Optimal strategy in managing advanced melanoma

The advent of immune checkpoint inhibitors and combination therapy with BRAF inhibitors and MEK inhibitors has dramatically improved the prognosis of advanced melanoma. However, since acral melanoma and mucosal melanoma, which are rare in Western countries but are major subtypes of melanoma in East Asia, including Japan, have a low frequency of BRAF mutations, there are currently no treatment options other than immune checkpoint inhibitors in most such cases. Furthermore, owing to a lower tumor mutation burden, immune checkpoint inhibitors are less effective in acral and mucosal melanoma than in cutaneous melanoma. The aim of this review was to summarize the current status and future prospects for the treatment of advanced melanoma, comparing cutaneous melanoma, acral melanoma, and mucosal melanoma.


| INTRODUC TI ON
Melanoma is known as a highly immunogenic tumor because of the frequent occurrence of vitiligo and spontaneous regression of the primary tumor. 1 Although numerous therapies to induce tumorspecific immune responses, such as peptide therapy, dendritic cell therapy, and tumor-infiltrating lymphocyte therapy, as well as therapies to enhance nonspecific immune responses with interleukin 2 and interferons, have been attempted, no immunotherapy had been proven effective in phase 3 trials until the advent of ipilimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody (Ab). 2,3Molecules that suppress immune responses against self or excessive immune responses, such as CTLA-4 and programmed cell death 1 (PD-1), are called immune checkpoint molecules, and malignant neoplasms utilize immune suppression mechanisms mediated by these molecules to escape the host's immune surveillance mechanisms. 4Drugs that activate cellular immunity against tumors by blocking inhibitory signals mediated by immune checkpoint molecules are called immune checkpoint inhibitors (ICIs).In addition to anti-CTLA-4 and anti-PD-1 Abs, anti-programmed death ligand 1 (PD-L1) and anti-lymphocyte-activation gene 3 (LAG3) Abs have been used in clinical practice based on the results of randomized controlled trials (RCTs) (Table 1).Whole-exome sequencing has shown that melanoma is one of the most frequently somatic mutated malignancies. 5,6The tumor mutation burden (TMB) of melanoma is dependent on ultraviolet light (UV) exposure and exhibits the following order: head and neck region (chronic sun-exposed areas) > trunk, and upper and lower limbs (intermittently sunexposed areas) > sun-protected areas. 710] Under the 2018 World Health Organization classification, melanoma is classified as melanomas arising in sun-exposed skin (low cumulative sun damage [CSD] melanoma/superficial spreading melanoma, high-CSD melanoma/lentigo maligna melanoma, and desmoplastic melanoma) and melanomas arising at sun-shielded sites or without known etiological associations with UV radiation exposure (such as acral melanoma [AM], mucosal melanoma [MM], and uveal melanoma). 11In this review, low-CSD melanoma and high-CSD melanoma are collectively referred to as cutaneous melanoma (CM), and desmoplastic melanoma and uveal melanoma are not discussed.Those of East Asian ethnicity, including the Japanese, have a very low incidence of melanoma, less than 1/10th of that of Caucasians, 12 and the frequency of each    melanoma subtype is known to differ greatly between East Asians and Caucasians.In Caucasians, most cases occur on skin affected by UV light, whereas AM, which occurs on the palms, soles, and under the nails, and MM are rare. 13In contrast, AM and MM are the major subtypes of melanoma in the Japanese, accounting for about 40% and 15% of the total, respectively. 14,15CM, AM, and MM differ considerably at the gene level as well: whole-genome sequencing analysis revealed that single-nucleotide variants (SNVs) and insertions/deletions are more common in CM, while structural rearrangements are more common in AM and MM. 16,17Since frameshifts caused by SNVs and insertions/ deletions are likely to induce peptides that can be neoantigens, CM is more likely to respond to immunotherapy than AM and MM. 18In addition, when melanomas are classified into BRAF-mutant, RAS-mutant, NF1-loss, and triple wild type, 19 about half of CM cases have BRAF mutations, while only 10%-20% of AM and MM cases have them. 17,20On the other hand, triple wild type is found in less than 10% of CM cases, but accounts for 30%-40% in AM and MM. 17,21,22Mutations in the KIT gene are found in 10%-20% of AM and MM cases. 21,22Currently, BRAF and MEK inhibitors are the only molecular-targeted therapies in use as standard therapy, and although some efficacy has been observed in clinical trials targeting NRAS and KIT, 23,24 no drug has demonstrated a significant survival benefit, and future development is awaited.

