10.5826/dpc.1401a26
Introduction: Pembrolizumab is well-tolerated in pediatric patients with advanced tumors, consistent with results in adults. However, information on the safety and efficacy of adjuvant pembrolizumab in children and adolescents with melanoma is lacking.
Objectives: To compare pembrolizumab versus high-dose interferon-α2b (HDI) as adjuvant therapy in pediatric patients with melanoma.
Methods: We performed a retrospective study of pediatric patients diagnosed with melanoma between January 2008 and April 2022. Relapse-free survival (RFS) and the 1-year RFS rate were compared between patients receiving adjuvant pembrolizumab or HDI. 
Results: Seventy-five pediatric patients with melanoma were screened from a database of 6,013 patients. Twenty-four patients were finally enrolled, of whom 9 received pembrolizumab and 15 received HDI as adjuvant therapy. By August 31, 2022, the median follow-up times were 23.6 months and 98.7 months in the pembrolizumab and HDI groups, respectively. There was no significant difference in median RFS between two groups (not reached versus 38.7 months, P = 0.11). The median overall survival was not reached in either group. The 1-year RFS rates were 88.9% and 66.7% in the pembrolizumab and HDI groups, respectively. All adverse events in the pembrolizumab group were grade 1 or 2, but grade 3–5 adverse events occurred in two (13%) patients receiving HDI.
Conclusions: RFS was similar in pediatric patients with melanoma receiving adjuvant pembrolizumab or HDI, but pembrolizumab was associated with a reduced risk of recurrence and a more favorable safety profile. However, due to the small sample size and differences in follow-up time, larger and prospective studies are still warranted to explore better adjuvant therapies for pediatric melanoma.
text/xml
2160-9381
3517
en
Lu Si
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Melanoma
Pembrolizumab Versus High-Dose Interferon-α2b as Adjuvant Therapy for Pediatric Melanoma: A Retrospective Study 
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2024-01-31
2023-05-08
2024-01-31
2024-02-21
e2024026
Dermatol Pract Concept
Introduction: Pembrolizumab is well-tolerated in pediatric patients with advanced tumors, consistent with results in adults. However, information on the safety and efficacy of adjuvant pembrolizumab in children and adolescents with melanoma is lacking.
Objectives: To compare pembrolizumab versus high-dose interferon-α2b (HDI) as adjuvant therapy in pediatric patients with melanoma.
Methods: We performed a retrospective study of pediatric patients diagnosed with melanoma between January 2008 and April 2022. Relapse-free survival (RFS) and the 1-year RFS rate were compared between patients receiving adjuvant pembrolizumab or HDI. 
Results: Seventy-five pediatric patients with melanoma were screened from a database of 6,013 patients. Twenty-four patients were finally enrolled, of whom 9 received pembrolizumab and 15 received HDI as adjuvant therapy. By August 31, 2022, the median follow-up times were 23.6 months and 98.7 months in the pembrolizumab and HDI groups, respectively. There was no significant difference in median RFS between two groups (not reached versus 38.7 months, P = 0.11). The median overall survival was not reached in either group. The 1-year RFS rates were 88.9% and 66.7% in the pembrolizumab and HDI groups, respectively. All adverse events in the pembrolizumab group were grade 1 or 2, but grade 3–5 adverse events occurred in two (13%) patients receiving HDI.
Conclusions: RFS was similar in pediatric patients with melanoma receiving adjuvant pembrolizumab or HDI, but pembrolizumab was associated with a reduced risk of recurrence and a more favorable safety profile. However, due to the small sample size and differences in follow-up time, larger and prospective studies are still warranted to explore better adjuvant therapies for pediatric melanoma.
Lu Si
2024/01/31
10.5826/dpc.1401a26
e2024026
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Institute
2160-9381
Melanoma
en
e2024026
Marjanska A, Galazka P, Marjanski M, Wysocki M, Styczynski J. Efficacy and Toxicity of Pembrolizumab in Pediatric Metastatic Recurrent Melanoma. Anticancer Res. 2019;39(7):3945-3947. DOI:10.21873/anticanres.13547. PMID: 31262925.
Pembrolizumab Versus High-Dose Interferon-α2b as Adjuvant Therapy for Pediatric Melanoma: A Retrospective Study 
https://dpcj.org/index.php/dpc/article/download/3517/2423
Pembrolizumab Versus High-Dose Interferon-α2b as
   Adjuvant Therapy for Pediatric Melanoma:
            A Retrospective Study
      Yu Du1, Zhonghui Qi1, Xianbin Liang2, Jie Dai1, Xiaoting Wei1, Xue Bai1, Lili Mao1,
        Zhihong Chi1, Chuanliang Cui1, Bin Lian1, Bixia Tang1, Xuan Wang1, Yu Chen3,
                                     Jun Guo1, Lu Si1


