脑转移和一线治疗后转移性黑色素瘤的生存结局：前瞻性皮肤癌登记处 ADOREG 对 1704 例患者的多中心 DeCOG 研究。

Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG.

机构信息

Department of Dermatology and Venereology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIO ABCD), Cologne, Germany.

出版信息

J Immunother Cancer. 2023 Apr;11(4). doi: 10.1136/jitc-2022-005828.

DOI:10.1136/jitc-2022-005828

PMID:37028819

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10083858/

Abstract

BACKGROUND

Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.

METHODS

Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).

RESULTS

Of 1704 patients, 916 were BRAF wild-type (BRAF) and 788 were BRAF V600 mutant (BRAF). Median follow-up time after start of 1L-therapy was 40.4 months. BRAF patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAF patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAF patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAF patients. In BRAF patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAF patients. For BRAF patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.

CONCLUSIONS

In BRAF patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAF patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

摘要

背景

尽管有有效的全身治疗方法，但仍有相当数量的晚期黑色素瘤患者会发生脑转移。本研究调查了根据一线治疗类型，脑转移的发生率、诊断时间和生存结果的差异。

方法

从前瞻性多中心真实世界皮肤癌登记处 ADOREG 中确定了在开始一线治疗（1L-therapy）时无脑转移的转移性、不可切除的黑色素瘤（AJCCv8 分期 IIIC-V）患者。研究终点为脑转移的发生率、脑转移无进展生存期（BMFS）、无进展生存期（PFS）和总生存期（OS）。

结果

在 1704 名患者中，916 名是 BRAF 野生型（BRAF），788 名是 BRAF V600 突变型（BRAF）。1L-therapy 后中位随访时间为 40.4 个月。BRAF 患者接受了免疫检查点抑制剂（ICI）联合 CTLA-4+PD-1（n=281）或 PD-1（n=544）作为 1L-therapy。在 BRAF 患者中，1L-therapy 中有 415 名患者接受了 ICI（CTLA-4+PD-1，n=108；PD-1，n=264），373 名患者接受了 BRAF+MEK 靶向治疗（TT）。在 24 个月后，与 PD-1±CTLA-4 相比，BRAF+MEK 的 1L-therapy 导致脑转移的发生率更高（BRAF+MEK，30.3%；CTLA-4+PD-1，22.2%；PD-1，14.0%）。多变量分析显示，与 PD-1±CTLA-4 相比，BRAF 患者在接受 BRAF+MEK 的 1L-therapy 时更早出现脑转移（CTLA-4+PD-1：HR 0.560，95%CI 0.332 至 0.945，p=0.030；PD-1：HR 0.575，95%CI 0.372 至 0.888，p=0.013）。1L-therapy 的类型、肿瘤分期和年龄是 BRAF 患者 BMFS 的独立预后因素。在 BRAF 患者中，肿瘤分期与 BMFS 较长相关；ECOG 表现状态（ECOG-PS）、乳酸脱氢酶（LDH）和肿瘤分期与 OS 相关。与 PD-1 相比，CTLA-4+PD-1 并不能改善 BRAF 患者的 BMFS、PFS 或 OS。对于 BRAF 患者，多变量 Cox 回归显示 ECOG-PS、1L-therapy 的类型、肿瘤分期和 LDH 是 PFS 和 OS 的独立预后因素。与 PD-1 相比，1L-therapy 联合 CTLA-4+PD-1 可延长 OS（HR 1.97，95%CI 1.122 至 3.455，p=0.018）或 BRAF+MEK（HR 2.41，95%CI 1.432 至 4.054，p=0.001），而 PD-1 并不优于 BRAF+MEK。

结论

在 BRAF 患者中，与 BRAF+MEK TT 相比，PD-1±CTLA-4 ICI 的 1L-therapy 导致脑转移的发生和发展更延迟且更不频繁。与 PD-1 和 BRAF+MEK 相比，1L-therapy 联合 CTLA-4+PD-1 可改善 OS。在 BRAF 患者中，与 PD-1 相比，CTLA-4+PD-1 并未改善脑转移和生存结局。