University Hospital Zürich Skin Cancer Center, Zürich, Switzerland.
Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale," Naples, Italy.
JAMA Oncol. 2020 Dec 1;6(12):1957-1966. doi: 10.1001/jamaoncol.2020.4401.
In recent years, the management of metastatic melanoma has been transformed by the emergence of immune checkpoint inhibitors and targeted therapies that significantly improve patient survival. The complementary response kinetics of these treatment approaches, supported by mechanistic evidence that targeted therapy affects immune aspects of the tumor microenvironment, suggest that the optimal combination or sequencing of immune checkpoint inhibitors and targeted therapy may provide additional clinical benefit.
Clinical responses to BRAF and/or MEK inhibitors are associated with immune changes within the tumor microenvironment that have the potential to increase the sensitivity of BRAF V600-mutant melanoma to immune checkpoint inhibitors. The combination of immune checkpoint inhibitors with targeted therapy may therefore increase duration of response, improve tumor control, extend survival, and increase the proportion of patients experiencing durable benefit. A targeted therapy-immune checkpoint inhibitor sequencing approach may also be supported by this evidence, but clinical questions regarding optimal timing, duration, and patient selection remain.
This review outlines the rationale and preclinical evidence that support immune checkpoint inhibitor plus targeted therapy combination and sequencing strategies in melanoma and highlights the results available to date from clinical trials exploring these approaches to treatment. Several late-stage trials are under way looking to answer open questions in this field and address the continuing debate surrounding up-front combination vs sequencing. As phase 3 data have begun to emerge, trial designs and available data from key studies are discussed in the context of their resultant implications for clinical practice.
近年来，免疫检查点抑制剂和靶向治疗的出现改变了转移性黑色素瘤的治疗方法，显著提高了患者的生存率。这些治疗方法的互补反应动力学，以及靶向治疗影响肿瘤微环境免疫方面的机制证据表明，免疫检查点抑制剂和靶向治疗的最佳组合或序贯治疗可能提供额外的临床获益。
BRAF 和/或 MEK 抑制剂的临床反应与肿瘤微环境中的免疫变化相关，这些变化有可能增加 BRAF V600 突变黑色素瘤对免疫检查点抑制剂的敏感性。因此，免疫检查点抑制剂与靶向治疗的联合可能会延长反应持续时间、改善肿瘤控制、延长生存时间，并增加经历持久获益的患者比例。这种证据也支持靶向治疗-免疫检查点抑制剂序贯治疗方法，但关于最佳时机、持续时间和患者选择的临床问题仍然存在。
本文综述了支持黑色素瘤免疫检查点抑制剂联合靶向治疗联合和序贯策略的原理和临床前证据，并重点介绍了迄今为止探索这些治疗方法的临床试验结果。目前正在进行几项后期试验，旨在回答该领域的未决问题，并解决围绕一线联合治疗与序贯治疗的持续争论。随着 3 期数据的陆续出现，本文讨论了试验设计和关键研究的现有数据，以及它们对临床实践的影响。