1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Melanoma and Sarcoma,
  Peking University Cancer Hospital and Institute, Beijing, China
2 Department of Oncology, The Third People’s Hospital of Zhengzhou, Zhengzhou, China
3 Department of Medical Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian Province, China



Key words: PD-1, interferon, children, adolescents, melanoma

Citation: Du Y, Qi Z, Liang X, et al. Pembrolizumab Versus High-Dose Interferon-α2b as Adjuvant Therapy for Pediatric Melanoma:
A Retrospective Study. Dermatol Pract Concept. 2024;14(1):e2024026. DOI: https://doi.org/10.5826/dpc.1401a26
Accepted: July 16, 2023; Published: January 2024
Copyright: ©2024 Du 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: Yu Du, Zhonghui Qi and Xianbin Liang contributed equally to this work. All authors have contributed significantly to this
publication.




  ABSTRACT             Introduction: Pembrolizumab is well-tolerated in pediatric patients with advanced tumors, consistent
                       with results in adults. However, information on the safety and efficacy of adjuvant pembrolizumab in
                       children and adolescents with melanoma is lacking.
                       Objectives: To compare pembrolizumab versus high-dose interferon-α2b (HDI) as adjuvant therapy
                       in pediatric patients with melanoma.
                       Methods: We performed a retrospective study of pediatric patients diagnosed with melanoma be-
                       tween January 2008 and April 2022. Relapse-free survival (RFS) and the 1-year RFS rate were com-
                       pared between patients receiving adjuvant pembrolizumab or HDI.
                       Results: Seventy-five pediatric patients with melanoma were screened from a database of 6,013 pa-
                       tients. Twenty-four patients were finally enrolled, of whom 9 received pembrolizumab and 15 received
                       HDI as adjuvant therapy. By August 31, 2022, the median follow-up times were 23.6 months and 98.7
                       months in the pembrolizumab and HDI groups, respectively. There was no significant difference in me-
                       dian RFS between two groups (not reached versus 38.7 months, P = 0.11). The median overall survival
                       was not reached in either group. The 1-year RFS rates were 88.9% and 66.7% in the pembrolizumab
                       and HDI groups, respectively. All adverse events in the pembrolizumab group were grade 1 or 2, but
                       grade 3–5 adverse events occurred in two (13%) patients receiving HDI.


Original Article | Dermatol Pract Concept. 2024;14(1):e2024026                                                                          1
                      Conclusions: RFS was similar in pediatric patients with melanoma receiving adjuvant pembrolizumab
                      or HDI, but pembrolizumab was associated with a reduced risk of recurrence and a more favorable
                      safety profile. However, due to the small sample size and differences in follow-up time, larger and
                      prospective studies are still warranted to explore better adjuvant therapies for pediatric melanoma.




Corresponding Author: Lu Si, Department of Melanoma and            (PD-1) have not been explored as adjuvant therapies for
Sarcoma, Peking University Cancer Hospital and Institute, No. 52
                                                                   pediatric melanoma.
Fucheng Road, Haidian District, Beijing, 100142, China. E-mail:
silu15_silu@126.com.                                                  Previous clinical trials demonstrated that adjuvant
                                                                   high-dose interferon (IFN)-α2b (HDI) had similar safety
                                                                   profiles in pediatric and adult melanoma patients [5]. In
                                                                   this study, we retrospectively analyzed and compared the

