Efficacy and safety of regorafenib in patients with metastatic and/or unresectable gastrointestinal stromal tumor harboring secondary mutation with exon 17: Interim report of a phase II trial.

Abstract

e22511 Background: Metastatic gastrointestinal stromal tumor (GIST) is a life-threatening disease with no suitable therapy after discovering secondary mutations with exon 17. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Previous in-vitro study showed that regorafenib has inhibitory effect on GIST cells harboring exon 17 mutation. Thus, we performed a phase II trial in patients with advanced GIST harboring secondary KIT mutations with exon 17 to examine the clinical benefit and safety of regorafenib treatment (ClinicalTrials.gov identifier: NCT02606097). Methods: Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary endpoint was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] for more than 16 weeks). Results: From May 2014 to May 2015, 15 patients were enrolled at four Taiwan centers for this interim report. CBR was 80%. Five patients achieved PR, and 7 exhibited SD for more than 16 weeks. Median progression-free survival (PFS) was not reachable. Adverse events occurred rapidly after treatment initiation and might be managed via dose modification. The most common grade 3 toxicities was hand-foot-skin reaction (HFSR; 8/15; 55.3%), followed by hypertension (5/15; 33.3%). Conclusions: Regorafenib has significant PFS benefit in patients with advanced GIST harboring secondary KIT mutation with exon 17, especially for patient with stable disease status at enrollment. However, higher frequency of grade III toxicity was observed, especially for HFSR. Further investigation of mechanism responsible for grade III toxicity is urgently needed. Clinical trial information: NCT02606097.