| DE VELOPMENT OF I CIs AND THEIR IMPAC T IN RE AL-WORLD CLINIC AL PR AC TI CE
Anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies (Abs) block the interaction between CTLA-4 expressed by cytotoxic T cells (CTLs) and co-stimulatory molecules expressed by antigenpresenting cells (APCs), thereby blocking inhibitory signals and maintaining CTL activation. 25In the first clinical trial of repeated doses of ipilimumab, reported in 2003, three of 14 patients responded and nine had severe adverse events, including colitis, hepatitis, and hypophysitis, the recovery of all of which was achieved with corticosteroids or hormone replacement. 26Following the results of large phase 3 trials (MDX010-20 2 and CA184-024 3 ), the approval of ipilimumab in the USA in 2011 and in the EU in 2012 marked a major turning point in the treatment of advanced or unresectable melanoma.Although the overall response rate (ORR) of ipilimumab is not high, at about 15% for first-line treatment 3 and 10% for second-line treatment, 2 it has characteristics that are critically different from those of conventional cytotoxic anticancer drugs, in that long-term survival can be expected in responders.
A pooled analysis of approximately 5000 cases from prospective trials and expanded access programs showed 3-year overall survival (OS) of 21%, with a plateauing survival curve thereafter. 27Since CTLA-4 suppressed excessive immune responses, including those to self-antigens, anti-CTLA-4 Abs can cause a variety of autoimmune reactions, such as autoimmune colitis, hepatitis, thyroiditis, hypophysitis, and interstitial pneumonia. 2,3These are referred to as immune-related adverse events (irAEs), many of which can be controlled with corticosteroids or immunosuppressants, but may require lifelong replacement therapy.
On the other hand, PD-1 was discovered in 1992 as a gene whose expression is enhanced when T cells induce cell death, 28 but studies on knockout mice revealed that it is a molecule that suppresses immune reactions. 29Some malignant tumors express the ligands PD-L1 and PD-L2, and achieve immune escape by transmitting suppressive signals to activated T cells via PD-1.Anti-PD-1 Abs maintain CTL activation by blocking these suppressive signals. 30In July 2014, nivolumab was approved in Japan as the world's first anti-PD-1 Ab, followed 2 months later by pembrolizumab in the USA.Nivolumab and pembrolizumab are considered equally effective, with ORRs of 42%-45% for nivolumab (CheckMate 066 31 and 067 32 ) and 46% for pembrolizumab (KEYNOTE-006 33 ) in first-line treatment, and 27% for nivolumab (CheckMate 037 34 ) and 22%-34% for pembrolizumab in second-line treatment and higher (KEYNOTE-002 35 and 006 33 ).
Long-term survival was also observed with anti-PD-1 Abs as well as ipilimumab, with 6.5-year OS of 42% reported with nivolumab in first-line treatment 36 and 7-year OS of 37.8% reported with pembrolizumab in first-line treatment. 37Since anti-PD-1 Abs are significantly more effective and have a lower incidence of serious irAEs than ipilimumab, [31][32][33] anti-PD-1 Abs are now the mainstay of advanced melanoma treatment in guidelines. 38,39nce the anti-CTLA-4 Ab acts in the priming phase and the anti-PD-1 Ab acts in the effector phase, the combination of these two was expected to enhance efficacy.A phase 1 dose-escalation trial was initiated in 2010 (CA209-004), which resulted in the use of 1 mg of nivolumab per kg and 3 mg of ipilimumab per kg in combination. 40Based on the results of this phase 1 study, a phase 2 RCT (CheckMate 069) comparing nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) for four doses followed by nivolumab (3 mg/ kg) (niv/ipi) with placebo plus ipilimumab (3 mg/kg) for four doses followed by placebo (placebo/ipi) in treatment-naive, BRAF wildtype advanced melanoma was conducted. 41The primary endpoint of ORR was 61% for niv/ipi and 11% for placebo/ipi, whereas severe AEs were observed in 54% of niv/ipi and 24% of placebo/ipi patients.This led to the approval of nivolumab plus ipilimumab combination therapy for BRAF wild-type melanoma in the USA in September 2015, which was later extended to BRAF-mutated melanoma.CheckMate 069 was followed by a phase 3 trial (CheckMate 067) comparing niv/ipi or nivolumab monotherapy with ipilimumab monotherapy in previously untreated advanced melanoma. 32,36Co-primary endpoints were progression-free survival (PFS) and OS, and median PFS was 11.5, 6.9, and 2.9 months in the niv/ipi, nivolumab, and ipilimumab groups, respectively.