Introduction                                                       outcomes of pediatric patients with completely resected
                                                                   ­
                                                                   ­melanoma treated with adjuvant pembrolizumab or HDI.
Melanoma is a rare disease in the pediatric popula-
tion ­compared with its incidence in adults, with an inci-
dence of 0.7–0.8 per million per year in the first decade
                                                                   Methods
of life, rising to >10 per million per year in adolescents         Study Design and Patients
aged 15–19 years [1]. There are three subtypes of pedi-
                                                                   This was a multicenter, retrospective study of pembroli-
atric melanoma: spitzoid melanoma, melanoma arising in
                                                                   zumab versus HDI as adjuvant therapy in pediatric pa-
a congenital melanocytic nevus, and conventional (also
                                                                   tients with melanoma treated at three tertiary hospitals in
known as adult-type) melanoma [2]. Spitzoid melanoma
                                                                   China. The eligibility criteria (Figure 1) were: 1) <18-years-
is one of the most common subtypes of pediatric mela-
                                                                   old; 2) diagnosis of completely resected stage IIB/IIC/III/
noma, showing distinct histopathological and genetic pat-
                                                                   IV melanoma; 3) diagnosis from January 1, 2008 to April
terns compared with adult melanoma, including a greater
                                                                   30, 2022; 4) pembrolizumab adjuvant therapy (2 mg/kg
Breslow thickness at diagnosis [3]. Most published data
                                                                   up to a ­maximum of 200 mg every 3 weeks via intrave-
on pediatric melanoma have involved retrospective, single-­
                                                                   nous infusion) or HDI adjuvant therapy (18×106 IU/m2 per
institution studies with small samples or case reports, and
                                                                   day IFN-α2b subcutaneously on days 1–5 for 4 weeks, fol-
few prospective studies have been conducted. Although
                                                                   lowed by 9×106 IU/m2 per day IFN-α2b three times a week
various therapies, including ipilimumab, pembrolizumab,
                                                                   subcutaneously) within 3 months after surgery. Clinical
nivolumab, and combination BRAF-MEK inhibitors, make
                                                                   data were extracted from medical records, including age,
a huge difference in the treatment of melanoma in adults,
                                                                   sex, primary site, histologic subtype, Breslow tumor thick-
scanty information on the use of these therapies in pediat-
                                                                   ness, ulceration, date of surgery, date of recurrence, date
ric melanoma is available.
                                                                   of death, and side effects graded according to the National
    Pembrolizumab is a highly selective, humanized, IgG4
                                                                   Cancer Institute common toxicity criteria version 4.03.
monoclonal antibody with a favorable safety profile and
                                                                   Relapse-free survival (RFS) was defined as the time from
good efficacy and durability, which has been approved
                                                                   the start of adjuvant treatment to the date of first recur-
by the US Food and Drug Administration (FDA) for the
                                                                   rence (local, regional, or distant metastasis) or death from
treatment of several tumor types, including melanoma,
                                                                   any cause. The 1-year RFS rate, overall survival (OS), and
in both adults and children. An interim analysis of the
                                                                   safety were also assessed. Informed written consent was
KEYNOTE-051 study reported on the use of pembroli-
­
                                                                   obtained from all patients. This study was approved by the
zumab in children with advanced cancer, including eight
                                                                   Institutional Review Board of Peking University Cancer
cases of pediatric melanoma. Pembrolizumab showed fa-
                                                                   Hospital and was conducted according to Declaration of
vorable tolerance and encouraging antitumor activity in
                                                                   Helsinki Principles.
pediatric patients with relapsed or refractory Hodgkin
lymphoma, but had low antitumor activity in most pediat-
                                                                   Statistical Analysis
ric tumor types [4]. Inhibitors of programmed cell death-1
                                                                   All statistical analyses were performed using R version 4.2.1.
                                                                   Survival curves were plotted using the Kaplan-Meier method




2                                                                      Original Article | Dermatol Pract Concept. 2024;14(1):e2024026
Figure 1. Flowchart of inclusion and exclusion criteria for this study.



