TENERGY: multicenter phase II study of Atezolizumab monotherapy following definitive Chemoradiotherapy with 5-FU plus Cisplatin in patients with unresectable locally advanced esophageal squamous cell carcinoma
TENERGY: multicenter phase II study of Atezolizumab monotherapy following definitive Chemoradiotherapy with 5-FU plus Cisplatin in patients with unresectable locally advanced esophageal squamous cell carcinoma
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DOI：
10.1186/s12885-020-06716-5
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发表时间：
2020-04-20
期刊：
影响因子：
3.8
通讯作者：
Kojima, Takashi
中科院分区：
文献类型：
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作者：
Bando, Hideaki;Kotani, Daisuke;Kojima, Takashi
不能切除的局部晚期食管鳞状细胞癌（ESCC）患者的标准治疗是使用5-FU加顺铂的确定性放化疗（CRT）。然而，完全缓解（CR）率较低，为11- 25%，导致中位总生存期（OS）为9-10个月。在局部晚期非小细胞肺癌患者中，已经报道了通过将免疫疗法与放射相结合来提高治疗效果。使用ESCC细胞系的结果表明，在完成CRT后不久用抗PD-L1药物进行序贯治疗是最有效的组合。方法TENERGY试验是一项多中心、II期、概念验证研究，旨在评估atezolizumab在局部晚期ESCC患者接受确定性CRT后的疗效和安全性。主要的入选标准是不可切除的局部晚期ESCC，无远处转移，完成60戈伊放疗加两个伴随化疗周期（顺铂70 mg/m2，第1天，5-FU 700 mg/m2，第1-4天，每28天一次），以及足够的器官功能。CRT后6周内，受试者将开始每3周一次服用1200 mg atezolizumab，并持续至12个月或疾病进展。主要终点是研究者评估确认的CR率。次要终点包括总缓解率、无进展生存期（PFS）、OS、不良事件和中心评估确认的CR率。我们将招募50例患者（40例原发性局部晚期ESCC和10例术后局部复发性ESCC）。我们将从主要研究中心获得活检标本，并在3个时间点（CRT前、CRT后和atezolizumab开始后4周）采集血液，用于探索性生物标志物研究。我们将分析免疫活性细胞的表型、新抗原、肿瘤突变负荷、PD-L1状态和人类白细胞抗原单体型分析。讨论CRT和atezolizumab序贯联合治疗的协同效应应可提高CR率，从而改善不可切除的局部晚期ESCC患者的生存率。由于CRT是早期至局部晚期ESCC患者的标准治疗选择，因此CRT和atezolizumab序贯联合治疗有可能改变标准ESCC治疗。
Background The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy (CRT) using 5-FU plus cisplatin. However, complete response (CR) rates are low at 11-25%, resulting in 9-10 months of median overall survival (OS). An improved therapeutic efficacy by combining immunotherapy with radiation has been reported in patients with locally advanced non-small cell lung cancer. The results using ESCC cell lines suggest sequential treatment with anti-PD-L1 agents soon after completion of CRT is the most effective combination. Methods TENERGY trial is a multicenter, phase II, proof-of-concept study to assess the efficacy and safety of atezolizumab following definitive CRT in patients with locally advanced ESCC. The main inclusion criteria are unresectable locally advanced ESCC without distant metastasis, completion of 60 Gy of radiation plus two concomitant cycles of chemotherapy (cisplatin 70 mg/m(2) on day 1 and 5-FU 700 mg/m(2) on days 1-4, every 28 days), and adequate organ function. Within 6 weeks after CRT, participants will start taking 1200 mg of atezolizumab every three weeks and continue until 12 months or disease progression. The primary endpoint is the confirmed CR rate by the investigator's assessment. Secondary endpoints include overall response rate, progression-free survival (PFS), OS, adverse events, and confirmed CR rate by central assessment. We will enroll 50 patients (40 with primary locally advanced ESCC and 10 with postoperative locoregionally recurrent ESCC). We will obtain biopsies from the primary site and will collect blood at 3 time points (before CRT, after CRT, and four weeks after the start of atezolizumab) for an exploratory biomarker study. We will analyze the phenotype of immune-competent cells, neoantigens, tumor mutational burden, PD-L1 status, and Human Leukocyte Antigen haplotyping. Discussion The synergistic efficacies of the sequential combination of CRT and atezolizumab should improve the CR rate, resulting in survival improvement for patients with unresectable locally advanced ESCC. Because CRT is a standard treatment option for patients with early stage to locally advanced ESCC, the sequential combination of CRT and atezolizumab has the potential to change the standard ESCC treatments.