 patients (18.6%) developed cIRAEs, with pru-
                       ritus (12.8%) and maculopapular eruption (8.1%) being the most common. Kaplan–Meier plot with
                       log-rank test showed that patients developing any type of cIRAE had longer progression-free survival
                       than those without (P = 0.023) and a better objective-response-rate (50% versus 18.5%, P = 0.008).




Original Article | Dermatol Pract Concept. 2023;13(3):e2023127                                                                      1
                      Conclusions: Most common cIRAEs in our study were pruritus and maculopapular rash. The inci-
                      dence of cIRAEs was lower in our Indian cohort compared to that reported in Caucasian cohorts.
                      Development of cutaneous immune-related adverse event in cancer patients on ICI was associated
                      with a longer progression-free-survival and a better objective-response-rate. Thus, cIRAEs may serve
                      as a surrogate marker for better patient outcomes.




Introduction                                                       Methods
Immune checkpoint inhibitors (ICI) are a class of immuno-          This was a single-institution retrospective study of patients
therapeutic agents which act upon the immune check points          receiving ICIs (nivolumab, pembrolizumab, atezolizumab
- programmed cell death 1 (PD-1), programmed cell death            and ipilimumab) from January 2017 to September 2021. The
ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4              study was approved by the hospital institution review board.
(CTLA-4), that regulate T-cell activity [1]. Under normal cir-     Medical records of all patients with cancers treated with at
cumstances, immune check points protect the host cells from        least one dose of PD-1 antibodies (nivolumab or pembroli-
immune response. However, these pathways are also utilized         zumab), PD-L1 antibodies (atezolizumab) or CTLA-4 an-
by cancers to escape the host immunity and their inhibition        tibodies (ipilimumab) during the study period were drawn
results in enhancement of immune response and prevents             from the hospital medical records database and analyzed.
tumor escape causing tumor destruction. This enhanced im-          Information regarding patient demographics and character-
mune response is non-specific and can have collateral effects      istics, nature of the malignancies, ICI used, total duration
on the normal cells leading to a new spectrum of adverse           of treatment, any adverse events during ICI therapy, grade
events called immune-related adverse events (IRAEs). IRAEs         of the adverse events, time till progression, time till death
can potentially involve any system and in severe cases can lead    were retrieved from medical records. Treatments given for
to treatment discontinuation or even death. Cutaneous IRAEs        cutaneous adverse events and their outcomes were recorded.
(cIRAEs) are one of the most common IRAEs and can have             Wherever possible, telephonic follow-up was performed to
myriad presentations [2]. Since both tumor regression and          complete missing records. Responses were assessed clinically
IRAEs are a result of enhanced immune response, the pres-          and radiologically and classified according to standard tu-
ence of IRAEs may correlate with greater antitumor response        mor response evaluation criteria - the Response Evaluation
and studies have shown that IRAEs, particularly cIRAEs may         Criteria in Solid Tumors (RECIST) version 1.1 and Positron
be associated with better patient survival outcomes [3–6].         Emission Tomography Response Evaluation Criteria in Solid
However, much of the available literature on immune check-         Tumors (PERCIST) version 1.0. Adverse events during immu-
point inhibitors and their IRAEs is based on trials and data       notherapy were documented and graded using the Common
from Western countries and there is an inadequate representa-      Terminology Criteria for Adverse Events (CTCAE) v 5.0. In
tion of other populations particularly the Indian population.      the patients with cIRAEs, response of cIRAEs to their respec-
Reports suggest that immune checkpoint inhibitors can vari-        tive dermatological treatment was graded as no improve-
ation in activity and toxicity spectrum among various ethnic-      ment, partial improvement (an improvement by one CTCAE
ities such as lower incidence of IRAEs and poorer survival         grade) or significant improvement (an improvement by two
outcomes in Hispanics compared to Caucasian populations            or more CTCAE grades or improvement to grade 0). Data
[7–10]. Thus, there is a need for further data on the use of ICI   censoring was done in October 2021. Overall-response-rates
and various IRAEs in under-represented population groups.          (ORR), overall survival (OS) and progression-free-survival
    In our study, we aim to study the real-world incidence         (PFS) were calculated and compared between patients hav-
and manifestations of cIRAEs seen in Indian patients on im-        ing cutaneous adverse events and those not having cutaneous
mune checkpoint inhibitor therapy and investigate the rela-        adverse events.
tionship between cIRAEs and patient survival.                         Tumor response was graded as complete response (CR),
                                                                   partial response (PR), progressive disease (PD) and stable

