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Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer

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Summary

Background Dulanermin is a recombinant soluble human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that activates apoptotic pathways by binding to proapoptotic death receptor (DR) 4 and DR5. The purpose of this study was to evaluate the efficacy and safety of dulanermin combined with vinorelbine and cisplatin (NP) as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Experimental design Patients were randomly assigned to receive NP chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 30 mg/m2 on days 2 to 4) for up to six cycles plus dulanermin (75 μg/kg on days 1 to 14) or placebo every three weeks until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS), and the secondary end points included objective response rate (ORR), overall survival (OS), and safety evaluation. Results Between October 2009 and June 2012, 452 untreated patients with stage IIIB to IV NSCLC were randomly assigned to receive dulanermin plus NP (n = 342) and placebo plus NP (n = 110). Median PFS was 6.4 months in the dulanermin arm versus 3.5 months in the placebo arm (hazard ratio (HR), 0.4034; 95% CI, 0.3181 to 0.5117, p < 0.0001). ORR was 46.78% in the dulanermin arm versus 30.00% in the placebo arm (p = 0.0019). Median OS was 14.6 months in the dulanermin arm versus 13.9 months in the placebo arm (HR, 0.94; 95% CI, 0.74 to 1.21, p = 0.64). The most common grade ≥ 3 adverse events (AEs) were oligochromemia, leukopenia, neutropenia, and oligocythemia. Overall incidence of AEs, grade ≥ 3 AEs, and serious AEs were similar across the two arms. Conclusion Addition of dulanermin to the NP regimen significantly improved PFS and ORR. However, our results showed that the combination of dulanermin with chemotherapy had a synergic activity and favorable toxic profile in the treatment of patients with advanced NSCLC.

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Acknowledgements

The authors thank the patients who participated in this study and express appreciation of the assistance and understanding of their families. The authors also thank the study-site staff for their support.

Funding

The work was also funded by Shanghai Biomedical Technology fund (grant number 08431901100), National Innovation Fund (grant number 10C26213100701), and National Science and Technology Major Project fund (grant number 2010ZX09401-301).

Author information

Author notes

  1. Xuenong Ouyang and Meiqi Shi contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Fuzhou General Hospital of Nan**g Military Command, Fuzong Clinical College, Fujian Medical University, Fuzhou, China

    Xuenong Ouyang & Fangwei Jie

  2. Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nan**g Medical University affiliated Cancer Hospital, No.42 Baiziting, Xuanwu District, Nan**g, Jiangsu,, 210009, China

    Meiqi Shi & Jifeng Feng

  3. Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, Harbin, China

    Yuxian Bai

  4. Department of Medical Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Peng Shen

  5. Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China

    Zhuang Yu

  6. Department of Chemotherapy, Qilu Hospital of Shandong University, **an, Shandong, China

    ** Zhang

  7. Department of Oncology, The Second **angya Hospital of Central South University, Changsha, Hunan, China

    Chunhong Hu

  8. Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou, Henan, China

    **tao Ma

  9. Department of Respiratory Medicine, Shanghai East Hospital, Tongji University, Shanghai, China

    Yongjie Liang

  10. Department of Medical Oncology, Hunan Cancer Hospital, Changsha, Hunan, China

    Anlan Wang

  11. Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

    Bing Lu

  12. Department of Respiratory Medicine, Nan**g General Hospital of Nan**g Military Command, Nan**g, Jiangsu, China

    Yi Shi

  13. Department of Oncology, Nan**g First Hospital, Nan**g Medical University, Nan**g, Jiangsu, China

    **fei Chen

  14. Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China

    Zhixiang Zhuang

  15. Department of Medical Oncology, Changzheng Hospital, Shanghai, China

    Jiejun Wang

  16. Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Jian** Huang

  17. Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China

    Changhui Wang

  18. Department of Respiratory Medicine, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China

    Chunxue Bai

  19. Department of Respiratory, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    **n Zhou

  20. Department of Respiratory Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, China

    Qiang Li

  21. Department of Epidemiology and Biostatistics, School of Public Health, Nan**g Medical University, Nan**g, Jiangsu, China

    Feng Chen & Hao Yu

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  1. Xuenong Ouyang
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Corresponding author

Correspondence to Jifeng Feng.

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Conflict of interest

All authors received research funding from Gebaide Biotechnology Co., Ltd. for conducting the study and preparing this report. No potential conflicts of interest were disclosed.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all individual patients included in the study.

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Ouyang, X., Shi, M., Jie, F. et al. Phase III study of dulanermin (recombinant human tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand) combined with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer. Invest New Drugs 36, 315–322 (2018). https://doi.org/10.1007/s10637-017-0536-y

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