Jiaran Zhang,Lu Si,Jun Guo

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Department of Melanoma ＆amp;Sarcoma,Peking University Cancer Hospital ＆amp;Institute,Beijing 100142,China

Melanoma remains a rare malignant tumor with high mortality and increasing incidence in China.Due to ethnic characteristics,acral and mucosal melanomas are the predominant subtypes in Asia,many research advances have been made in melanoma these years,especially for these two subtypes.In keeping with the development of key research on melanoma,the National Health Commission of the People’s Republic of China organized experts to revise the Chinese guidelines for diagnosis and treatment of melanoma in 2021,and theNational guidelines for diagnosis and treatment of melanoma 2022 in China (English version)was also updated (1).The prior English version was published in 2019 (2),the 2022 English version was updated with new evidence-based recommendations,aiming to provide the latest evidence updates and share the diagnosis and treatment of melanoma in China.Changes mainly include the treatment of patients with positive sentinel lymph nodes and the systemic treatment of advanced melanoma in different primaries.

Management of melanoma patients with regional lymph nodes has evolved dramatically in recent years,some clinical trials are now available to guide treatment decisions.Evidence showed that immediate complete lymph node dissection (CLND) is not necessary for patients with positive sentinel lymph node (SLN),nodal ultrasound monitoring is recommended until regional nodal metastases confirmed.MSLT-II trial compared CLND with observation after positive sentinel node biopsy.There was a small but significant difference in disease-free survival (DFS) [(68±1.7)% and (63±1.7)%,respectively,P=0.05),however,there was no difference in 3-year melanoma specific survival [(86±1.3)% and(86±1.2)%,respectively,P=0.42).Although CLND did not improve prognosis in MSLT-II population,the trial demonstrated that immediate CLND increased disease control rate (DCR) in regional lymph node,and providing staging information.

Based upon improved knowledge of molecular mechanism and tumor microenvironment of melanoma,a real revolution has taken place in treatment.Besides chemotherapy,two new classes of systemic therapeutic agents are now available for advanced melanoma,immunotherapy (anti-PD-1 antibodies: pembrolizumab,toripalimab) and targeted therapy (BRAF/MEK inhibitors).Two clinical trials provide the evidence base for anti-PD-1 antibodies used in treatment of melanoma in China.Keynote-151 was the first clinical trial to evaluate pembrolizumab in Chinese melanoma patients,promoting the approval of pembrolizumab in China.In Keynote-151,patients (37.9% had acral melanoma and 14.6% had mucosal melanoma) who underwent first-line therapy received pembrolizumab as second line,DCR was 38.2%,overall response rate (ORR) was 15.8% for acral melanoma,13.3% for mucosal melanoma.Median duration of response (mDOR) was 8.4 months,median progressionfree survival (mPFS) was 2.8 months,and median overall survival (mOS) was 12.1 months.Meanwhile,in POLARIS-01 trial,toripalimab was tested in 127 advanced melanoma patients (50 acral and 22 mucosal melanoma),ORR was 17.3%,DCR was 57.5%,and mOS benefit was 22.2 months.These data suggest anti PD-1/PD-L1 therapy demonstrated great efficacy and safety in advanced melanoma,even in Chinese patients who have more aggressive melanoma subtypes than other populations.Targeted therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib also showed an improved survival.A phase II trial led by Dr.Guo of Peking University Cancer Hospital ＆amp;Institute proved dabrafenib plus trametinib effectiveness in treating melanoma (ORR was 65.9% and PFS was 10.3 months),and confirmed the results of D+T regimen in Chinese patients,which was in consistent with international researches.Dabrafenib combined with trametinib for BRAF V600 mutationpositive advanced melanoma was approved in China in 2019,and also approved for adjuvant therapy in stage IIIBRAF-mutated melanoma.

Melanoma has four main subtypes with distinct molecular signatures,treatment decisions need to be guided based on different primaries.Mucosal melanoma typically responds worse to the therapy approved for the more common,and our research data demonstrated antitumor activity of the combination of VEGF inhibition and PD-1 blockade in patients with metastatic mucosal melanoma.Axitinib in combination with toripalimab was tested in a phase I trial on 29 treatment-na?ve advanced mucosal melanoma patients,showing an improved response with an ORR of 48.3% and DCR of 82.6%,the mPFS was 7.5 months,and the mOS was 12.7 months.Anti-PD-1/PD-L1 combined with anti-angiogenic drugs is expected to become the standard regimen in the future.Prognosis for patients with acral melanoma is also poor,anti-PD-1/PD-L1 monotherapy is less effective in acral melanoma,combination therapy is supposed to be a promising strategy,clinical trials directed at acral melanoma is ongoing.Uveal melanoma is usually associated with poor prognosis,there is little evidence for the optimal treatment of advanced uveal melanoma.Once uveal melanoma becomes metastatic,therapy options are limited.For uveal melanoma with liver metastasis,a combination of chemotherapy with hepatic arterial chemoembolization is used,immunotherapy has low response here.Standard and effective therapy strategies for uveal melanoma are still lacking,newer treatments should be explored.

In short,this revised English version guidelines provide the least evidence updates at various levels including diagnosis,staging and treatment,especially for the predominant subtypes acral and mucosal melanoma in Chinese patients,highlighting key points and new recommendations from the latest trials.The aim of this work is to promote international communication between China and overseas for melanoma patients,and help direct standardized melanoma diagnosis and treatments.

Acknowledgements

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Conflicts of Interest: The authors have no conflicts of interest to declare.