晚期转移性黑色素瘤患者的生存：MAP 激酶通路抑制和免疫检查点抑制的影响-2019 年更新。

Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019.

机构信息

Department of Dermatology, University Hospital Essen, University of Duisburg-Essen & German Cancer Consortium Heidelberg, Germany.

Bremen, Germany.

出版信息

Eur J Cancer. 2020 May;130:126-138. doi: 10.1016/j.ejca.2020.02.021. Epub 2020 Mar 13.

DOI:10.1016/j.ejca.2020.02.021

PMID:32179447

Abstract

BACKGROUND

Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanoma patients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking.

METHODS

We performed an exploratory analysis of survival data from selected clinical trials representative for these two treatment strategies in advanced metastatic melanoma. 84 Kaplan-Meier survival curves from 26 trials were digitised and grouped by therapy strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging.

RESULTS

Survival curves grouped together by therapy strategy revealed a high concordance, with a larger extent in the first-line setting compared to higher treatment lines. In first-line therapy, the averaged 3-year OS proportions were 41.3% for BRAF plus MEK inhibition, 49.9% for PD-1 inhibition, and 58.4% for CTLA-4 plus PD-1 inhibition. Comparison of the mean PFS and OS curves of kinase inhibition and checkpoint blockade revealed a superiority of combined BRAF plus MEK inhibition within the first 12 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockade. In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years; averaged 3-year OS proportions were 42.4% for BRAF plus MEK inhibition, and 40.1% for PD-1 inhibition.

CONCLUSIONS

and relevance: These results need confirmation by head-to-head comparative randomised clinical trials.

摘要

背景

近年来，特别是 MAP 激酶通路抑制剂（BRAF、MEK）和免疫检查点抑制剂（CTLA-4、PD-1）的治疗策略已被应用于测试，以观察其对转移性黑色素瘤患者长期生存的差异影响。在这两种治疗组中，各种药物、剂量方案和联合方案已被广泛研究。然而，关于这两种策略相互比较的前瞻性头对头比较试验的结果仍然缺乏。

方法

我们对代表这两种治疗策略的晚期转移性黑色素瘤的选定临床试验的生存数据进行了探索性分析。从 26 项试验中数字化了 84 个 Kaplan-Meier 生存曲线，并按治疗策略和治疗线进行分组。对于这些组中的每一组，通过加权平均生成无进展生存期（PFS）和总生存期（OS）的平均生存曲线。

结果

按治疗策略分组的生存曲线显示出高度一致性，在一线治疗中比在更高线治疗中更为显著。在一线治疗中，BRAF 加 MEK 抑制的平均 3 年 OS 比例为 41.3%，PD-1 抑制为 49.9%，CTLA-4 加 PD-1 抑制为 58.4%。激酶抑制和检查点阻断的平均 PFS 和 OS 曲线的比较显示，在最初的 12 个月内，联合 BRAF 加 MEK 抑制具有优越性，之后单独或联合使用 PD-1 阻断剂具有优越性。在二线或更高线治疗中，BRAF 加 MEK 抑制在头三年中优于抗 PD-1 单药治疗；BRAF 加 MEK 抑制的平均 3 年 OS 比例为 42.4%，PD-1 抑制为 40.1%。