Ⅲ期黑色素瘤围手术期治疗的现状与展望

doi:10.19401/j.cnki.1007-3639.2022.12.001

中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (12): 1133-1146.doi: 10.19401/j.cnki.1007-3639.2022.12.001

Ⅲ期黑色素瘤围手术期治疗的现状与展望

徐宇¹(), 陈勇¹, 杨吉龙²^,³, 朱冠男⁴()

1.复旦大学附属肿瘤医院骨软组织外科，复旦大学上海医学院肿瘤学系，上海 200032
2.天津医科大学肿瘤医院骨与软组织肿瘤科，国家恶性肿瘤临床医学研究中心，天津 300060
3.天津市恶性肿瘤临床医学研究中心，天津市肿瘤防治重点实验室，天津市肿瘤分子流行病重点实验室，天津 300060
4.空军军医大学（第四军医大学）西京皮肤医院，陕西西安 710032

收稿日期:2022-11-22 修回日期:2022-12-27 出版日期:2022-12-30 发布日期:2023-02-02
通信作者: 朱冠男（ORCID: 0000-0002-2980-0074），副主任医师。
作者简介:徐宇（ORCID：0000-0002-0894-5311），副主任医师。
朱冠男，医学博士，副主任医师，硕士生导师。现任空军军医大学（第四军医大学）西京医院皮肤科性病真菌中心主任，中国抗癌协会黑色素瘤专业委员会常务委员兼秘书长，中国指南科学性、透明性和适用性评级（STAR）皮肤科专业委员会副主任委员，陕西省医师协会皮肤科医师分会青年委员会副主任委员，中国医师协会皮肤科医师分会自身免疫病学组委员，欧洲化脓性汗腺炎基金会（EHSF）成员。主持国家自然科学基金2项，军队人才项目基金1项；以第一作者及通信作者在SCI收录期刊上发表论文20余篇，其中多篇发表在Journal of Investigative Dermatology、Autophagy、Journal of Allergy and Clinical Immunology、Cancer Letters等业内顶尖期刊。
基金资助:
国家自然科学基金(82172607);国家自然科学基金(82272857);国家自然科学基金(81802636);临港实验室基金(LG-QS-202205-11);上海市科学技术委员会科研计划(19411951700)

Current status and prospect of perioperative treatment of stage Ⅲ melanoma

XU Yu¹(), CHEN Yong¹, YANG Jilong²^,³, ZHU Guannan⁴()

1. Department of Musculoskeletal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
2. Departments of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China
3. Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Molecular Cancer Epidemiology, Tianjin 300060, China
4. Department of Dermatology, Xijing Hospital, Air Force Military Medical University (Fourth Military Medical University), Xi’an 710032, Shaanxi Province, China

Received:2022-11-22 Revised:2022-12-27 Published:2022-12-30 Online:2023-02-02
Contact: ZHU Guannan

摘要/Abstract

摘要：

黑色素瘤是一种恶性程度极高的肿瘤，早期黑色素瘤经手术切除多可治愈，但对于高危型病例（ⅡB~Ⅳ期），辅助治疗是延长患者生命、改善预后的重要手段。近年来随着系统治疗药物的蓬勃发展，对于Ⅲ期可切除病例的围手术期治疗理念不断发生变化。本文着眼于外科手术规范及对预后的影响、术后辅助治疗选择、新辅助治疗的进展等热点问题进行梳理，并结合来源于中国患者的治疗数据进行分析讨论，希望为中国Ⅲ期黑色素瘤的围手术期治疗选择提供新的思路。

关键词: 黑色素瘤, 围手术期治疗, 辅助治疗, 新辅助治疗

Abstract:

Melanoma is one of the most dangerous tumors due to its high-grade malignancy. Though patients in early stage can be completely cured by surgery, for high-risk cases (stage ⅡB-Ⅳ), adjuvant therapy is of great importance to prolong the survival and improve the prognosis. In recent years, thanks to the booming development of systemic regimen, the perioperative managements for stage Ⅲ cases have been continuously evolving. In the current paper, we focused on the role of lymph node biopsy and surgical resection, postoperative adjuvant therapy options, as well as the cutting-edge neoadjuvant therapy development, aiming to provide new perioperative strategies for stage Ⅲ melanoma patients.

