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

Abstract

10009 Background: Treatment (tx) options are limited after GIST pts develop resistance to IM and SU. SOR inhibits KIT, VEGFR, PDGFR-β, and BRAF kinases. In preclinical GIST models, SOR inhibits many secondary resistance mutations, including IM-RES ATP-binding pocket and IM/SU-RES activation loop mutations (Heinrich, Proc ASCO 2009). Methods: We performed a multi-center, phase II trial of SOR in KIT-expressing GIST pts who had disease progression (PD) on IM by RECIST. After FDA approval of SU for GIST, the amended study required PD after both IM and SU. Pts received SOR 400 mg orally twice daily. Primary endpoint: objective response rate. A Simon minimax 2-stage design required 1 response in 18 pts for a 2nd stage, and 4 responses in 32 IM/SU RES pts for further study. Results: 38 pts (6 IM-RES, 32 IM/SU-RES) enrolled 1/06-9/09 at 6 centers. Pt characteristics: male 55%; median age 57 (range 42-85); PS 0/1/2: 47%/47%/5%; liver metastases 74%; primary drug resistance (PD ≤ 6 mo): IM 3%, SU 59%. Baseline mutations: exon 11 65%, exon 9 15%, PDGFR-α 4%. Median cycles: 4 (range 1-40); 42% received SOR ≥ 6 mo, 26% ≥ 1 year (yr). Dose reductions: 61%. 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%. Survival: median progression-free: 5.2 mo (95% CI: 3.4, 7.4); median overall 11.6 mo (95% CI: 8.8, 14.3); 1-yr 50%; 2-yr 26%. 32% of pts with primary SU-RES had PR or SD ≥ 6 mo on SOR. Grade 3/4 toxicities (% pts): hand-foot syndrome 45%, hypertension 21%, diarrhea 8%, hypophosphatemia 8%, GI bleed 5%, thrombosis 3%, GI perforation 3%, intracranial hemorrhage 3%. Conclusions: SOR has definite activity in IM/SU-resistant GIST, with a disease control rate of 68%. Prolonged disease control is possible, even in pts with primary SU resistance. Though well-tolerated, dose reductions are often required. Further investigation of SOR in GIST is warranted. Supported by NCI grant N01-CM-62201.