Meanwhile, median OS was 72.1, 36.9, and 19.9 months, respectively.Niv/ipi and nivolumab were significantly more effective than ipilimumab, and although the study design did not provide sufficient power to identify a significant difference between niv/ ipi and nivolumab, it is recognized that niv/ipi is more efficacious than nivolumab.Meanwhile, because the incidence of serious irAEs is also very high (niv/ipi 59%, nivolumab 21%, ipilimumab 28%), niv/ipi should be considered a treatment for patients with good performance status and in facilities that can handle irAEs.
Although it represents off-label use, niv3/ipi1 is a treatment that would be considered especially in cases with a high risk of irAE.
The difference in efficacy between niv/ipi and nivolumab has been shown to vary markedly depending on the presence or absence of BRAF mutations. 43In the subgroup analysis at the 6.5-year follow-up of CheckMate 067, while there was little difference in efficacy between niv/ipi and nivolumab in BRAF wild-type patients (6-year PFS 34% vs 31%, 6.5-year OS 46% vs 42%), niv/ipi substantially outperformed nivolumab in BRAF-mutated patients (6year PFS 38% vs 23%, 6.5-year OS 57% vs 43%). 36Some reports suggest that niv/ipi is highly effective in BRAF-mutated melanoma because regulatory T cells, accumulated in the tumor microenvironment, are removed by anti-CTLA-4 Ab. 44,45 However, there are negative reports, 46 and at this point it remains to be elucidated why niv/ipi is more effective in BRAF-mutated melanoma.
LAG3 is expressed on activated CTLs and suppresses cellular immunity by binding to MHC class II on APCs. 47A phase 2/3 RCT (RELATIVITY-047) compared anti-LAG3 Ab relatlimab plus nivolumab combination therapy (rela/niv) with nivolumab monotherapy. 48The primary endpoint, median PFS, was 10.  49 In a phase 1/2 study (RELATIVITY-020 part D) of rela/niv in advanced melanoma, two cohorts were established: part D1 allowed only one line of a prior anti-PD-1-containing regimen and part D2 allowed multiple prior lines of anti-PD-1/L1-containing regimens. 50The ORR was 12% in D1 and 9.2% in D2, and the median PFS was 2.1 months in D1 and 3.2 months in D2.

