title: Predictive biomarkers for the efficacy of cetuximab combined with cisplatin and capecitabine in advanced gastric or esophagogastric junction adenocarcinoma: a prospective multicenter phase 2 trial.
abstract: Cetuximab presents a potential therapy for gastric or esophagogastric junction adenocarcinoma. We aim to evaluate the predictive value of potential biomarkers of cetuximab efficacy. In this prospective phase 2 trial (NCT00477711), we enrolled untreated 47 patients with un-resectable or metastatic gastric or esophagogastric junction adenocarcinoma from seven sites in China. Patients with histologically confirmed adenocarcinoma were given cisplatin (80 mg/m2, triweekly), capecitabine (2,000 mg/m2, triweekly for 2 weeks), and cetuximab weekly (400 mg/m2 at first infusion and 250 mg/m2 subsequently). Sample size was calculated using Simon's two-stage design. The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and predictive biomarkers. The ORR was 53.2%, median PFS 5.2 months, and OS 10.8 months. The most frequent toxicities included neutropenia (25.0%), nausea/vomiting (11.5%), and rash/desquamation (9.6%). Patients with grade 2-4 rash achieved a significantly better ORR, longer PFS, and OS than those with grade 0-1 rash. Seven patients (15.9%) with epidermal growth factor receptor (EGFR) strong expression (3+) showed great tumor shrinkage, longer PFS (7.1 months), and OS (16.6 months). EGFR gene amplification was detected in four patients (8.5%), all of whom responded well. Compared to patients with lower levels of transforming growth factor-alpha (TGF-α), those with high levels showed better response and longer PFS (6.0 vs 2.7 months, p=0.001) and OS (12.9 vs 7.0 months, p=0.001). C+XP was well tolerated and effective for advanced gastric or esophagogastric junction adenocarcinoma as first-line therapy. Severity of skin rash and TGF-α level correlated with efficacy, and EGFR overexpression might predict cetuximab efficacy.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, 100142, China, zhangxiaotianmed@163.com.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhang
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Huilong
authors.initials: H
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Nong
authors.initials: N
authors.lastname: Xu
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Bai
authors.forename: Jiejun
authors.initials: J
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Shen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D000069287:Capecitabine; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D066246:ErbB Receptors / Q000235:genetics*; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D016211:Transforming Growth Factor alpha; D003841:Deoxycytidine; D000069287:Capecitabine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil