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eMethods 1. Systematic review and meta-analysis protocol

Research objectives:

This review will seek to establish, through the available literature, the treatment outcomes of metastatic Acral Melanoma and metastatic Acral Lentiginous Melanoma

Inclusion criteria

People of any age, gender or background with Acral Melanoma or Acral Lentiginous Melanoma with treatment given and outcome recorded.

Search strategy Search terms:

“acral melanoma”

“acral lentiginous melanoma”

“hand melanoma”

“foot melanoma”

“plantar melanoma”

“nail melanoma”

“nail apparatus melanoma”

Search databases Pubmed

MEDLINE EMBASE

Google scholar and google for “Acral Melanoma” and “Acral Lentiginous Melanoma”

The references of selected articles will also be hand searched for any relevant studies. There will be no restriction on language.

Searches will be screened based on their title and abstract. The full texts of relevant articles will be read and two reviewers will independently select articles based on the inclusion and exclusion criteria. Any discrepancy will be resolved by a third reviewer. The reference lists of selected articles will be hand searched for any further relevant studies.

Quality assessment

The quality of all selected studies will be evaluated through Newcastle-Ottawa Scale for non-randomized studies and the Cochrane Collaboration Tool for assessing risk of bias in randomized trials.

Data items for extraction Author

Year

Study design

Included patients characteristics

Treatment given (Where separate treatment regimens are given as different treatment arms, list these as separate rows)

Total Melanoma sample size Females in Total Melanoma sample Mean age of Total Melanoma sample

Standard deviation of age of Total Melanoma sample Range of age of Total Melanoma sample

Treatment outcome of Total Melanoma sample (based on RECIST criteria – the following if reported) Complete response for Total Melanoma sample

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Partial response for Total Melanoma sample Stable disease for Total Melanoma sample

Progression-free survival for Total Melanoma sample, including from Kaplan Meier curves Overall survival for Total Melanoma sample, including from Kaplan Meier curves

Acral melanoma (AM) sample size Females in Acral melanoma (AM) sample Mean age of Acral melanoma (AM) sample

Standard deviation of age of Acral melanoma (AM) sample Range of age of Acral melanoma (AM) sample

Treatment outcome of Acral melanoma (AM) (based on RECIST criteria – the following if reported) Complete response for Acral melanoma (AM) sample

Partial response for Acral melanoma (AM) sample Stable disease for Acral melanoma (AM) sample

Progression-free survival for Acral melanoma (AM) sample, including from Kaplan Meier curves Overall survival for Acral melanoma (AM) sample, including from Kaplan Meier curves

Acral Lentiginous melanoma (ALM) sample size Females in Acral Lentiginous melanoma (ALM) sample Mean age of Acral Lentiginous melanoma (ALM) sample

Standard deviation of age of Acral Lentiginous melanoma (ALM) sample Range of age of Acral Lentiginous melanoma (ALM) sample

Treatment outcome of acral lentiginous melanoma (ALM) (based on RECIST criteria – the following if reported)

Complete response for Acral Lentiginous melanoma (ALM) sample Partial response for Acral Lentiginous melanoma (ALM) sample Stable disease for Acral Lentiginous melanoma (ALM) sample

Progression-free survival for Acral Lentiginous melanoma (ALM) sample, including from Kaplan Meier curves

Overall survival for Acral Lentiginous melanoma (ALM) sample, including from Kaplan Meier curves All the above data will be extracted on a standardised excel spreadsheet by two reviewers.

Strategy for data synthesis.

Random-effects model for data analysis based on event rates (ER) and 95% confidence interval (CI). Pooled Kaplan Meier curves will be created. Results will be analysed by location of melanoma (for example acral, mucosal, non-acral cutaneous), and by type of therapy (for example checkpoint inhibitor, KIT-targeted).

Analysis of subgroups or subsets.

