Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
JE-UK Institute for Cancer Research, JEUK Company Ltd, Gumi-City, Kyungbuk, Korea.
Cancer. 2020 Oct 15;126(20):4521-4531. doi: 10.1002/cncr.33123. Epub 2020 Aug 4.
The objective of the current study was to investigate the clinical activity of, safety of, and predictive biomarkers for afatinib, an irreversible pan-ErbB kinase inhibitor, in patients with recurrent and/or metastatic esophageal squamous cell carcinoma (R/M-ESCC).
Patients with R/M-ESCC that was refractory to platinum-based chemotherapy were enrolled in the current multicenter, single-arm, phase 2 study and received afatinib at a dose of 40 mg/day. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, overall survival, the disease control rate, and the safety profile. To identify predictive biomarkers, single-nucleotide variations, short insertions/deletions, and somatic copy number alterations were assessed using whole-exome sequencing and their associations with clinical outcomes were analyzed.
Among 49 enrolled patients, the objective response rate and disease control rate were 14.3% and 73.3%, respectively. With a median follow-up of 6.6 months, the median progression-free survival and overall survival were 3.4 months and 6.3 months, respectively. Treatment-related adverse events were noted to have occurred in 33 patients (67.3%), with the majority being of grade 1 to 2 (adverse events were graded and recorded based on the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). Whole-exome sequencing demonstrated that the ESCC genomes of patients who demonstrated a response to afatinib were enriched with genomic alterations of TP53 and epidermal growth factor receptor (EGFR). As a predictive marker, a score derived from TP53 disruptive mutations and EGFR amplifications and/or missense mutations demonstrated a significant association with the response to afatinib. The score based on the mutational status of EGFR and TP53 achieved a performance of an area under the curve of 0.86 in predicting the sensitivity of afatinib.
The results of the current study demonstrated that afatinib can confer modest clinical benefits with manageable toxicity in patients with platinum-resistant R/M-ESCC. Identification of TP53 alterations and EGFR amplifications may serve as predictive markers with which to identify patients with R/M-ESCC who may benefit from afatinib.
Esophageal squamous cell carcinoma (ESCC) is a type of cancer with a dismal prognosis and very limited treatment options. The clinical efficacy of afatinib was evaluated in patients with recurrent and/or metastatic ESCC, with adverse events demonstrating the modest efficacy with manageable toxicity of this irreversible, pan-ErbB kinase inhibitor. Whole-exome sequencing analysis of 41 cases of ESCC further revealed that the patients harboring epidermal growth factor receptor (EGFR) amplifications and disruptive TP53 mutations are more likely to benefit from treatment with afatinib. The results of the current study have highlighted the clinical value of EGFR and TP53 as predictive biomarkers of platinum-resistant recurrent and/or metastatic ESCC for afatinib sensitivity.
本研究旨在探讨不可逆泛 ErbB 激酶抑制剂阿法替尼在铂类耐药复发性和/或转移性食管鳞状细胞癌（R/M-ESCC）患者中的临床疗效、安全性和预测性生物标志物。
本多中心、单臂、二期研究入组了铂类耐药的 R/M-ESCC 患者，接受阿法替尼 40mg/天治疗。主要终点为客观缓解率。次要终点包括无进展生存期、总生存期、疾病控制率和安全性。通过全外显子组测序评估单核苷酸变异、短插入/缺失和体细胞拷贝数改变，并分析其与临床结局的关系。
49 例入组患者中，客观缓解率和疾病控制率分别为 14.3%和 73.3%。中位随访 6.6 个月时，中位无进展生存期和总生存期分别为 3.4 个月和 6.3 个月。33 例（67.3%）患者发生治疗相关不良事件，大多数为 1-2 级（根据美国国立癌症研究所不良事件通用术语标准[版本 4.03]对不良事件进行分级和记录）。全外显子组测序显示，阿法替尼治疗有效的患者的 ESCC 基因组中富含 TP53 和表皮生长因子受体（EGFR）的基因组改变。作为预测标志物，基于 TP53 破坏性突变和 EGFR 扩增和/或错义突变的评分与阿法替尼的反应显著相关。基于 EGFR 和 TP53 突变状态的评分在预测阿法替尼的敏感性方面获得了 0.86 的曲线下面积。
本研究结果表明，阿法替尼在铂类耐药的 R/M-ESCC 患者中具有适度的临床获益和可管理的毒性。TP53 改变和 EGFR 扩增的鉴定可能作为预测标志物，以识别可能从阿法替尼治疗中获益的 R/M-ESCC 患者。