Objectives                                                         disease (SD) based on standard tumor response evaluation
                                                                   criteria – RECIST and PERCIST. Overall response rate
To study the various cIRAEs in Indian patients on ICI ther-        (ORR) was defined as the proportion of patients who have a
apy and to analyze the association between cIRAEs and pa-          partial or complete response to therapy, excluding stable dis-
tient survival outcomes.                                           ease. Progression free survival (PFS) was defined as the time



2                                                                      Original Article | Dermatol Pract Concept. 2023;13(3):e2023127
elapsed since treatment initiation until disease progression         and endocrinological adverse events (15.1%) were the most
or death from any cause, whichever comes first. Progression          common IRAEs noted. Median time of onset of IRAEs of
was defined as clinical worsening of the disease or radio-           any type was two months. The various IRAEs are repre-
logical progression as per RECIST v 1.1 / PERCIST v 1.0 or           sented in Table 2.
death due to any cause. Overall survival (OS) is defined as                  Twenty-four cIRAEs of any grade occurred in 16 pa-
the time as the time elapsed since treatment initiation until        tients (18.6%) - pruritus in 11 patients (12.8%, 4 with
death from any cause. Patients were censored at the date of          isolated pruritus and 7 with pruritis in addition to other
last follow-up if still alive at the time of the analysis.
    Statistical analysis was performed using IBM SPSS ver-
sion 20.0 software (SPSS Inc, Chicago, USA). Categorical                              Table 1. Patient Characteristics.
variables were expressed using frequency and percentage.                       Clinical Characteristics               N (%)
Continuous variables are expressed as mean ± SD or the me-               Median age at ICI initiation            60.5 (IQR:48-71)
dian and interquartile range [IQR]. Chi-square test with con-            Gender (male)                             64 (74.4%)
tinuity correction was used to test the statistical significance         Cancers
of differences in overall response rate between patients with
                                                                         Lung cancer                               26 (30.2%)
and without adverse events. To compute the survival prob-
                                                                         Hepatocellular carcinoma                  12 (13.9%)
ability and the survival comparison between patients with
                                                                         Renal cell carcinoma                      10 (11.6%)
and without adverse events, Kaplan–Meier analysis with log-
                                                                         Oropharyngeal SCC                         10 (11.6%)
rank test was used. Multivariable analysis of both PFS and
                                                                         Melanoma                                   8 (9.3%)
OS was performed with Cox proportional hazard regression
models. A p value of <0.05 was considered to be statistically            Hodgkin lymphoma                           7 (8.1%)

significant.                                                             Endometrial cancer                         3 (3.5%)
                                                                         Urothelial carcinoma                       2 (2.3%)
                                                                         Esophageal adenocarcinoma                  2 (2.3%)
Results                                                                           a
                                                                         Others                                     6 (7.2%)
A total of 86 patients (M:F 64:22) of median age 60.5 years              ICI
(IQR:18 –83) were included. This was an umbrella study                   Nivolumab                                 51 (59.3%)
comprising of multiple malignancies, with lung cancer being              Pembrolizumab                             29 (33.7%)
the most common malignancy (26 patients, 30.2%). Other                   Atezolizumab                               5 (5.8%)
common malignancies included hepatocellular carcinoma                    Combination (Nivolumab +                   1 (1.2%)
(12 patients, 13.9%), renal cell carcinoma (10 patients,                 Ipilimumab)
11.6%) and oropharyngeal squamous cell carcinoma (10 pa-                 Grade of adverse events
tients, 11.6%).                                                          1                                         13 (15.1%)
    The median duration of ICI therapy was three months                  2                                         20 (23.2%)
(IQR 2-6) with a median of five cycles (IQR 3-8.75).
                                                                         3                                          8 (9.3%)
Fifty-one patients (59.3%) were treated with nivolumab,
                                                                         4                                          1 (1.2%)
29 (33.7%) with pembrolizumab, five (5.8%) with atezoli-
                                                                     a
zumab and one (1.2%) with combination of ipilimumab and               Other cancers includes metastatic breast cancer, carcinoma stom-
                                                                     ach, pineal anaplastic astrocytoma, head and neck squamous cell
nivolumab. Patient demographics are presented in Table 1.
                                                                     carcinoma, nasal adenoid cystic carcinoma and testicular germ cell
    A total of 42 IRAEs of any grade occurred in 28 patients         tumor accounting for 1 patient (1.2%) each.
(32.5%) with six patients (6.97%) having adverse events              ICI = immune checkpoint inhibitors; SCC = squamous cell
involving more than one organ system. Cutaneous (18.6%)              carcinoma.