Key words: Melanoma, Perioperative treatment, Adjuvant therapy, Neoadjuvant therapy

中图分类号:

R739.5

徐宇, 陈勇, 杨吉龙, 朱冠男. Ⅲ期黑色素瘤围手术期治疗的现状与展望[J]. 中国癌症杂志, 2022, 32(12): 1133-1146.

XU Yu, CHEN Yong, YANG Jilong, ZHU Guannan. Current status and prospect of perioperative treatment of stage Ⅲ melanoma[J]. China Oncology, 2022, 32(12): 1133-1146.

图/表 1

表1

正在进行的Ⅲ期恶性黑色素瘤新辅助治疗研究汇总"

NCT No.	Title	Research status	Treatment method	Main outcome indicators
NCT04207086	A phase Ⅱ study of neoadjuvant pembrolizumab and lenvatinib for resectable stage Ⅲ melanoma (Neo PeLe)	Active, not recruiting	Pembrolizumab+lenvatinib 6 weeks; Surgery; Pembrolizumab 46 weeks	① pCR rate; ② Anti-tumor immune response
NCT03842943	Neoadjuvant combination immunotherapy for stage Ⅲ melanoma	Recruiting	Talimogene laherparepvec (T-VEC)+ pembrolizumab before surgery, T-VEC is injected into the palpable lymph node once every 3 weeks for 6 months or until the target lesion is completely relieved; Pembrolizumab was used once every 3 weeks for 6 consecutive months and continued to be used for 1 year after operation	pCR rate
NCT04330430	Neo-adjuvant T-VEC+nivolumab combination therapy for resectable early metastatic (stage ⅢB/C/D-Ⅳ M_1a) melanoma with injectable disease (NIVEC)	Recruiting	T-VEC+nivolumab before surgery	pCR rate
NCT04331093	Neoadjuvant SHR-1210 plus apatinib for resectable stage Ⅲ-Ⅳ acral melanoma	Recruiting	SHR-1210+apatinib before surgery	pCR rate
NCT03618641	CMP-001 in combination with nivolumab in stage ⅢB/C/D melanoma patients with clinically apparent lymph node disease	Active, not recruiting	Nivolumab+CMP-001 before surgery	mpCR rate
NCT04197882	Clinical study to evaluate OrienX010 in combination with toripalimab as neoadjuvant treatment in advanced melanoma	Active, not recruiting	OrienX010+toripalimab before surgery, toripalimab after surgery	pCR rate
NCT05176470	Neoadjuvant admin autologous tumor infiltrating lymphocytes and pembrolizumab for treatment of advanced melanoma patients	Recruiting	Pembrolizumab+cyclophosphamide+ fludarabine before surgery, pembrolizumab after surgery	① Feasibility of MK-3475 and LN-144/Lifileucel as neoadjuvant therapy in patients with ⅢB-D melanoma; ② Incidence rate of grade 3 and above adverse reactions (immune-related and unrelated)
NCT04949113	Neoadjuvant ipilimumab plus nivolumab versus standard adjuvant nivolumab in macroscopic stage Ⅲ melanoma (NADINA)	Recruiting	Trial group: Neoadjuvant ipilimumab+ nivolumab after surgery; Control group: Nivolumab after surgery	EFS
NCT04139902	Neoadjuvant PD-1 inhibitor dostarlimab (TSR-042) vs combination of Tim-3 inhibitor cobolimab (TSR-022) and PD-1 inhibitor dostarlimab (TSR-042) in melanoma (Neo-MEL-T)	Recruiting	Trial group: Dostarlimab (TSR-042) before surgery combined TSR-022; Control group: Dostarlimab (TSR-042)	mpCR rate
NCT04708418	A study evaluating whether pembrolizumab alone or in combination with CMP-001 improves efficacy in patients with operable melanoma	Recruiting	Group 1: Pembrolizumab before surgery，pembrolizumab after surgery; Group 2: CMP-001+ pembrolizumab before surgery, pembrolizumab after surgery	pCR rate
NCT03698019	A study to compare the administration of pembrolizumab after surgery versus administration both before and after surgery for high-risk melanoma	Active, not recruiting	Control group: Pembrolizumab after surgery; Trial group: Pembrolizumab before surgery+pembrolizumab after surgery	EFS