| DE VELOPMENT OF S MALL-MOLECULE MOLECUL AR-TARG E TED THER APY
In 2002, it was reported that BRAF V600E mutation is frequently found in melanoma. 51BRAF is a serine/threonine kinase belonging to the RAF kinase family and transduces cell growth stimulation through the RAS-RAF-MEK-ERK signaling pathway. 52BRAF with V600E mutation is constitutively active and BRAF has been shown to be one of the important driver genes of melanoma. 51The first BRAF inhibitor, vemurafenib, was approved in the USA in 2011 following the results of a phase 3 trial (BRIM-3) comparing it to dacarbazine in BRAF-mutated melanoma. 53In 2013, the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib were also approved following the results of phase 3 trials (BREAK-3 for dabrafenib 54 and METRIC for trametinib 55 ).Although they have high response rates of approximately 50%, the median PFS is around 5 months and early resistance occurs.Meanwhile, secondary tumors such as squamous cell carcinoma rarely occur with BRAF inhibitors. 53,547][58][59] BRAF/MEKi is now the standard of care for BRAF-mutated melanoma, and three combinations have been developed based on the results of RCTs (Table 1).In a phase 3 trial (coBRIM) examining the efficacy of vemurafenib plus cobimetinib (vem/cobi), ORR, 5-year PFS, and 5-year OS were 70%, 14%, and 31%, respectively. 56,60Two phase 3 trials (COMBI-v and COMBI-d) investigated the effect of dabrafenib plus trametinib (dab/tra) with an ORR of 64%-68%, and a pooled analysis of COMBI-d and COMBI-v showed 5-year PFS of 19% and 5-year OS of 34%. 57,58,61 the phase 3 COLUMBUS trial, encorafenib plus binimetinib (enco/ bini) had an ORR of 64.1%, 5-year PFS of 22.9%, and 5-year OS of 34.7%. 59,627][58][59] In dab/tra, pyrexia is particularly frequent (about 70%), 57,58 and in enco/bini, serous retinal detachment is a characteristic adverse event. 59The pooled analysis of COMBI-v and COMBI-d showed that dab/tra was highly effective in patients with LDH in the normal range and <3 metastatic organs, and the 5-year OS was very high (70%) in patients who achieved complete response (CR). 61The results of coBRIM and COLUMBUS studies were similar, suggesting that BRAF/MEKi alone may be able to maintain long-term response in selected patients with BRAF-mutated melanoma. 60,62

| COMB INATI ON THER APY OF I CIS AND B R AF/MEK I IN B R AF-MUTATED MEL ANOMA
In expectation of the high response rate of BRAF/MEKi and sustained efficacy of ICIs, a three-drug combination of an ICI and BRAF/MEKi is being developed for BRAF-mutated melanoma.In a phase 3 trial (IMspire150) comparing the PD-L1 Ab atezolizumab plus vem/cobi with vem/cobi, the primary endpoint, median PFS, was 15.1 months in the triplet therapy and 10.6 months in vem/cobi, which were significantly different. 63In addition, the triplet regimen atezolizumab plus vem/cobi was approved in the USA in 2020.However, median OS in the second interim analysis was 39.0 months for the triplet therapy and 25.8 months for vem/cobi, which are not significantly different (HR: 0.84, p = 0.14). 64The National Comprehensive Cancer Network melanoma guidelines do not recommend the triplet regimen as first-line treatment for BRAF-mutated melanoma.In addition, a phase 3 study (COMBI-i) comparing the three-drug combination of the anti-PD-1 Ab spartalizumab plus dab/tra with dab/ tra failed to demonstrate a significant improvement of the primary endpoint, PFS. 65

| S EQUENTIAL THER APY OF I CIS AND B R AF/MEK I IN B R AF-MUTATED MEL ANOMA
In CheckMate 067, about 50% of niv/ipi-treated patients achieved CR or partial response (PR) at 1 year, and approximately 80% of them maintained their response at 5 years. 36In the pooled analysis of COMBI-v and COMBI-d, 19% of dab/tra-treated patients achieved a CR and 71% of them maintained this response at 5 years. 61Thus, some patients can be predicted to have a good prognosis with only first-line treatment, but in most cases sequential treatment is required.RCTs have examined whether BRAF/ MEKi or niv/ipi is the best first-line treatment for BRAF-mutated melanoma.A phase 3 trial (DREAMseq) in previously untreated BRAF-mutated melanoma compared niv/ipi as first line and then switched to dab/tra at disease progression with dab/tra as first line and then switched to niv/ipi at disease progression. 65The 2year OS, the primary endpoint, was 71.8% in patients who started first-line therapy with niv/ipi, whereas it was 51.5% those who started first-line therapy with dab/tra, which differed significantly.
The ORR for dab/tra was stable at 43% in the first line and 47.8% in the second line, while the ORR for niv/ipi decreased to 46% in the first line and 29.6% in the second line.
In a phase 2 trial (SECOMBIT) in previously untreated BRAFmutated melanoma, patients were randomized to receive niv/ipi as the first line and then switch to enco/bini at disease progression (arm A), enco/bini as the first line and then switch to niv/ipi at disease progression (arm B), or enco/bini and then switch to niv/ipi after 8 weeks of treatment, and enco/bini at disease progression (arm C).