Total melanoma, Acral melanoma / Acral Lentiginous melanoma subsets will be analysed. If there are sufficient studies, responses to immunotherapy and targeted therapy will be analysed

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PRISMA 2009 Checklist

Section/topic # Checklist item Reported

on page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both.

1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and

implications of key findings; systematic review registration number.

2

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known.

3

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions,

comparisons, outcomes, and study design (PICOS).

3

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide

registration information including registration number.

eMethods

1

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

3-4

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify

additional studies) in the search and date last searched.

3

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be

repeated.

3

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,

included in the meta-analysis).

3-4

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes

for obtaining and confirming data from investigators.

4

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and

simplifications made.

4

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was

done at the study or outcome level), and how this information is to be used in any data synthesis.

4

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).

4-5

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency

(e.g., I2) for each meta-analysis.

5

Page 1 of 2

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PRISMA 2009 Checklist

Section/topic # Checklist item Reported

on page # Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective

reporting within studies).

5

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating

which were pre-specified.

N/A

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at

each stage, ideally with a flow diagram.

Figure 1

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and

provide the citations.

Table 1

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12).

Table 1

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each

intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

Figures 2-7

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

5-6

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15).

5

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]).

N/A

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to

key groups (e.g., healthcare providers, users, and policy makers).

6-7

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of

identified research, reporting bias).

7

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.

7-8

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the

systematic review.

8

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097.

doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma-statement.org.Page 2 of 2

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eTable 2. Summary of studies for acral melanoma and acral lentiginous melanoma

Study Country Study design (critical appraisal score)*

Sample size

Treatment regime

Therapy type No. with Complete response

No. with Partial response

No.

with Stable disease

No. with Progression of disease

Kaplan Meier curves

Progression free survival (PFS) in months (range)

Overall survival (OS) in months

Bai et al, 2017¹

China Retrospective cohort (good quality)

13 Vemurafenib BRAF-

Targeted therapy

- - - - - 5.4 (3.5-

8.7)

11.7

Carvajal et al, 2011²

USA Phase II

clinical trial (good quality)

8 Imatinib

mesylate

KIT-targeted therapy

1 2 4 1 - -

Guo et al, 2015³

China Prospective cohort (good quality)

16 Nab-paclitaxel and carboplatin

Chemotherapy 0 1 12 3 PFS

OS

6 (1-23) 17

Hodi et al, 2013⁴

USA Phase II

6 Imatinib KIT-targeted

therapy

0 0 2 4 - - 12.9

Kalinksy et al, 2017⁵

USA Phase II

21 Dasatanib KIT-targeted therapy

- - - - PFS

OS

2.8 (1.6- 5.7)

21.1

Kato et al, 2019⁶

Japan Retrospective cohort (good quality)

3 Nivolumab or Pembrolizumab

Checkpoint inhibitor therapy

0 0 1 1 - - -

Kiyohara et al, 2020⁷

Japan Phase IIa clinical trial (good quality)

3 hemagglutinating viral

immunotherapy Viral

immunotherapy

0 0 0 3 - - -

Klemen et al, 2020⁸

USA Retrospective cohort study (good quality)

22 Anti-CTLA-4 and/or Anti-PD-1

- - - - OS - 17

Maeda et al, 2019⁹

Japan Retrospective cohort study (good quality)

16 Nivolumab Checkpoint

inhibitor therapy

0 3 4 9 - - 31.7

Nakamura et al, 2020¹⁰

193 Anti-PD-1 Checkpoint

inhibitor therapy

12 20 60 98 PFS

OS

4.1 18.2

Nathan et al, 2019¹¹

Multicentre European

Phase II clinical trial (good quality)

inhibitor therapy

- - - - OS - 25.8

Shoushtari et al, 2016¹²

USA Retrospective cohort study (good quality)

25 Nivolumab or Pembrolizumab

2 6 7 10 PFS

OS

4.1 -

Si et al, 2019¹³

China Phase Ib clinical trial (good quality)

38 Pembrolizumab Checkpoint inhibitor therapy

0 6 10 18 - - -

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Takahashi et al, 2020¹⁴

6 Nivolumab and Ipilimumab

- - - - PFS

OS

4 Not

reached Tang et al,

2019¹⁵

China Phase I clinical trial (good quality)

13 JS001 (Anti-PD- 1 antibody)

1 2 3 7 - - -

Tang et al.