Table 1. Clinical characteristics of pediatric patients treated with pembrolizumab as adjuvant therapy.
   ID        Age           Sex             Location                          Stage                     Mutation               ECOG
 P1        6           M          right heel                     T4bN0M0/IIC                    unknown                        0
 P2       14           F          vulvar mucosa                  T4bN0M0/IIC                    wild                           1
 P3       13           F          vulvar skin                    T3bN1bM0/IIIC                  NRAS Q61R                      0
 P4       15           M          right thigh                    T4aN3bM0/IIIC                  wild                           0
 P5       15           F          right buttock                  T4bN0M0/IIC                    wild                           1
 P6       11           F          left forearm                   T4bN0M0/IIC                    wild                           0
 P7        7           F          face                           T2aN1bM0/IIIB                  wild                           0
 P8       14           F          right calf                     T3bN1cM0/IIIC                  BRAF V600E                     0
 P9        7           F          left upper arm                 T4bN0M0/IIC                    wild                           0

ECOG = Eastern Cooperative Oncology Group performance status score.



and compared between groups using log-rank tests. Categor-                were 12 (50%) male and 12 (50%) female patients, and the
                                   2
ical data were analyzed using χ or Fisher’s exact tests.                  median age was 13.5 years (interquartile range 9.5–14.5).
                                                                          Twenty-two (92%) patients had stage II/III melanoma and
                                                                          only two (8%) patients had stage IV melanoma. There were
Results                                                                   18 cases of cutaneous, three acral, one mucosal, and two
                                                                          primary unknown melanomas. Most patients had a BRAF/
Patient Characteristics
                                                                          RAS/NF1 triple wild-type genotype, while one patient had a
Seventy-five pediatric patients with melanoma were screened               BRAF V600E mutation and two patients had NRAS Q61R
from a database of 6013 patients at three hospitals between               mutations. There was no significant difference in baseline
January 1, 2008 and April 30, 2022. Twenty-eight patients                 characteristics between the two groups (Table 3).
had completely resected stage IIB/IIC/III/IV melanoma, of
whom 24 patients were treated with pembrolizumab (N = 9;
Table 1) or HDI (N = 15; Table 2) as adjuvant therapy. There




Original Article | Dermatol Pract Concept. 2024;14(1):e2024026                                                                       3
      Table 2. Clinical characteristics of pediatric patients treated with high-dose interferon-α2b as
                                              adjuvant therapy.
    ID         Age       Sex                Location                      Stage                      Mutation            ECOG
 H1        13        M         left upper arm                   T4bN0M0/IIC                   unknown                       0
 H2        15        M         left upper arm                   TxN1bM0/III                   wild                          0
 H3        14        F         left middle finger               T4bN2bM0/IIIC                 wild                          1
 H4        14        M         right groin                      TxN3bM0/III                   unknown                       1
 H5        13        M         not known                        TxNxM0/III                    wild                          1
 H6        12        M         scalp                            T4aN0M0/IIB                   wild                          0
 H7        16        M         left upper arm                   T4bN0M0/IIC                   unknown                       0
 H8        15        M         not known                        TxNxM1c/IV                    unknown                       1
 H9        8         M         right knee                       TxN0M1a/IV                    wild                          1
 H10       17        F         vulvar skin                      T4bN0M0/IIC                   NRAS Q61R                     0
 H11       8         F         dorsum of right foot             TxN3aM0/III                   wild                          0
 H12       14        M         right shoulder                   T3aN1aM0/IIIB                 unknown                       0
 H13       11        F         left heel                        T3bN0M0/IIB                   unknown                       0
 H14       8         F         scalp                            T4aN2cM0/IIIC                 unknown                       0
 H15       14        M         scalp                            T4aN0M0/IIB                   wild                          0

ECOG = Eastern Cooperative Oncology Group performance status score.