NCT03567889	Efficacy of daromun neoadjuvant intratumoral treatment in clinical stage ⅢB/C melanoma patients (NeoDREAM)	Recruiting	Trial group: Daromun before surgery+ postoperative adjuvant therapy; Control group: Postoperative adjuvant therapy	RFS
NCT02938299	Neoadjuvant L19IL2/L19TNF-pivotal study	Recruiting	Trial group: Neoadjuvant therapy L19IL2/L19TNF+surgery; Control group: Surgery	RFS rate
NCT04401995	Study of TLR9 agonist vidutolimod (CMP-001) in combination with nivolumab vs nivolumab	Recruiting	Trial group 1: Nivolumab+vidutolimod (CMP-001) + [¹⁸F]F-AraG PET/CT; Trial group 2: Nivolumab+ [¹⁸F]F-AraG PET/CT	mpCR rate
NCT03554083	NeoACTIVATE: Neoadjuvant therapy for patients with high risk stage Ⅲ melanoma	Recruiting	Trial group 1: Before surgery, vemurafenib +cobimetinib+atezolizumab; Trial group 2: Before surgery, cobimetinib+ atezolizumab; Trial group 3: Before surgery, atezolizumab+tiragolumab	① pCR rate of stage Ⅲ BRAF mutation patients (neoadjuvant therapy); ② pCR rate of stage Ⅲ BRAF wild type patients (neoadjuvant therapy); ③ Median RFS (adjuvant therapy)
NCT02977052	Optimal neoadjuvant combination scheme of ipilimumab and nivolumab	Active, not recruiting	Trial group 1: Before surgery, ipilimumab 3 mg/kg+nivolumab 1 mg/kg; Trial group 2: Before surgery, ipilimumab 1 mg/kg+nivolumab 3 mg/kg; Trial group 3: Before surgery, ipilimumab 3 mg/kg+nivolumab 3 mg/kg	① Immune-related advers effects; ② Response rate (RECIST 1.1) ③ pCR rate; ④ The draining lymph node reaches pCR or npCR; ⑤ Or npCR, and 24-month RFS rate of patients who did not receive CLND; ⑥ No pCR, nivolumab after surgery+radiotherapy/BRAF^V600E mutation patients recedved dabrafenib+trametinib for 24 months, RFS rate
NCT04133948	Multicenter phase 1b trial testing the neoadjuvant combination of domatinostat, nivolumab and ipilimumab in IFN-gamma signature-low and IFN-gamma signature-high RECIST 1.1-measurable stage Ⅲ cutaneous or unknown primary melanoma (DONIMI)	Active, not recruiting	Trial group 1: High IFN-gamma level, nivolumab before surgery; Trial group 2:High IFN-gamma level, nivolumab+domatinostat before surgery; Trial group 3: Low IFN-gamma level, nivolumab+domatinostat before surgery; Trial group 4: Low IFN-gamma level, nivolumab+ipilimumab+domatinostat before surgery	① Security (measured by complying with the time design in the research scheme); ② Scheme feasibility is measured by complying with the time design in the research scheme)
NCT04303169	Substudy 02C: safety and efficacy of pembrolizumab in combination with investigational agents or pembrolizumab alone in participants with stage Ⅲ melanoma who are candidates for neoadjuvant therapy (MK-3475-02C/KEYMAKER-U02)	Recruiting	Group 1: Pembrolizumab+vibostolimab before surgery, pembrolizumab after surgery; Group 2:Pembrolizumab+V937 before surgery, pembrolizumab after surgery; Group 3: Pembrolizumab before surgery, pembrolizumab after surgery; Group 4: Pembrolizumab+MK-4830 before surgery, pembrolizumab after surgery; Group 5: Favezelimab+pembrolizumab before surgery, pembrolizumab after surgery; Group 6: Pembrolizumab+all-trans retinoic acid (ATRA) before surgery, pembrolizumab after surgery	① Adverse reaction; ② Proportion of patients who stopped the study due to adverse reaction; ③ pCR rate
