Min Hee Hong1, Seong Gu Heo2, Yun-Gyoo Lee3, Hyo Song Kim1, Keon Uk Park4, Hoon-Gu Kim5, Yoon Ho Ko6, Ik-Joo Chung7, Young Joo Min8, Min Kyoung Kim9, Kyu Ryung Kim10,11, Jinseon Yoo10,11, Tae-Min Kim10,11, Hye Ryun Kim1, Byoung Chul Cho1,2. 1. Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea. 2. JE-UK Institute for Cancer Research, JEUK Company Ltd, Gumi-City, Kyungbuk, Korea. 3. Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. 4. Division of Hematology/Oncology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea. 5. Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea. 6. Division of Oncology, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. 7. Department of Hemato-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea. 8. Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea. 9. Department of Internal Medicine, Yeungnam University Medical Center, Daegu, Korea. 10. Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea. 11. Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Abstract
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: 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.
BACKGROUND: 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). METHODS: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. RESULTS: 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. CONCLUSIONS: 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. LAY SUMMARY: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.