Efficacy                                                         treatment due to adverse events. One patient in the pem-
By the cut-off date of August 31, 2022, the median follow-up     brolizumab group discontinued treatment due to disease
times were 23.6 months (95% CI: 8.9–not reached [NR])            recurrence and one patient discontinued treatment due to
for the pembrolizumab group and 98.7 months (95% CI:             an adverse event. One patient treated with pembrolizumab
63.9–NR) for the HDI group. Six (6/9, 67%) patients in the       was still receiving treatment by August 31, 2022. Adverse
pembrolizumab group and 10 (10/15, 67%) patients in the          events with any cause occurred in 79% (19/24) of patients
HDI group completed 1 year of treatment. Eleven (46%) pa-        overall, 44% (4/9) of patients in the pembrolizumab group,
tients had disease recurrence, including one (1/9, 11%) in       and 100% of patients in the HDI group (15/15) (P = 0.003).
the pembrolizumab group and 10 (10/15, 67%) in the HDI           The adverse events are summarized in Table 4. Most adverse
group. The patient in the pembrolizumab group who re-            events were grade 1 or 2, and grade 3 treatment-related ad-
lapsed had a NRAS Q61R mutation. One (1/9, 11%) patient          verse events (TRAEs), including neutropenia, alanine amino-
in the pembrolizumab group and five patients (5/15, 33%) in      transferase (ALT) elevation, and aspartate aminotransferase
the HDI group relapsed with distant metastases. No patients      (AST) elevation, only occurred in two patients in the HDI
in the pembrolizumab group and six (6/15, 40%) patients          group. The most common adverse events in the HDI group
in the HDI group died. The median RFS was not reached in         were myelosuppression, pyrexia, and nausea. Adverse events
the pembrolizumab group and the median RFS in the HDI            did not lead to any deaths in either group. There were fewer
group was 38.7 months (95% CI: 10.8–NR; hazard ratio             adverse events in the pembrolizumab group compared with
0.23; 95% CI: 0.06–0.82; P = 0.11) (Figure 2). The median        the HDI group, including hyperthyroidism (N = 2, grade 1),
OS was not reached in either group. The 1-year RFS rates         rash (N = 2, grade 1), ALT elevation (N = 1, grade 1), AST
were 88.9% (95% CI: 70.6–100) and 66.7% (95% CI:                 elevation (N = 1, grade 1), leucopenia (N = 1, grade 1), neu-
46.6–95.3) and the 2-year RFS rates were 88.9% (95% CI:          tropenia (N = 1, grade 1), and alopecia (N = 1, grade 2).
70.6–100) and 60.0% (95% CI: 39.7–90.7) in the pembroli-
zumab and HDI groups, respectively.                              Conclusions
Safety                                                           Pediatric melanoma is a rare type of tumor in the pediat-
Five (33%) patients in the HDI group discontinued treat-         ric population, qualifying as an “orphan” disease according
ment due to disease recurrence but no patient discontinued       to the definition adopted by pediatric cooperative groups
                                                                 for rare childhood tumors in Europe [6]. Given its rarity,




4                                                                     Original Article | Dermatol Pract Concept. 2024;14(1):e2024026
                                       Table 3. Baseline characteristics of patients.
                                                      Pembrolizumab                     HDI
                                                          (n=9)                        (n=15)                         P
 Age
   Mean (SD)                                              11.3(3.7)                   12.8(2.9)                    0.290
   ≤ 10                                                     3(33)                       3(20)                      0.635
   > 10                                                     6(67)                      12(80)
 Sex                                                                                                               0.089
   Male                                                     2(22)                      10(67)
   Female                                                   7(78)                       5(33)
 Subtype                                                                                                           0.583
   Cutaneous                                                7(78)                      11(73)
   Acral                                                    1(11)                       2(13)
   Mucosal                                                  1(11)                         0
   Primary unknown                                               0                      2(13)
 Stage                                                                                                             0.833
   II                                                       5(56)                       6(40)
   III                                                      4(44)                       7(47)
   IV                                                            0                      2(13)
 Mutation status                                                                                                   0.170
   BRAF                                                     1(11)                       0(0)
   RAS                                                      1(11)                       1(7)
   NF1                                                      0(0.0)                      0(0)
   BRAF/RAS/NF1 triple wild type                            6(67)                       7(47)
   Unknown                                                  1(11)                       7(47)
 ECOG PS                                                                                                           0.669
   0                                                        7(78)                      10(67)
   1                                                        2(22)                       5(33)

