Melanoma treatment is leading the neo-adjuvant systemic (NAS) therapy field. It is hypothesized that having the entire tumor in situ, with all of the heterogeneous tumor antigens, allows the patient’s immune system to have a broader response to the tumor in all its shapes and forms. This translates into a higher clinical efficacy. Another benefit of NAS therapy potentially includes identifying patients who have a favorable response, which could offer an opportunity for the de-escalation of the extent of surgery and the need for adjuvant radiotherapy and/or adjuvant systemic therapy, as well as tailoring the follow-up in terms of the frequency of visits and cross-sectional imaging. In this paper, we will review the rationale for NAS therapy in resectable metastatic melanoma and the results obtained so far, both for immunotherapy and for BRAF/MEKi therapy, and discuss the response assessment and interpretation, toxicity and surgical considerations. All the trials that have been reported up to now have been investigator-initiated phase I/II trials with either single-agent anti-PD-1, combination anti-CTLA-4 and anti-PD-1 or BRAF/MEK inhibition. The results have been good but are especially encouraging for immunotherapies, showing high durable recurrence-free survival rates. Combination immunotherapy seems superior, with a higher rate of pathologic responses, particularly in patients with a major pathologic response (MPR = pathologic complete response [pCR] + near-pCR [max 10% viable tumor cells]) of 60% vs. 25–30%. The SWOG S1801 trial has recently shown a 23% improvement in event-free survival (EFS) after 2 years for pembrolizumab when giving 3 doses as NAS therapy and 15 as adjuvant versus 18 as adjuvant only. The community is keen to see the first results (expected in 2024) of the phase 3 NADINA trial (NCT04949113), which randomized patients between surgery + adjuvant anti-PD-1 and two NAS therapy courses of a combination of ipilimumab + nivolumab, followed by surgery and a response-driven adjuvant regimen or follow-up. We are on the eve of neo-adjuvant systemic (NAS) therapy, particularly immunotherapy, becoming the novel standard of care for macroscopic stage III melanoma.
黑色素瘤治疗正引领新辅助系统治疗领域的发展。其理论基础在于，保留完整的原位肿瘤及其所有异质性肿瘤抗原，可使患者免疫系统对肿瘤产生更广泛、更全面的应答，从而转化为更高的临床疗效。新辅助系统治疗的潜在优势还包括：识别治疗反应良好的患者，为降低手术范围、减少辅助放疗和/或辅助系统治疗需求提供可能，并可根据个体反应调整随访频率和影像学检查方案。本文综述了可切除转移性黑色素瘤新辅助系统治疗的理论依据，系统梳理了免疫治疗及BRAF/MEK抑制剂治疗已取得的成果，并就疗效评估与解读、毒性反应及手术考量展开讨论。目前所有已报道的试验均为研究者发起的I/II期研究，涉及单药抗PD-1治疗、抗CTLA-4联合抗PD-1治疗或BRAF/MEK抑制剂治疗。结果显示疗效良好，其中免疫治疗尤其令人鼓舞，展现出较高的持久无复发生存率。联合免疫治疗似乎更具优势，其病理缓解率更高，特别是在主要病理缓解患者中（MPR=病理完全缓解[pCR]+近完全缓解[存活肿瘤细胞≤10%]）达到60%，而单药治疗仅为25-30%。SWOG S1801试验最新数据显示，帕博利珠单抗采用3周期新辅助治疗联合15周期辅助治疗的方案，较单纯18周期辅助治疗在2年无事件生存率上提升23%。学界正密切关注III期NADINA试验的首批结果（预计2024年公布），该试验将患者随机分配至手术联合辅助抗PD-1治疗组，或伊匹木单抗联合纳武利尤单抗双周期新辅助治疗后手术、再根据反应决定辅助治疗方案或随访观察组。我们正处在新辅助系统治疗（特别是免疫治疗）即将成为宏观III期黑色素瘤全新标准治疗模式的前夜。
肿瘤(癌症)患者之家