The 3-year OS was 62%, 54%, and 60% in arm A, arm B, and arm C, respectively. 66Based on the results of these RCTs, niv/ipi is recommended as first-line treatment for BRAF-mutated melanoma. 39

| DE VELOPMENT S TATUS OF MEL ANOMA TRE ATMENT IN JAPAN
Table 2 provides a summary of key prospective clinical trials conducted in Japan.A single-arm phase 2 study (CA184-202) of ipilimumab (10 mg/kg) plus dacarbazine combination therapy, conducted based on CA184-024, 3 was terminated early due to a high incidence of severe hepatitis. 67Following the results of a subsequent single-arm phase 2 study (CA184-396) with ipilimumab (3 mg/kg) (severe AEs 15%, ORR 10%), 68 ipilimumab was approved in 2015.
However, the number of cases in which ipilimumab was used in firstline therapy was limited because nivolumab was already approved.
A retrospective analysis of the effect of ipilimumab in 61 patients TA B L E 2 Representative prospective clinical trials in Japan.| 329 UCHI previously treated with anti-PD-1 Abs reported a median OS of 7.0 months and an ORR of 4.9%. 69 a single-arm phase 2 study (ONO-4538-02, n = 35) with nivolumab (2 mg/kg, once every three weeks) in the second line or later, ORR was 28.6% and 2-year OS was 42.9%. 70The next singlearm phase 2 study (ONO-4538-08, n = 24) with nivolumab (3 mg/ kg, once every two weeks) in first-line therapy showed an ORR of 34.8% and 5-year OS of 26.1%. 71,72In addition, in a single-arm phase 1b study with pembrolizumab (KEYNOTE-041, n = 42), the ORR was 24.3% and median OS was 25.1 months. 73The results of these phase 2 studies of nivolumab and pembrolizumab in Japan tended to show lower effectiveness than those of CheckMate 037, 34 CheckMate 066, 31 and KEYNOTE-006, 33 which was thought to be because approximately half of the participants in these studies had AM or MM (ONO-4538-02 included 26% AM, ONO-4538-08 included 29.2%
This study included eight CM, seven AM, and 12 MM cases, with an ORR of 75% for CM, 42.9% for AM, and 33.3% for MM. 76,77The safety profile was like that of CheckMate 067 and niv/ipi was approved in May 2018.In a retrospective observational study with niv/ipi (n = 100) at the National Cancer Center Hospital, the ORR for all subjects was 24%, median PFS was 3.3 months, and median OS was 14.5 months.In previously untreated patients (n = 48), ORR was 33.3%, median PFS was 6.5 months, and median OS was 25.3 months, and in previously treated patients (n = 52), ORR was 15.4%, median PFS was 2.5 months, and median OS was 7.5 months.

MM (n = 36
) had an ORR of 16.7%, median PFS of 3.3 months, and median OS of 14.3 months. 78In a retrospective observational study of 111 patients whose first ICI treatment was niv/ipi (prior BRAF/ MEKi allowed), the ORR for all subjects was 35% and the 2-year OS was 50.4%.The 2-year OS of 33 CM, 28 AM, and 26 MM patients was 45.5%, 63.0%, and 50.0%, respectively. 79r targeted therapy, small phase 1 and 2 studies with vemurafenib and dab/tra were conducted and showed efficacy and safety similar to the international phase 3 studies. 80,81Vemurafenib was approved in December 2014 and dab/tra in March 2016.Several facilities in Japan participated in the COLUMBUS study, 59 which led to enco/bini being approved in January 2019.In a retrospective observational study with dab/tra or enco/bini (n = 112), the ORR for all subjects was 75%, median PFS was 13.0 months, and median OS was 35 months, comparable to the findings in international phase 3 trials.In a subgroup analysis, the ORR of patients treated with prior ICI (n = 34) was 73.5% and it was 64.3% for AM/MM (n = 14), indicating a high response regardless of treatment status or melanoma subtype. 82though it appears that there are no ethnic differences in the efficacy of BRAF/MEKi, the efficacy of ICIs in Japan tends to be lower than that in phase 3 trials in the USA and Europe, where most participants are Caucasian.This has been attributed to the high prevalence of AM and MM in Japan, which are less responsive to ICIs.However, recent reports suggest that even CM does not have a higher TMB in East Asians, indicating that ICIs are less effective in East Asians than in Caucasians. 83An international retrospective observational study with patients from the USA, Australia, and China analyzed the effect of anti-PD-1 Abs by ethnicity and melanoma subgroup. 84e 1135 patients included 814 Caucasians, 300 East Asians, 13 Hispanics, and eight Africans, with analyses conducted using the following two groups: Caucasians (n = 814) and East Asians/Hispanics/ Africans (n = 321).Regarding melanoma subtypes, CM and unknown primary (UP) were placed in the same group (n = 849, including 710 Caucasians and 139 East Asians and others) and AM, MM, and uveal melanoma (UM) were placed in another group (n = 286, including 104 Caucasians and 182 East Asians and others).The differences between the two groups were analyzed.As for background differences, 37% of Caucasians and 21% of East Asians and others were BRAF-mutated, whereas 49% of Caucasians and 25% of East Asians and others were previously untreated.Overall, the ORR for Caucasians was 49% and median PFS was 9.8 months, while the ORR for East Asians and others was 17% and median PFS was 4.1 months.
