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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

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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.

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Acknowledgments

We thank all participating patients and their families, the study investigators, study nurses, study monitors, data managers, and all other members of the study team. We thank Merck Ltd, China, for supplying cetuximab. However, Merck made no contribution to the content of the manuscript. This work was supported by the National Natural Science Foundation of China (No. 81172110), National High Technology Research and Development Program (No. 2006AA 02A 402-B02, 2012AA 02A 504), and Beijing Municipal Science & Technology Commission Program “Exploring the utilization of molecular markers in the individual treatment of gastric cancer based on the clinical research cohort.”

Conflict of interest

All authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. 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

    Xiaotian Zhang & Lin Shen

  2. Department of Gastrointestinal Oncology 307 Hospital, PLA, Beijing, 100161, China

    Jianming Xu

  3. Department of Medical Oncology, Beijing Military General Hospital, Beijing, 100142, China

    Huilong Liu

  4. Cancer Institute and Hospital, Chinese Academy of Medical Science, Beijing, 100021, China

    Lin Yang

  5. Affliated Hospital, Medical School, Qingdao University, Qingdao, 266003, Shangdong Province, China

    Jun Liang

  6. First Affiliated Hospital, Zhejiang University, Hangzhou, 310006, Zhejiang Province, China

    Nong Xu

  7. Tumor Hospital, Affiliated to Harbin Medical School, Harbin, 150081, Heilongjiang Province, China

    Yuxian Bai

  8. Changzheng Hospital, Second Military Medical University, Shanghai, 200041, China

    Jiejun Wang

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  1. Xiaotian Zhang
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Correspondence to Jianming Xu or Lin Shen.

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Xiaotian Zhang and Jianming Xu are co-first authors.

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Zhang, X., Xu, J., Liu, H. et al. 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. Med Oncol 31, 226 (2014). https://doi.org/10.1007/s12032-014-0226-y

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