A multicenter phase II study of regorafenib in patients (pts) with advanced gastrointestinal stromal tumor (GIST), after therapy with imatinib (IM) and sunitinib (SU).

Abstract

10007 Background: Resistance remains a challenge in GIST after the failure of IM and SU. Regorafenib, a novel oral kinase inhibitor, blocks VEGFR2-3, c-KIT, TIE2, PDGFR beta, FGFR1, RET, RAF and p38 MAPK and has a broad spectrum of antitumor activity in preclinical and early phase trials. We conducted an investigator initiated, multi-center phase II trial of regorafenib in patients with advanced GIST after prior therapy with at least IM and SU. Methods: Eligible pts received regorafenib 160mg/day orally d1-21 of each 28d cycle. Pts were assessed for response by RECIST 1.1 every 2 cycles. Primary endpoint was clinical benefit rate (CBR) defined as CR, PR, and SD > 16 weeks. Tumor genotyping and optional pre and d15 tumor biopsies were performed. Results: 34 pts were enrolled from Feb 2010 – Dec 2010. 33 pts received at least one dose of study drug. Median age was 54 yrs, median number of prior therapies = 3. As of Dec 1, 2010, 121 cycles of regorafenib have been administered (range 1 – 11). 19 pts required at least one dose reduction due to toxicity. Most common grade 3 treatment emergent toxicities were hypertension, hand-foot skin reaction, and hypophosphatemia, (29%, 25% and 14% of pts respectively). There were two grade 4 events, one hyperuricemia and one thrombosis. As of Dec 30, 2010, 22 eligible pts had been on protocol for at least 16 wks. 12 had restaging scans after 16 wks showing sustained clinical benefit (2 PR, 10 SD) CBR 54.5% (90% CI, 35.3% - 72.9%). 1 pt progressed at 7 wks. 2 pts withdrew prior to 16 wks. The remaining 7 pts demonstrated stable disease at a range of 14.9 - 15.6 wks. Therefore, 19 of 22 pts were without disease progression after 4 cycles of study drug dosing. Benefit was seen in pts whose tumors had primary KIT exon 11 mutations, KIT exon 9 mutations or wildtype kinase genotype. Immunoblotting of pre-study and day15 matched biopsies demonstrated ~50% inhibition of KIT and AKT phosphorylation, in 3 of 4 patients, all with SD for at least 4 cycles. Conclusions: Regorafenib has significant activity in pts with advanced GIST previously treated with IM and SU. An international phase III trial is currently underway in pts with advanced GIST following treatment with IM and SU.