In the CM/UP cohort, the ORR and median PFS for Caucasians (54%, 14.2 months) were significantly better than for East Asians and others (20%, 5.4 months).In the AM/MM/UM cohort, on the other hand, the ORR for Caucasians was 18% and median PFS was 3.0 months, while the ORR for East Asians and others was 15% and median PFS was 3.6 months.This showed no difference in the effect of anti-PD-1 Abs between Caucasians and East Asians and others.
The reason why the efficacy of anti-PD-1 Abs in CM/UP is higher in Caucasians than in East Asians and others, whereas no ethnic differences in efficacy were observed in AM/MM/UM, is that Caucasians are more UV-sensitive and may have a higher UV-induced TMB.
In a retrospective observational study of 336 BRAF-mutated melanomas in Japan, 236 patients were treated with BRAF/MEKi, 64 with anti-PD-1 Ab, and 36 with niv/ipi as first-line therapy. 85th a median follow-up of 19.9 months, ORR was significantly higher for BRAF/MEKi (69% for BRAF/MEKi, 27% for anti-PD-1 Ab, and 28% for niv/ipi); median PFS was also significantly prolonged for BRAF/MEKi (14.7 months for BRAF/MEKi, 5.4 months for anti-PD-1 Ab, and 5.8 months for niv/ipi).Meanwhile, median OS was 34.6 months for BRAF/MEKi, 37.0 months for anti-PD-1 Ab, and not reached for niv/ipi, with no significant difference among the groups.The ORR for second-line treatment was unchanged from that of first-line treatment for BRAF/MEKi (64%), but decreased for ICI (15% for anti-PD-1 Ab, 17% for niv/ipi).
Comparison of first-line treatment groups of BRAF/MEKi and niv/ ipi by propensity score matching showed no difference in PFS (HR 1.78 for niv/ipi, p = 0.15) and in OS (HR 1.003, p = 0.95).Based on the results of DREAMseq and SECOMBIT, ICIs (especially nib/ ipi) are recommended as first-line therapy for BRAF-mutated melanoma. 39However, it is unclear whether niv/ipi is optimal as first-line therapy for BRAF-mutated melanoma in East Asians, including Japanese, as ICIs may be less effective even in cutaneous melanoma.

| TRE ATMENT OF AM AND MM
Owing to less UV exposure, the TMB is lower in AM and MM than in CM, 5,6 and ICIs are thus considered less effective in AM and MM than in CM.Nevertheless, the frequency of BRAF mutations in AM and MM is much lower than in CM, 20,86 forcing most cases to rely on ICIs for treatment.Few prospective clinical trials have been conducted exclusively on MM and AM because these conditions are rare in Caucasians, accounting for 1%-2% of all melanomas. 13,87In addition, although the frequency is high in East Asians, the absolute number of melanomas is small. 14,15 a single-arm phase was analyzed. 91In the analysis of MM, ORR was 23.3%, 37.1%, and 8.3% for nivolumab, niv/ipi, and ipilimumab, and median PFS was 3 months, 5.9, and 2.7 months, respectively.In cutaneous melanoma, ORR was 40.9%, 60.4%, and 21.2% for nivolumab, niv/ipi, and ipilimumab, and median PFS was 6.2, 11.7, and 3.9 months, respectively.For all treatments, the effect on MM was lower than that on CM, but even for MM, the efficacy of niv/ipi exceeded that of nivolumab alone.
