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

Abstract

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.

Keywords: GIST; exon 17; regorafenib.

Conflict of interest statement

CONFLICTS OF INTEREST

The authors have declared no conflicts of interest.

Figures

Figure 1. Regorafenib showed a treatment response in a patient with gastrointestinal stromal tumor with lung metastasis harboring a secondary mutation of exon 17

(A) Pretreatment CT with contrast showed a mass measuring 5.5cm over the right lung. (B) Post-treatment CT with contrast showed the mass had decreased to 3.6 cm over the right lung. (C) Direct sequence analysis of DNA from this specimen revealed a missense mutation at D816E in exon 17.

Figure 2. Flowchart for patient selection for regorafenib treatment in patients with metastatic and/or unresectable gastrointestinal stromal tumors harboring secondary mutations of exon 17

Intent-to-treat (ITT) population included all enrolled subjects who took at least one dose of study medication and satisfy the eligible criteria. Subjects included in Per-Protocol (PP) population are those who met the following criteria: 1) at least one dose of study medication; 2) satisfy the eligible criteria; 3) without any protocol violation; and 4) with drug compliance greater than or equal to two cycles. population included subjects who took at least one dose of study medication.

Figure 3. Kaplan–Meier plot of progression free survival in patients with gastrointestinal stromal tumor with exon 17 mutations treated with regorafenib

Figure 4. Kaplan–Meier plot of progression free survival in patients with gastrointestinal stromal tumor with exon 17 mutations who had stable disease and progressive disease at enrollment treated with regorafenib

Figure 5. Toxicities of any grade (potentially study drug related) and average/median dose of study, occurring in the 24-month treatment period

(A) Hand-and-foot skin reactions, (B) hypertension, and (C) hepatic toxicity.