Research Papers:

A phase II trial of regorafenib in patients with metastatic and/or a unresectable gastrointestinal stromal tumor harboring secondary mutations of exon 17

Chun-Nan Yeh _, Ming-Huang Chen, Yen-Yang Chen, Ching-Yao Yang, Chueh-Chuan Yen, Chin-Yuan Tzen, Li-Tzong Chen and Jen-Shi Cen

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Oncotarget. 2017; 8:44121-44130. https://doi.org/10.18632/oncotarget.17310

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Chun-Nan Yeh1, Ming-Huang Chen2,3, Yen-Yang Chen4, Ching-Yao Yang5, Chueh-Chuan Yen3, Chin-Yuan Tzen6, Li-Tzong Chen7 and Jen-Shi Chen8

1Department of Surgery, GIST Team, Chang Gung Memorial Hospital and University, Taoyuan 333, Taiwan

2School of Medicine, National Yang-Ming University, Taipei 112, Taiwan

3Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan

4Department of Internal Medicine, Division of Hematology-Oncology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung 833, Taiwan

5Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 100, Taiwan

6Department of Pathology and Laboratory Medicine, Cathay General Hospital, Taipei 100, Taiwan

7National Institute of Cancer Research, National Health Research Institutes, Tainan 70456, Taiwan

8Division of Hematology-Oncology, GIST Team, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan 333, Taiwan

Correspondence to:

Chun-Nan Yeh, email: [email protected]

Keywords: regorafenib, GIST, exon 17

Received: January 17, 2017    Accepted: March 31, 2017    Published: April 21, 2017


Background: Gastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%–90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2–3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown.

Patients and Methods: Documented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1–21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety.

Results: Between June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%).

Conclusion: Regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted.

Trial registration: This trial is registered at ClinicalTrials.gov in November 2015, number NCT02606097.

Key message: This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.

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