肿瘤突变负担可预测 MSI-H 转移性结直肠癌对免疫检查点抑制剂的反应。

Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer.

机构信息

Foundation Medicine, Inc., Cambridge.

Center for Informatics, City of Hope National Medical Center, Duarte; Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte.

出版信息

Ann Oncol. 2019 Jul 1;30(7):1096-1103. doi: 10.1093/annonc/mdz134.

DOI:10.1093/annonc/mdz134

PMID:31038663

Abstract

BACKGROUND

Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed.

METHODS

Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point.

RESULTS

A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P < 0.001) and PFS, by univariate (P < 0.001) and multivariate analysis (P < 0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18 months) while the median PFS for TMBlow was 2 months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point.

CONCLUSIONS

TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.

摘要

背景

微卫星不稳定性 (MSI) 是对免疫检查点抑制剂 (ICPIs) 反应的生物标志物。在微卫星高度不稳定 (MSI-H) 的转移性结直肠癌 (mCRC) 中，PD-1 抑制剂已显示出高疾病控制率和良好的无进展生存期 (PFS)；然而，报道的 pembrolizumab 和 nivolumab 反应率各不相同，通常 <50%，这表明需要额外的预测生物标志物。

方法

从五个机构接受 PD-1/L1 抑制剂治疗的 MSI-H mCRC 患者的临床病理数据通过基于杂交捕获的下一代测序 (NGS) 收集。肿瘤突变负担 (TMB) 是在 0.8-1.1 Mb 测序 DNA 上确定的，并以突变/Mb 报告。通过单变量和多变量分析分析了潜在的反应和进展时间的生物标志物。一旦 TMB 被确认为预测生物标志物，就对 18140 个独特的 CRC 患者的更大数据集进行了分析，以确定确定的 TMB 切点的相关性。

结果

共 22 例患者接受 PD-1/L1 抑制剂治疗，其中 19 例接受 pembrolizumab 单药治疗。在测试的变量中，TMB 与客观反应 (OR; P<0.001) 和 PFS 具有最强的关联，无论是单变量 (P<0.001) 还是多变量分析 (P<0.01)。使用对数秩统计，TMB 的最佳预测切点估计在 37 到 41 个突变/Mb 之间。所有 13 例 TMBhigh 病例均有反应，而 9 例 TMBlow 病例中有 6 例出现疾病进展。TMBhigh 的中位 PFS 尚未达到 (中位随访 >18 个月)，而 TMBlow 的中位 PFS 为 2 个月。在由 NGS 评估的大型 MSI-H mCRC 人群 (821/18，140 例；4.5%) 中，TMB 为 37.4 个突变/Mb，对应于第 35 个百分位切点。