2020¹⁶

China Phase II clinical trial (good quality)

50 Toripalimab (Anti-PD-1 antibody)

- - - - PFS

OS

3.2 Not

reached Wen et al,

2017a¹⁷

China Retrospective cohort study (good quality)

7 Ipilimumab.

Patients without disease progression received pembrolizumab

0 0 1 6 PFS

OS

- -

Wen et al, 2017b¹⁷

13 Pembrolizumab Checkpoint inhibitor therapy

0 3 2 8 PFS

OS

- -

Wen et al, 2017c¹⁷

2 Ipilimumab and pembrolizumab

1 0 1 0 PFS

OS

- -

Yamazaki et al, 2019¹⁸

Japan Phase II clinical trial (good quality)

inhibitor therapy

- - - - OS - -

Yamazaki et al, 2020¹⁹

94 Ipilimumab Checkpoint

inhibitor therapy

- - - - OS - 7.2

*Clinical appraisal performed using the Newcastle Ottawa Scale converted to Agency for Healthcare Research and Quality standards (good, fair, and poor).

References:

1. Bai X, Si L, Chi Z, et al. Efficacy and tolerability of vemurafenib in BRAF-mutant acral and mucosal melanoma. J Clin Oncol. 2017;35(15 S1).

2. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327-34.

3. Guo Y-q, Ding Y, Li D-d, et al. Efficacy and safety of nab-paclitaxel combined with carboplatin in Chinese patients with melanoma. Med Oncol.

2015;32(9):234.

4. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31(26):3182.

5. Kalinsky K, Lee S, Rubin KM, et al. A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma:

A trial of the ECOG‐ACRIN Cancer Research Group (E2607). Cancer. 2017;123(14):2688-97.

6. Kato J, Hida T, Someya M, et al. Efficacy of combined radiotherapy and anti-programmed death 1 therapy in acral and mucosal melanoma. J

Dermatol. 2019;46(4):328-33.

7. Kiyohara Y, Yoshikawa S, Otsuka M, et al. Melanoma patient response to nivolumab treatment for metastatic lung lesions: Multi-OMICS analysis in

Project HOPE. J Dermatol. 2017;44(10):1156-9.

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8. Klemen ND, Wang M, Rubinstein JC, et al. Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma. J Immunother Cancer. 2020;8(1).

9. Maeda T, Yoshino K, Nagai K, et al. Efficacy of nivolumab monotherapy against acral lentiginous melanoma and mucosal melanoma in Asian patients.

Br J Dermatol. 2019;180(5):1230-1.

10. Nakamura Y, Namikawa K, Yoshino K, et al. Anti-PD1 checkpoint inhibitor therapy in acral melanoma: A multicentre study of 193 Japanese patients.

Ann Oncol. 2020.

11. Nathan P, Ascierto PA, Haanen J, et al. Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172). Eur J Cancer. 2019;119:168-78.

12. Shoushtari AN, Munhoz RR, Kuk D, et al. The efficacy of anti‐PD‐1 agents in acral and mucosal melanoma. Cancer. 2016;122(21):3354-62.

13. Si L, Zhang X, Shu Y, et al. A phase Ib study of pembrolizumab as second-line therapy for Chinese patients with advanced or metastatic melanoma (KEYNOTE-151). Transl Oncol. 2019;12(6):828-35.

14. Takahashi A, Namikawa K, Ogata D, et al. Real‐world efficacy and safety data of nivolumab and ipilimumab combination therapy in Japanese patients with advanced melanoma. J Dermatol. 2020.