                         Table 2. Immune-Related Adverse Events (IRAEs) and their grades.
                  IRAE                      Grade 1              Grade 2                Grade 3           Grade 4             Total
 Cutaneous                                      9                   9                      6                 0                 24
 Thyroid disorders                              1                  11                      1                 0                 13
 Neurological                                   1                   0                      1                 0                  2
 Conjunctivitis                                 1                   0                      0                 0                  1
 Diarrhea                                       1                   0                      0                 0                  1
 Intracranial hypertension                      0                   0                      0                 1                  1



Original Article | Dermatol Pract Concept. 2023;13(3):e2023127                                                                        3
cutaneous lesions), maculopapular rash in 7 (8.1%), vitiligo          of one month. In one patient with psoriasiform eruption –
in 2 (2.3%) and erythema multiforme, exfoliative dermatitis,          Nivolumab dosing was changed from once in two weeks to
psoriasiform eruption, mucositis in one patient each (1.2%).          once in four weeks.
No hair or nail changes were noted. There were 9 grade                    Of the 15 patients treated for cIRAEs, 12 patients ex-
1 cIRAEs (37.5%), 9 grade 2 events (37.5%) and 6 grade 3              perienced significant improvement following treatment,
events (25%). No grade 4 cIRAEs were noted. The different             one patient had partial improvement, two patients had no
cIRAEs and their grades are represented in Table 3.                   improvement.
    Of the 16 patients, ten (62.5%) received nivolumab, five              Patients with IRAEs had a longer median PFS (6 months
(31.25%) pembrolizumab and one (6.25%) received a com-                versus 3 months, P = 0.016) and a longer median OS
bination of ipilimumab and nivolumab. cIRAEs occurred af-             (15 months versus 8 months, P = 0.03) compared to patients
ter median of 2.75 months (IQR 2-3) from the initiation of            without any adverse events. ORR was also significantly
ICI (median cycles of ICI: 4; IQR: 3-6).                              higher (39.2% versus 17.2%, P = 0.02). Kaplan-Meier
    Of the 16 patients with cIRAEs, 11 (68.75%) were man-             curves (PFS and OS) comparing patients with and without
aged with topicals, antihistamines or a combination of both.          IRAEs are represented in Figure 1.
Four patients required systemic immunosuppression.                        Median PFS (8 months versus 3 months, P = 0.023) and
    In addition to medical management, four patients (25%)            ORR (50% versus 18.5%, P = 0.008) were significantly
with grade 3 maculopapular rash (2), exfoliative dermati-             higher in patients with cIRAEs compared to those without
tis (1) and erythema multiforme with mucositis (1) required           cIRAEs (inclusive of patients who had AEs in organs other
an interruption in ICI therapy until the resolution of lesions.       than skin). Median OS was also longer (15 months versus
The patient with erythema multiforme developed further                10 months). However, this association was not statistically
grade 4 complications (intracranial hypertension) and ICIs            significant (P = 0.246). Kaplan-Meier curves (PFS and OS)
were stopped. The other patients were restarted on ICI                comparing patients with and without cIRAEs are repre-
therapy under careful observation after a drug-free period            sented in Figure 2.