ECOG PS = Eastern Cooperative Oncology Group performance status score.
HDI = high-dose interferon-α2b; SD = standard deviation.




epidemiological and natural history studies of pediatric mel-         the use of different therapies for melanomas in children and
anoma are not well-understood. Distinct from melanoma in              adolescents. Current management guidelines for pediatric
adults, spitzoid melanoma is one of the most common his-              melanoma are mainly based on experience of therapies in
tologic subtypes in pediatric patients with melanoma. Inter-          adults, and the efficacy and safety of these therapies in pe-
estingly, a recent meta-analysis including 1002 patients with         diatric patients remains unclear. Considering the differences
melanoma have demonstrated that spitzoid melanoma with                between pediatric and adult melanoma, there is thus a need
higher occurrence in children younger than 10 years harbors           to identify effective systemic adjuvant therapies to reduce the
higher Breslow thickness and more propensity to nodal metas-          risk of recurrence and improve survival in pediatric patients
tasis than non-spitzoid melanomas, but shows a more indolent          with melanoma.
biological behavior and a better prognosis [7]. Additionally,            Adjuvant therapy with PD-1 inhibitors reduced the risk
nevus-associated melanoma is more frequently observed in              of recurrence or death by 40%–50% and significantly in-
children than in adults, as a higher number of pediatric mel-         creased RFS in patients with resected stage III/IV melanoma
anomas are associated with congenital nevi in younger pa-             [8-10]. Adjuvant immunotherapy is currently a standard
tients. All these results suggest a different biological behavior     treatment for stage III/IV cutaneous melanoma, but there
of pediatric melanoma from the adult melanoma. Compared               is no standard adjuvant therapy for stage IIB and IIC mel-
with melanoma in adults, there is limited evidence to support         anomas. In the phase 3 KEYNOTE-716 study, adjuvant




Original Article | Dermatol Pract Concept. 2024;14(1):e2024026                                                                     5
    Figure 2. Kaplan-Meier estimates of recurrence-free survival in pediatric patients with melanoma treated with pembrolizumab or high-
    dose interferon-α2b.
    CI = confidence interval; HR = hazard ratio.


          Table 4. Adverse events in pediatric patients with melanoma treated with pembrolizumab
                                        or high-dose interferon-α2b.
                                                        Pembrolizumab (N = 9)                                HDI (N = 15)
            Adverse event, N (%)                        Any                 Grade ≥3                 Any                 Grade ≥3
 Any cause adverse event                                4(44)                   0                  15(100)                  2(13)
 Treatment-related adverse event                        4(44)                   0                  15(100)                  2(13)
 Leucopenia                                             1(11)                   0                   14(93)                   0
 Neutropenia                                            1(11)                   0                   13(87)                  1(7)
 Pyrexia                                                  0                     0                   13(87)                   0
 Nausea                                                   0                     0                    7(47)                   0
 Hyperthyroidism                                        2(22)                   0                      0                     0
 ALT elevation                                          1(11)                   0                    3(20)                  1(7)
 AST elevation                                          1(11)                   0                    3(20)                  1(7)
 Rash                                                   2(22)                   0                    2(13)                   0
 Fatigue                                                  0                     0                    4(27)                   0
 Myalgia                                                  0                     0                    2(13)                   0
 Alopecia                                               1(11)                   0                      0                     0
 Thrombocytopenia                                         0                     0                    1(7)                    0
 Wenckebach block                                         0                     0                    1(7)                    0


pembrolizumab significantly reduced the risk of recurrence              pembrolizumab and placebo groups, respectively [11]. In ad-
or death in patients with resected stage IIB or IIC melanoma,           dition, each group included one pediatric patient, and on the
compared with placebo, with 12-month RFS rates of 90%                   basis of these data, the FDA approved pembrolizumab as ad-
and 83% and 18-month RFS rates of 86% and 77% in the                    juvant therapy for adult and pediatric patients with high-risk



