CHICAGO—Regorafenib, a novel oral kinase inhibitor that has demonstrated a broad spectrum of antitumor activity in preclinical and early phase trials, showed clinical benefit in patients with advanced gastrointestinal stromal tumors (GIST) after prior therapy with imatinib or sunitinib failed, as reported at the American Society of Clinical Oncology’s 2011 Annual Meeting by Suzanne George, MD, of the Dana-Farber Cancer Institute, Boston.

Regorafenib is a structurally distinct oral tyrosine kinase inhibitor with inhibitory activity against several kinases, including VEGFR2,3, KIT, TIE2, PDGFR, FGFR, and BRAF. In this investigator-initiated, multicenter Phase 2 trial, 34 patients who had failed at least imatinib and sunitinib were enrolled from February 2010 to December 2010.  Regorafenib 160mg/day was administered orally on Days 1 through 21 of each 28-day cycle.

Patients were assessed for response by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) after every two cycles. The primary endpoint was clinical benefit rate (CBR) defined as complete response (CR), partial response (PR), and stable disease (SD ≥16 weeks). Secondary endpoints included objective response rate, progression-free survival (PFS), overall survival, safety, and tolerability. Tumor genotyping and optional pre and d15 tumor biopsies were performed.

The results showed that 33 patients (median age: 56; median number of prior therapies: two) received at least one dose of study drug. As of May 1, 2011, 221 cycles of regorafenib had been administered. A total of 27 patients (82%) required at least one dose reduction due to toxicity. The most common Grade 3 treatment-emergent toxicities were hypertension, hand-foot skin reaction, and hypophosphatemia, (36%, 21% and 15% of patients, respectively). There were three Grade 4 events: two hyperuricemia and one thromboembolic. This side effect profile is similar to what has been reported previously with regorafenib.

Best response to date is a CBR of 73% (n=24), including three PR and 21 SD. Median PFS was 10.0 months. Dr. George noted that CBR was seen in patients whose tumors had primary KIT exon 11 mutations, KIT exon 9 mutations, or wild-type kinase genotype. Immunoblotting of prestudy and Day 15 matched biopsies demonstrated an approximate 50% inhibition of KIT and AKT phosphorylation in three of four patients, all with SD for at least four cycles.

An international Phase 3 registration trial of regorafenib in patients with advanced GIST following failure of imatinib and sunitinib is actively accruing patients to confirm and expand the findings from this study.