           Table 3. Nature and grades of Cutaneous Immune-Related Adverse Events (cIRAEs).
                    No. of Patients         Total
                         (%)               cIRAEs               Nature              Grade 1       Grade 2      Grade 3       Grade 4
                       16 (18.6%)            24      Pruritus                           5             5            1             0
                                                     Maculopapular rash                 3             2            2             0
                                                     Vitiligo like                      1             1            0             0
                                                     depigmentation
                                                     Psoriasiform eruption              0             1            0             0
                                                     Erythroderma                       0             0            1             0
    Cutaneous                                        Erythema multiforme                0             0            1             0
      IRAEs                                          Mucositis                          0             0            1             0




Figure 1. Kaplan Meier survival curves comparing (A) progression free survival and (B) overall survival between patients with and without
immune-related adverse events (IRAEs).



4                                                                          Original Article | Dermatol Pract Concept. 2023;13(3):e2023127
Figure 2. Kaplan Meier survival curves comparing (A) progression free survival and (B) overall survival between patients with and without
cutaneous immune-related adverse events (cIRAEs).



    Cox proportional hazard regression showed any IRAE                malignant melanoma. Though other studies have reported
(hazard ratio: 0.558, P = 0.033) and cIRAEs (hazard ra-               adverse events like bullous pemphigoid, lichenoid eruption,
tio: 0.698, P = 0.046) to have a significant association with         acneiform eruptions, neutrophilic disorders and sarcoid like
increased PFS. Development of any IRAE was also associ-               lesions, we did not see any such reactions. We also did not
ated with significantly increased OS (hazard ratio: 0.453,            encounter any SCARs like SJS/TEN, DRESS and AGEP that
P = 0.028), whereas cIRAEs were not.                                  have been reported in other studies [17].
                                                                          cIRAEs occurred at a median duration of 2.75 months

Conclusions                                                           after initiation of ICI therapy whereas other IRAEs (other
                                                                      than skin) occurred earlier (median duration: 2 months).
ICIs are effective in treating various cancers and have revolu-           In a previous study on the characteristics of cIRAEs and
tionized cancer treatment, however, studies and trials on ICI         non-cutaneous IRAEs, cIRAEs were found to precede and
safety and efficacy have inadequate representation of Indian          increase the risk of other organ involvement in the same pa-
population. We have conducted a real-world study charac-              tient on ICI therapy [18]. In our study, of the six patients
terizing the cIRAEs seen in an Indian cohort on ICI therapy.          who developed both cutaneous and non-cutaneous IRAEs,
ICI response rates can be variable and reports have indicated         only two patients had cutaneous involvement prior to the
that the presence of IRAEs maybe associated with a better             extracutaneous adverse events, whereas it was the reverse in
therapeutic effect especially in lung cancer and malignant            the other four.
melanoma. Identification of predictors of ICI response are                cIRAEs were well tolerated. The majority of the cuta-
important especially in low- and mid-income countries where           neous toxicities were mild and were managed with topicals
financial constraints and accessibility to advanced diagnostic        and antihistamines. Grade 1 and 2 cIRAEs formed 75 % of
procedures can be hurdles. We have studied the association            the total. Grade 4 dermatological IRAEs –were not seen in
between the presence of IRAEs and cIRAEs and treatment                our cohort.
efficacy in terms of tumor response and survival outcomes.                Of the 15, 14 had improvement in their symptoms with
    The incidence rates of cIRAEs can be variable with high           13 having significant improvement (fall of two grades or
incidences of up-to 70% being reported in patients [11]. A            fall to grade 0). One patient with psoriasiform eruption had
recent population level analysis of cIRAEs in patients receiv-        only moderate improvement – however, this patient was not
ing ICIs in the United States has observed an incidence of            treated with any immunomodulatory agents. Two patients
25.1% [12]. Similar incidence has been observed in a large            with vitiligo like depigmentation did not request any treat-
Taiwanese cohort (27.4%) [13]. Compared to this, we ob-               ment. However, these patients had only grade 1 and grade 2
served a relatively lower incidence of cIRAEs (18.6%).                vitiligo like depigmentation with limited area of involve-
    With regard to the individual types of cIRAEs, the ma-            ment. one of these patients had associated pruritus which
jority noted in our study were pruritus and maculopapular             was treated with antihistamines.
rash similar to prior literature focusing on ICI associated cu-           The occurrence of any IRAE was associated with a higher
taneous reactions [13–15]. Vitiligo like depigmentation has           ORR and a longer PFS and OS. Thus, the appearance of any
been commonly reported in melanoma patients treated with              IRAE in itself may be an indicator of better patient survival,
ICI [16]. This was also seen in our study, in two patients with       similar to findings reported in other studies [3,19]. Patients