NCT03769155	VX15/2503 with or without ipilimumab and/or nivolumab in patients with resectable stage ⅢB-D melanoma	Recruiting	Trial group 1: VX15/2503+nivolumab before surgery +surgery; Trial group 2: VX15/2503+ipilimumab before surgery +surgery; Trial group 3: VX15/2503+nivolumab +ipilimumab before surgery+surgery; Trial group 4: Nivolumab before surgery+surgery Control group: Surgery	Analysis of biomarker parameters: infiltration degree of CD8⁺T cells
NCT02231775	Dabrafenib and trametinib before and after surgery in treating patients with stage ⅢB-C melanoma with BRAF ^V600 mutation	Recruiting	Treatment (dabrafenib, trametinib and surgery); Neoadjuvant therapy (dabrafenib+ trametinib)+surgery; 1 week after surgery. If no disease progression or unacceptable toxicity occurred, continue dabrafenib+trametinib for 44 weeks	RFS
NCT01972347	Neoadjuvant dabrafenib+ trametinib for AJCC stage ⅢB-C BRAF^V600 mutation positive melanoma	Active, not recruiting	Dabrafenib+trametinib before surgery	After 12 weeks of neoadjuvant therapy, proportion of surviving melanoma tissues in lymph nodes or metastatic tumor tissues compared with baseline
NCT04310397	Dabrafenib, trametinib, and spartalizumab for the treatment of BRAF^V600E or BRAF^V600K mutation positive stage ⅢB/C/D melanoma (Neo PeLe)	Active, not recruiting	Single arm study: Neoadjuvant therapy dabrafenib+trametinib, pCR patients after surgery could be treated with dabrafenib+trametinib; non-pCR patients treated with spartalizumab+dabrafenib+ trametinib	RFS rate
NCT04221438	A phase Ⅱ neoadjuvant study of encorafenib with binimetinib in patients with resectable locoregional metastases from cutaneous or unknown primary melanoma (stage Ⅲ N₁B/C/D)	Recruiting	¹⁸F-FLT+encorafenib+binimetinib before surgery, encorafenib+binimetinib after surgery	① pCR rate; ② ¹⁸F-FLT PET/CT intake changes from baseline after 2 cycles of neoadjuvant therapy
NCT02858921	Neoadjuvant dabrafenib, trametinib and/or pembrolizumab in BRAF mutant resectable stage Ⅲ melanoma (Neo Trio)	Active, not recruiting	Group 1: Dabrafenib+trametinib, pembrolizumab sequential therapy; Dabrafenib 150 mg orally, bid+trainenib 2 mg, qd, 1 week; Pembrolizumab (2 mg/kg) was then injected intravenously at weeks 1, 3 and 6; Surgery; Pembrolizumab (2 mg/kg) every 3 weeks from the 6th week, for 46 weeks; Group 2: Dabrafenib+trametinib, combined with pembrolizumab; Dabrafenib 150 mg orally, bid+trametinib 2 mg orally, qd+pembrolizumab 200 mg iv, every 3 weeks for 6 weeks, surgery, pembrolizumab 46 weeks after surgery; Group 3: Pembrolizumab; Pembrolizumab 200 mg iv, once every 3 weeks, surgery at the 6th week, and continue to use until the 52nd week	pCR rate treated for 6 weeks
NCT05097378	Perioperative encobini in BRAF^V600 mutant stage Ⅲ (B/C/D) or oligometastatic stage Ⅳ melanoma (PREMIUM)	Not yet recruiting	Group 1: Before surgery, encorafeni+ binimetinib 8 weeks; Surgery; Encorafeni+binimetinib 44 weeks; Group 2: Surgery+the standard adjuvant treatment method selected by the researchers after surgery	pCR rate

表1

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Ⅲ期黑色素瘤围手术期治疗的现状与展望

Current status and prospect of perioperative treatment of stage Ⅲ melanoma

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