Final results of a University of Chicago phase II consortium trial of sorafenib (SOR) in patients (pts) with imatinib (IM)- and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST).

Abstract

4 Background: GIST pts who develop resistance to IM and SU have few therapeutic options. SOR inhibits KIT, VEGFR, PDGFR-β, and BRAF kinases. In preclinical models, SOR has activity against several IM-RES mutations that are resistant to SU (Heinrich. ASCO 2009). Methods: We performed a multi-center, phase II trial of SOR in unresectable, KIT-expressing GIST pts who had disease progression on IM by RECIST. After FDA approval of SU for IM-RES GIST, the study was amended in 2/07 to require progression after both IM and SU. Pts received SOR 400 mg orally twice daily. CT scans were obtained Q2 28-day cycles. The primary endpoint was objective response rate. A Simon minimax 2-stage design required 1 response in 18 pts to proceed to a second stage, and 4 responses in 32 IM/SU RES pts for further investigation. Results: 38 pts (6 IM-RES, 32 IM/SU-RES) enrolled 1/06-9/09 at 6 centers. Median follow-up for survivors: 31 months (mo). Pt characteristics: male 55%; median age 57 (range 42-85); PS 0/1/2: 47%/47%/6%. Median cycles: 4 (range 1-37). 63% pts had at least 1 dose reduction. Partial response (PR): 13% (1 IM-RES, 4 IM/SU-RES); stable disease (SD): 55% (3 IM-RES, 18 IM/SU-RES). Disease control rate (PR + SD): 68%. Median progression-free survival: 5.2 mo (95% CI: 3.4, 7.4). Median overall survival 11.6 mo (95% CI: 8.8, 18.0); 1-year survival 50%; 2-year survival 29%. Three pts remain on trial receiving study drug (1 PR at 34 mo; 2 SD at 18 and 37 mo). Grade 3/4 toxicities (% pts): hand-foot syndrome 45%, hypertension 21%, diarrhea 8%, hypophosphatemia 8%, GI bleed 5%, rash 5%, thrombosis 3%, GI perforation 3%, fatigue 3%, anemia 3%. Conclusions: SOR is active in IM-and SU-resistant GIST. Some pts treated with SOR experience prolonged disease control. SOR is well-tolerated in GIST pts, but dose reductions are often required. SOR warrants further investigation in GIST. Supported by NCI grant N01-CM-62201. [Table: see text]