Original Article | Dermatol Pract Concept. 2023;13(3):e2023127                                                                         5
with any cIRAEs had a significantly longer median PFS and a                      2020;12(7):3796–803. DOI:10.21037/jtd.2019.08.29. PMID:
higher ORR. Multivariable analysis also showed cIRAEs to                         32802459. PMCID: PMC7399433.
                                                                            8.   Florez MA, Kemnade JO, Chen N, et al. Persistent ethnicity-
be associated with a longer PFS. They were also associated
                                                                                 associated disparity in anti-tumor effectiveness of immune
with a longer OS; however, it was not statistically significant.
                                                                                 checkpoint inhibitors despite equal access. Cancer Res Commun.
This is in contrast with other studies where in cIRAEs were                      2022;2022(8):806–813.DOI: 10.1158/2767-9764.CRC-21-0143
associated with better survival outcomes with regard to both                     . PMID: 35966167. PMCID: PMC9367161.
PFS and OS [4,20–22].                                                       9.   Resnick K, Zang P, Travis Larsen T, et al. Impact of ethnicity and
    Limitations of the study are its retrospective design and                    immune-related adverse events (IRAE) on outcomes for non-small
                                                                                 cell lung cancer (NSCLC) patients treated with immune checkpoint
small sample size. Six out of the 16 patients with cutaneous
                                                                                 inhibitors. J Clin Oncol. 2022;40:16:suppl, e21115-e21115.
IRAEs also had other organ IRAEs which may be a con-
                                                                                 DOI: 10.1200/JCO.2022.40.16_suppl.e21115.
founding factor.                                                           10.   Peravali M, Gomes-Lima C, Tefera E, et al. Racial dispari-
    In conclusion, pruritus and maculopapular rash were the                      ties in immune-related adverse events of immune checkpoint
most common cIRAEs seen in our study of Indian patients                          inhibitors and association with survival based on clinical and
on ICI therapy which is similar to the profile of cIRAEs seen                    biochemical responses. World J Clin Oncol. 2021;12(2):103-
                                                                                 114. DOI:10.5306/wjco.v12.i2.103. PMID: 33680877. PMCID:
in other populations. However, the incidence of cIRAEs was
                                                                                 PMC7918525.
lower. cIRAEs were found to be associated with a superior
                                                                           11.   Schneider BJ, Naidoo J, Santomasso BD, et al. Management of
ORR and PFS. Compared to adverse events in other organ                           Immune-Related Adverse Events in Patients Treated With Im-
systems, cutaneous adverse events are readily evident on a                       mune Checkpoint Inhibitor Therapy: ASCO Guideline Update.
simple physical examination and do not usually require any                       J Clin Oncol. 2021;39(36):4073-4126. DOI:10.1200/JCO.21
investigations. Thus, cIRAEs may serve as an easily accessi-                     .01440. PMID: 34724392.
                                                                           12. Wongvibulsin S, Pahalyants V, Kalinich M, et al. Epidemiol-
ble and actional clinical surrogate marker for predicting the
                                                                               ogy and risk factors for the development of cutaneous toxici-
tumor response. This can especially be important in resource
                                                                               ties in patients treated with immune-checkpoint inhibitors: A
poor settings.                                                                 United States population-level analysis. J Am Acad Dermatol.
                                                                               2022;86(3):563-572. DOI:10.1016/j.jaad.2021.03.094. PMID:
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