Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial

Abstract

Purpose: Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. 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. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib.

Patients and 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 end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible.

Results: From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction.

Conclusion: Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.

Fig 1.

CONSORT diagram.

Fig 2.

Toxicities of any grade, at least possibly study drug related, occurring in > 25% of patients.

Fig 3.

Kaplan-Meier estimates of (A) progression-free survival (PFS) for the entire cohort (n = 33); (B) PFS by genotype for patients with exon 9 KIT mutations (n = 3), exon 11 KIT mutations (n = 19), and wild type for both KIT and PDGFRA (n = 8); and (C) overall survival (OS) for the entire cohort (n = 33). At time of analysis, 16 patients remained without disease progression. Median PFS for the entire cohort was 10.0 months (95% CI, 8.3 to 14.9 months); median OS has not yet been reached.

Fig 4.

Immunoblotting analyses of matched pre- and postregorafenib GI stromal tumor biopsies from four patients demonstrate KIT inactivation, expressed as percentage of preregorafenib KIT activation remaining in the matched postregorafenib sample [(postregorafenib phospho-KIT/total-KIT) ÷ (preregorafenib phospho-KIT/total KIT)]. Genomic analyses demonstrated KIT activation loop imatinib- and sunitinib-resistance mutations (mut) in each biopsy (D820Y in three patients, N822K in one patient). Total phosphatidylinositol 3-kinase (PI3-K) stain is a well-validated loading control, which serves as an indicator of cellular protein content in each biopsy.

Fig A1.

Immunoblotting analyses of matched pre- and postregorafenib GI stromal tumor biopsies from four patients demonstrating expression of activated and total KIT, AKT, and mitogen-activated protein kinase (MAPK). Protein quantifications, shown for the postregorafenib specimens, are normalized to a value of 1.0 for the matched preregorafenib specimens. Total phosphatidylinositol 3-kinase (PI3-K) stain is a well-validated loading control, which serves as an indicator of cellular protein content in each biopsy. mut, mutation.