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Stivarga Treatment for GIST


What is the evidence of regorafenib effectiveness against GIST?

Regorafenib was tested against GIST in Phase II and Phase III clinical trials summarized below. 

Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, Hohenberger P, Leahy M, von Mehren M, Joensuu H, Badalamenti G, Blackstein M, Le Cesne A, Schöffski P, Maki RG, Bauer S, Nguyen BB, Xu J, Nishida T, Chung J, Kappeler C, Kuss I, Laurent D, Casali PG; GRID study investigators.
Lancet. 2013 Jan 26;381(9863):295-302. doi:10.1016/S0140-6736(12)61857-1.
PubMed PMID: 23177515

Demetri et al (2013) reported results from the Phase III trial of regorafenib in patients with metastatic or unresectable GIST.  This study included 133 patients in the regorafenib arm and 66 in the placebo arm (who could cross over to receive regorafenib upon progression).  All subjects had previously taken at least imatinib and sunitinib, and over 40% had received prior third or higher line therapies.   Median progression-free survival (PFS) was 4.8 months in the regorafenib arm, with an interquartile range of 1.4 to 9.2 months, which was significantly longer than the 0.9 months PFS in the placebo arm.   Placebo subects who crossed over to receive regorafenib had a median 5.0 months PFS after crossover.  The disease control rate (partial response or stable disease) was 56% in the regorafenib group.  The most common side effects of regorafenib were hand-foot skin reaction, hypertension, and diarrhea.  The investigators did not report results separately by tumor genotype, but they plan to conduct this analysis later. 

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.

George S, Wang Q, Heinrich MC, Corless CL, Zhu M, Butrynski JE, Morgan JA,
Wagner AJ, Choy E, Tap WD, Yap JT, Van den Abbeele AD, Manola JB, Solomon SM,
Fletcher JA, von Mehren M, Demetri GD. 

J Clin Oncol. 2012 Jul 1;30(19):2401-7. doi: 10.1200/JCO.2011.39.9394.
PubMed PMID:22614970; PubMed Central PMCID: PMC3675695 (free access)


Does mutation status affect response to regorafenib?

Mutation data from the patients in the clinical trials have not yet been reported, but a 2013 poster did provide some results from in vitro (cell culture) research.

In vitro and in vivo activity of regorafenib (REGO) in drug-resistant gastrointestinal stromal tumors (GIST).
Abstract Number: 10510
Citation: J Clin Oncol 31, 2013 (suppl; abstr 10510)
Author(s): Cesar Serrano-Garcia, Michael C. Heinrich, Meijun Zhu, Chandrajit P. Raut, Grant Eilers, Gloria Ravegnini, George D. Demetri, Sebastian Bauer, Jonathan A. Fletcher, Suzanne George;

In this poster presentation at the 2013 ASCO meeting results were shown for regorafenib and other drugs used againsts GIST cell lines with different mutations, including imatinib-resistant strains.  Activation loop mutations were more potently inhibited by regorafenib than by sunitinib, and the gatekeeper mutation T6701 was inhibited by both regorafenib and sunitinib.  The ATP-binding pocket mutation V654A responded better to sunitinib than to regorafenib. 


2013 European Cancer Conference presentations about regorafenib

To view the following abstracts go to this link and enter the abstract number in the search box.

Abstract number: 3827
Time course of adverse events in the phase III GRID study of regorafenib in patients with metastatic gastrointestinal stromal tumors (GIST)
J. Blay, P.G. Casali, P. Reichardt, Y.K. Kang, P. Rutkowski, H. Gelderblom, P. Hohenberger, C. Kappeler, I. Kuss, G.D. Demetri

Abstract number: 3830
Health-related quality of life (HRQoL) of patients with advanced gastrointestinal stromal tumors (GIST) treated with regorafenib (REG) vs placebo (P) in the phase III GRID trial
J. Chang, P.G. Casali, P. Reichardt, Y.K. Kang, J.Y. Blay, Y. Wu, D. Odom, I. Kuss, G.D. Demetri

Abstract number: 3831
Exposure-efficacy analysis of regorafenib (REG) and its metabolites M-2 and M-5 in the phase III GRID study in patients (pts) with metastatic gastrointestinal stromal tumor (GIST)
G. Demetri, J.M.W. Smeets, P.G. Casali, P. Reichardt, Y.K. Kang, H. Joensuu, P. Rutkowski, J.Y. Blay, I. Kuss, Z. Jirakova Trnkova


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