Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: 3-year survival update and multi-omics analysis

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-01-05 DOI:10.1002/ctm2.70169

Jie Dai, Tianxiao Xu, Lifeng Li, Meiyu Fang, Jing Lin, Jun Cao, Xue Bai, Caili Li, Xiaoting Wei, Junjie Gu, Yaoyao Liu, Xuan Gao, Xuefeng Xia, Jun Guo, Yu Chen, Lili Mao, Lu Si

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Abstract

Background

Atezolizumab plus bevacizumab has shown promising efficacy in advanced mucosal melanoma in the multi-centre phase II study. This report updates 3-year survival outcomes and multi-omics analysis to identify potential response biomarkers.

Methods

Forty-three intention-to-treat (ITT) patients received intravenous administration of atezolizumab and bevacizumab every 3 weeks. Available samples underwent whole exome sequencing, transcriptome sequencing and targeted bisulphite sequencing to assess correlations with clinical outcomes.

Results

With a median follow-up of 40.3 months, the median overall survival (mOS) was 23.7 months (95% confidence interval [CI], 15.1–34), and the 3-year OS rate was 28.7% (95% CI, 17.6%–46.8%). Patients with upper site melanoma exhibited longer progression-free survival (PFS), higher tumour neoantigen burden (TNB) and greater copy number variations (CNVs) burden compared to those with lower site melanoma. NRAS mutations were associated with enhanced angiogenesis, with five of six patients achieving partial response. Inflammatory cell infiltration, angiogenic status and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators.

Conclusions

This 3-year updated analysis confirms the sustained efficacy of atezolizumab in combination of bevacizumab in patients with advanced mucosal melanoma. Inflammatory cell infiltration and angiogenic status were associated with therapeutic response. Furthermore, mucosal melanoma of upper site and NRAS mutation appear to be good predictors of response to immune checkpoint inhibitor and anti-angiogenic combination treatment. Targeting SMAD2 and p38 MAPK pathways may further improve the outcome of mucosal melanoma.

Key points

3-year follow-up study confirmed the therapeutic efficacy of atezolizumab combined with bevacizumab
Tumors in the upper site and NRAS mutations are more sensitive to treatment
Inflammatory cell infiltration, angiogenic status, and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators

Abstract Image

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Atezolizumab联合贝伐单抗治疗不可切除或转移性粘膜黑色素瘤患者：3年生存期更新和多组学分析

研究背景在多中心 II 期研究中，Atezolizumab 联合贝伐单抗对晚期粘膜黑色素瘤具有良好疗效。本报告更新了3年生存结果和多组学分析，以确定潜在的反应生物标志物：43例意向治疗（ITT）患者每3周接受一次阿特珠单抗和贝伐珠单抗的静脉注射。对现有样本进行全外显子组测序、转录组测序和靶向亚硫酸氢盐测序，以评估与临床结果的相关性：中位随访时间为 40.3 个月，中位总生存期（mOS）为 23.7 个月（95% 置信区间 [CI]，15.1-34），3 年 OS 率为 28.7%（95% CI，17.6%-46.8%）。与下部黑色素瘤患者相比，上部黑色素瘤患者的无进展生存期（PFS）更长，肿瘤新抗原负荷（TNB）更高，拷贝数变异（CNVs）负荷更大。NRAS突变与血管生成增强有关，六名患者中有五名获得了部分应答。炎症细胞浸润、血管生成状态以及SMAD2和p38 MAPK通路的激活可能是预后指标：这项为期3年的最新分析证实了阿特珠单抗联合贝伐单抗对晚期粘膜黑色素瘤患者的持续疗效。炎症细胞浸润和血管生成状态与治疗反应有关。此外，上部位粘膜黑色素瘤和NRAS突变似乎是免疫检查点抑制剂和抗血管生成联合治疗反应的良好预测因素。靶向SMAD2和p38 MAPK通路可进一步改善粘膜黑色素瘤的疗效：3年随访研究证实了阿特珠单抗联合贝伐单抗的疗效上部肿瘤和NRAS突变对治疗更敏感炎性细胞浸润、血管生成状态以及SMAD2和p38 MAPK通路的激活可能是预后指标。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.