一项安可达西单抗联合纳武利尤单抗对比纳武利尤单抗单药治疗晚期胃癌的随机、开放标签、Ⅱ期研究确定了与生存相关的生物标志物。

Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival.

机构信息

Medicine, Weill Cornell Medicine, New York, New York, USA

Medicine, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York, New York, USA.

出版信息

J Immunother Cancer. 2021 Dec;9(12). doi: 10.1136/jitc-2021-003580.

BACKGROUND

Matrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer.

METHODS

Phase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers.

RESULTS

144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-β fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (<1 year) survivors showed that GRB7 was associated with survival beyond 1 year. Human epidermal growth factor receptor 2 (HER2)-positive disease was associated with significantly longer survival (p=0.0077). Median tumor mutation burden (TMB) was 2.01; patients with TMB ≥median had longer survival (p=0.0025) and improved PFS (p=0.016). Based on a model accounting for TMB, TGF-β fibrosis, and HER2, TMB was the main driver of survival in this patient population.

CONCLUSION

Combination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-β were associated with improved outcomes.

TRIAL REGISTRATION NUMBER

NCT02864381 or GS-US-296--2013.

背景

基质金属蛋白酶 9（MMP9）选择性切割细胞外基质蛋白，有助于肿瘤生长和免疫抑制微环境。本研究评估了 MMP9 抑制剂安可达昔单抗（ADX）联合纳武利尤单抗（NIVO）治疗晚期胃癌的疗效。

方法

这是一项评估 ADX+NIVO 对比 NIVO 治疗既往治疗过的转移性胃或胃食管交界处（GEJ）腺癌患者的疗效、安全性和药代动力学的 2 期、开放标签、随机多中心研究。主要终点是客观缓解率（ORR）。次要终点包括无进展生存期（PFS）、总生存期（OS）和不良事件（AEs）。我们探索了疗效结果与生物标志物的相关性。

结果

共纳入 144 例患者，其中 141 例接受治疗：ADX+NIVO 组中 81%为白人，69%为男性，中位年龄为 61 岁；NIVO 单药组中 81%为白人，69%为男性，中位年龄为 62 岁。ADX+NIVO 组的 ORR 为 10%（95%CI，4 至 19），NIVO 单药组为 7%（95%CI，2 至 16）（OR：1.5（95%CI，0.4 至 6.1；p=0.8））。加用 ADX 并未带来应答或生存获益。两组治疗相关不良事件（AE）发生率相当；最常见的 AE 为疲劳、食欲下降、恶心和呕吐。程序性死亡配体 1、干扰素-γ（IFN）和肿瘤内 CD8+细胞密度与治疗应答或生存无关。与较短生存相关的基因特征是上皮-间充质基因特征；高转化生长因子（TGF）-β纤维化评分与 OS 呈负相关（p=0.036）。比较长期（≥1 年）和短期（＜1 年）生存者基线肿瘤的基因表达分析显示，GRB7 与生存时间超过 1 年相关。人表皮生长因子受体 2（HER2）阳性疾病与显著延长的生存相关（p=0.0077）。中位肿瘤突变负荷（TMB）为 2.01；TMB≥中位数的患者具有更长的生存（p=0.0025）和改善的 PFS（p=0.016）。基于考虑 TMB、TGF-β 纤维化和 HER2 的模型，TMB 是该患者人群生存的主要驱动因素。