T 细胞炎症基因表达谱、程序性死亡配体 1 表达和肿瘤突变负担可预测帕博利珠单抗治疗 20 种癌症患者的疗效：KEYNOTE-028。

T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028.

机构信息

Dana-Farber Cancer Institute, Boston, MA.

Seoul National University College of Medicine, Seoul, The Republic of Korea.

出版信息

J Clin Oncol. 2019 Feb 1;37(4):318-327. doi: 10.1200/JCO.2018.78.2276. Epub 2018 Dec 13.

DOI:10.1200/JCO.2018.78.2276

PMID:30557521

Abstract

PURPOSE

Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors.

METHODS

KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points.

RESULTS

ORRs (with 95% CIs) ranged from 0% (0.0% to 14.2%) in pancreatic cancer to 33% (15.6% to 55.3%) in small-cell lung cancer. Across cohorts, median (95% CI) PFS ranged from 1.7 months (1.5 to 2.9 months) to 6.8 months (1.9 to 14.1 months) in pancreatic and thyroid cancers, respectively, and median OS from 3.9 months (2.8 to 5.5 months) to 21.1 months (9.1 to 22.4 months) in vulvar and carcinoid tumors, respectively. Higher response rates and longer PFS were demonstrated in tumors with higher T-cell-inflamed GEP, PD-L1 expression, and/or TMB. Correlations of TMB with GEP and PD-L1 were low. Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response. Safety was similar and consistent with prior pembrolizumab reports.

CONCLUSION

A T-cell--inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types. These biomarkers (alone/in combination) may help identify patients who have a higher likelihood of response to anti-PD-1 therapies across a broad spectrum of cancers.

摘要

目的

能够预测多种肿瘤类型对抗程序性细胞死亡 1（PD-1）治疗反应的生物标志物包括 T 细胞炎症基因表达谱（GEP）、程序性死亡配体 1（PD-L1）表达和肿瘤突变负担（TMB）。在一项涵盖 20 个晚期实体瘤患者队列的临床试验中，评估了这些生物标志物与 pembrolizumab 临床疗效之间的关系。

方法

KEYNOTE-028（ClinicalTrials.gov 标识符：NCT02054806）是一项非随机、Ib 期临床试验，共纳入 475 名 PD-L1 阳性晚期实体瘤患者，接受 pembrolizumab 10mg/kg，每 2 周 1 次，持续 2 年，或直至确认疾病进展或出现不可接受的毒性。主要终点为客观缓解率（ORR；根据 RECIST v1.1，研究者评估）。次要终点包括安全性、无进展生存期（PFS）和总生存期（OS）。T 细胞炎症 GEP、PD-L1 表达和 TMB 与抗肿瘤活性之间的关系是探索性终点。

结果

在胰腺癌中 ORR（95%CI）为 0%（0.0%~~14.2%），在小细胞肺癌中为 33%（15.6%~~55.3%）。在各队列中，胰腺和甲状腺癌的中位（95%CI）PFS 分别为 1.7 个月（1.5~~2.9 个月）和 6.8 个月（1.9~~14.1 个月），外阴和类癌肿瘤的中位 OS 分别为 3.9 个月（2.8~~5.5 个月）和 21.1 个月（9.1~~22.4 个月）。在 T 细胞炎症 GEP、PD-L1 表达和/或 TMB 较高的肿瘤中，观察到更高的缓解率和更长的 PFS。TMB 与 GEP 和 PD-L1 的相关性较低。反应模式表明，同时具有高 TMB 和炎症标志物（GEP 或 PD-L1）的肿瘤患者代表了最有可能对治疗有反应的人群。安全性与之前 pembrolizumab 报告一致且相似。