A retrospective observational study of 329 patients with MM in Japan compared the efficacy of anti-PD-1 Ab (n = 263) with that of niv/ipi (n = 66) and showed no difference between them (ORR 26% vs 29%, median PFS 5.9 vs 6.8 months, median OS 20.4 vs 20.1 months). 92In addition, an international, retrospective, observational study compared the efficacy of anti-PD-1 Ab and niv/ipi in 545 cases of MM (331 Caucasians, 176 East Asians, 20 others). 93erall, 348 patients were treated with anti-PD-  94 In a retrospective observational study of 254 patients with AM in Japan, 209 were treated with anti-PD-1 Ab and 45 with niv/ipi. 95ORR was significantly higher with niv/ipi than with anti-PD-1 Ab (40% vs 16%).Median PFS was 6.6 months for niv/ipi and 4.7 months for anti-PD-1 Ab, and median OS was 43.6 months for niv/ipi and 20.7 months for anti-PD-1 Ab, with neither of these differences being significant.In an international retrospective observational study of 325 patients with AM (234 plantar, 69 subungual, and 22 palmar), 76% were Caucasian, 184 were treated with anti-PD-1 Ab, 59 with niv/ipi, and 82 with ipilimumab. 96ORR was 43% for niv/ipi, 26% for anti-PD-1 Ab, and 15% for ipilimumab, with the rate for niv/ipi being significantly higher.
Median PFS was 5.4 months for niv/ipi, 4.1 months for anti-PD-1 Ab, and 3.5 months for ipilimumab, with no significant difference between niv/ipi and anti-PD-1 Ab in this regard.Meanwhile, median OS did not differ significantly among the groups (niv/ipi 1.3 years, anti-PD-1 Ab 1.9 years, ipilimumab 1.9 years).There was also no difference in efficacy among plantar, subungual, and palmar groups.
The efficacy of ICIs for MM and AM appears to be inferior to that for CM.Furthermore, in MM and AM, there may be no advantage of niv/ ipi over anti-PD-1 Ab monotherapy, or if there is, it seems not to be as obvious as in the case of CM in Caucasian patients.tor.This achieved a favorable ORR of 48.3%, 97 but median PFS was 7.5 months and median OS was 20.7 months. 98Although validation in RCTs is needed, the advantage of toripalimab and axitinib over anti-PD-1 Ab monotherapy may not be large.A phase 2 trial is underway in Japan to evaluate the efficacy of imatinib in combination with pembrolizumab in patients with KIT-mutated melanoma, and the results are awaited. 99On the other hand, it has been pointed out that ICIs may not be as effective in East Asians as in Caucasians, even in CM, and a report from China showed no difference in TMB among CM, AM, and MM. 83It is necessary to conduct a comparative validation of TMB for CM by ethnicity and, based on the results, prospective trials to examine the efficacy of ICIs by ethnicity would be needed.It would be difficult to extrapolate the results of Caucasiandominated RCTs to the treatment of melanoma in East Asia, and evidence from RCTs of melanoma in East Asians is needed.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Authors declare no conflict of interests for this article.

Since
AM and MM have low TMB, the effects of ICIs on them are considered to be inferior to those on CM.This indicates the need for the further development of treatment options in East Asia, including Japan, where the frequency of AM and MM is high.No previous clinical trials with small-molecule molecular-targeted therapies for KIT and NRAS have demonstrated an advantage regarding OS, and combination therapies of ICIs with small-molecule moleculartargeted drugs are also being considered.A phase 1b trial conducted in China on patients with MM evaluated the efficacy of toripalimab, an anti-PD-1 Ab, in combination with axitinib, a multi-kinase inhibi- 1 Ab and 197 with niv/ipi, with no difference in efficacy between them in the overall