15. Tang B, Yan X, Sheng X, et al. Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol. 2019;12 (1).

16. Tang B, Chi Z, Chen Y-B, et al. Safety, Efficacy and Biomarker Analysis of Toripalimab in previously treated advanced melanoma: results of the POLARIS-01 multicenter phase II trial. Clin Cancer Res. 2020.

17. Wen X, Ding Y, Li J, et al. The experience of immune checkpoint inhibitors in Chinese patients with metastatic melanoma: a retrospective case series.

Cancer Immunol Immunother. 2017;66(9):1153-62.

18. Yamazaki N, Kiyohara Y, Uhara H, et al. Long‐term follow up of nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma. Cancer Sci. 2019;110(6):1995.

19. Yamazaki N, Kiyohara Y, Uhara H, et al. Real‐world safety and efficacy data of ipilimumab in Japanese radically unresectable malignant melanoma

patients: A postmarketing surveillance. J Dermatol. 2020.

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eFigure 1. Flow Diagram of Preferred Reporting Items for Systematic Reviews and Meta-analyses for the Systematic Literature Search

Records identified through database searching

(n = 5746)

Records after duplicates removed (n = 4601)

Records screened (n = 4601)

Records excluded on basis of title and abstract with

reasons (n = 4477)



Guideline



Comment



No inclusion of acral melanoma



Review



Case reports



Not relating to metastatic disease



Not relating to treatment Full-text articles assessed

for eligibility (n = 124)

Full-text articles excluded, with reasons

(n = 105)



Treatment outcomes of acral melanoma subset not reported Studies included in

quantitative synthesis (meta-analysis)

(n = 19)

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eFigure 2. Pooled Kaplan Meier – Progression free survival (PFS) of different melanoma subtypes

P values were calculated using the log-rank test. Crosses indicate censored events.

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eFigure 3:

Study-specific and meta-analysis of event rate to systemic therapy (a) complete response; (b) partial response; (c) stable disease; (d) progressive disease

a

b

c

Study name Statistics for each study Event rate and 95% CI Event Lower Upper

rate limit limit p-Value Carvajal et al. 2011 0.125 0.017 0.537 0.069 Guo et al. 2015 0.029 0.002 0.336 0.015 Hodi et al. 2013 0.071 0.004 0.577 0.081 Kato et al. 2019 0.125 0.007 0.734 0.198 Kiyohara et al. 2020 0.125 0.007 0.734 0.198 Maeda et al. 2019 0.029 0.002 0.336 0.015 Nakamura et al 2020 0.063 0.036 0.108 0.000 Shoushtari et al 2016 0.080 0.020 0.269 0.001 Si et al 2019 0.014 0.001 0.191 0.003 Tang et al 2019 0.077 0.011 0.391 0.017 Wen et al. 2017a 0.063 0.004 0.539 0.064 Wen et al. 2017b 0.036 0.002 0.384 0.022 Wen et al. 2017c 0.500 0.059 0.941 1.000 0.068 0.045 0.103 0.000

-1.00 -0.50 0.00 0.50 1.00

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d

-1.00 -0.50 0.00 0.50 1.00

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eFigure 4:

Study-specific and meta-analysis of event rate to anti-PD-1 therapy (a) complete response; (b) partial response; (c) stable disease; (d) progressive disease

a

b

C

d

rate limit limit p-Value Kato et al. 2019 0.125 0.007 0.734 0.198 Maeda et al. 2019 0.029 0.002 0.336 0.015 Nakamura et al 2020 0.063 0.036 0.108 0.000 Shoushtari et al 2016 0.080 0.020 0.269 0.001 Si et al 2019 0.014 0.001 0.191 0.003 Tang et al 2019 0.077 0.011 0.391 0.017 Wen et al. 2017b 0.036 0.002 0.384 0.022 0.062 0.039 0.097 0.000

-1.00 -0.50 0.00 0.50 1.00

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-1.00 -0.50 0.00 0.50 1.00