6                                                                           Original Article | Dermatol Pract Concept. 2024;14(1):e2024026
stage II and stage III melanomas. However, information on          most frequent grade 3–5 TRAEs were decreased lymphocyte
the use of immunotherapy as adjuvant therapy for pediatric         count and anemia. Two patients had grade 5 toxicities in-
patients is limited. Most studies have investigated immu-          cluding treatment-related pneumonitis, pleural effusion, and
notherapy in pediatric patients with advanced tumors. To           pulmonary edema [4]. In the current study, pembrolizumab
date, nivolumab (NCT0230445848 [12]), pembrolizumab                had a much lower incidence of TRAEs than HDI. The most
(NCT0233266849 [4]), atezolizumab (NCT0254160450 [13]),            common adverse events were hyperthyroidism and rash, and
and avelumab (NCT0345182551 [14]) have been inves-                 there were no grade 3–5 TRAEs in the pembrolizumab group.
tigated as monotherapies for recurrent and refractory pe-          In contrast, the incidences of myelosuppression (any grade:
diatric tumors, but only 3% of patients with solid tumors          93% versus 11%; grade ≥3: 7% versus 0), pyrexia (87% ver-
experienced an objective response across all four trials. Com-     sus 0), nausea (47% versus 0), elevated transaminase level
pared with adult cancers, most pediatric cancers have lower        (AST elevation: 27% versus 11%, ALT elevation: 27% versus
mutational burdens and fewer infiltrating T cells, which may       11%), and fatigue (27% versus 0) were higher in the HDI
account for this lack of efficacy [15]. The KEYNOTE-051            group than in the pembrolizumab group. Pembrolizumab
study found no objective responses in the eight enrolled           might thus be a better adjuvant treatment choice than HDI
pediatric patients with cutaneous melanoma who received            because of its more favorable safety and tolerability profile.
pembrolizumab treatment [4]. The combination of PD-1 and               This study had some limitations. It was a retrospective
cytotoxic T lymphocyte-associated antigen-4 blockade have          study and thus had some information bias. In addition, the
added benefit compared with monotherapy in adult patients;         follow-up time was shorter in the pembrolizumab group
however, the combination of ipilimumab/nivolumab does              compared with the HDI group. The study was also limited
not seem to exert synergistic effects in pediatric patients. In    by the small numbers of patients in both groups; however,
ADVL1412, only two pediatric patients achieved partial re-         the rarity of pediatric melanoma means that it is difficult
sponses among 55 evaluable patients receiving combination          to conduct large or prospective studies in these patients.
ipilimumab/nivolumab [16]. Overall, in contrast to the im-         Furthermore, HDI might not be the best control treatment,
pressive responses seen with adult cancers, most pediatric         given that it is no longer the standard adjuvant therapy for
cancers seem to have a poor response to immunotherapies.           cutaneous melanoma. The study was further limited by the
Whether the efficacy and safety profile of adjuvant pem-           lack of racial diversity, given that it only included Asian pe-
brolizumab treatment are the same in pediatric patients as         diatric patients.
in adult patients remains unclear. A case report described a           In summary, pembrolizumab was associated with a lower
7-year-old patient with recurrent metastatic melanoma who          risk of recurrence in pediatric patients with melanoma, com-
underwent complete resection of metastases and received            pared with HDI, but there was no significant difference in
adjuvant pembrolizumab. Although pembrolizumab treat-              RFS between the two treatments. Pembrolizumab also had
ment only lasted for 5 months because of adverse events (ar-       a more favorable safety profile, consistent with its toxic-
thritis and uveitis), the patient had no relapse within 1 year     ity spectrum in previous studies. These data suggested that
of follow-up [17]. Only one patient in the pembrolizumab           pembrolizumab might be better than HDI as an adjuvant
group in the current study had a recurrence and the 1-year         therapy for pediatric patients with melanoma. These findings
RFS rate was 88.9%. In addition, the median RFS was not            warrant further large, prospective and dedicated trials to
reached in pembrolizumab group. Thus, although there was           evaluate the efficacy and safety of adjuvant pembrolizumab
no significant difference between the pembrolizumab and            therapy for pediatric melanoma.
HDI groups, pembrolizumab seemed to be associated with a
lower risk of recurrence.
    The safety of adjuvant immunotherapies in pediatric
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