Treating GIST: Beyond Imatinib

The newest agent to receive US Food and Drug Administration (FDA) approval for treatment of GIST is regorafenib, another multi-targeted TKI. Regorafenib targets KIT, PDGFR, and VEGF receptors. In a phase 2 study, regorafenib produced four partial responses and stable disease in 22 patients who had failed treatment with imatinib and sunitinib.⁶ In the phase 3 GRID trial (Study of Regorafenib as a Third-line or Beyond Treatment for GIST), progression-free survival (PFS) was significantly longer with regorafenib than with placebo (Table 2); 38% of patients receiving regorafenib were progression-free at 6 months. At the time of the study report, median OS had not been reached in either treatment group. Objective response rates were low, although 52.6% of patients receiving regorafenib achieved durable stable disease (≥ 12 weeks) versus 9.1% of those who received placebo.⁷ KIT mutational status and the presence of PDGFRA did not affect response to regorafenib, which improved PFS versus placebo in all subsets of a mutational analysis.⁸ Regorafenib currently is approved as a third-line option for patients with GIST who previously have been treated with imatinib and sunitinib.

Table 2. Regorafenib for Treatment of GIST Following Imatinib and Sunitinib⁷

Other options for patients who experience treatment failure with imatinib and sunitinib include sorafenib, nilotinib, and dasatinib. Results to date in studies of these TKIs are less impressive, and none are FDA-approved for use in GIST. Response rates in previously treated patients with GIST are about 10% with sorafenib and nilotinib and stable disease rates of 57% and 37%, respectively, were reported.^9,10 A phase 3 study of nilotinib versus best supportive care for patients previously treated with imatinib and sunitinib found no significant difference in PFS overall, although post hoc subset analyses identified longer median OS with nilotinib.¹¹ Dasatinib may be an effective option for patients carrying the PDGFRA D842V mutation.¹ On the horizon is another multikinase inhibitor, famitinib, that targets KIT, PDGFR, VEGF-2, and others. In a phase 1 study of patients with advanced solid tumors including GIST, eight partial responses were achieved, including one patient with GIST. Although much more research is needed, famitinib eventually may offer another alternative for patients who fail to respond or develop resistance to current therapies.¹²

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Summary

TKI therapy, primarily with imatinib, remains the mainstay of medical treatment for GIST across the spectrum of disease presentation. Sunitinib and regorafenib, both multi-targeted TKIs, offer benefit for patients who have experienced treatment failure with prior therapies. Studies of novel TKIs and other targeted therapies, including heat shock protein 90, mammalian target of rapamycin (mTOR) inhibition, and the PI3K pathway, are underway in an effort to help patients who do not benefit from current therapies.

References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines: Soft tissue sarcoma. Version 1.2013. Available at www.nccn.org. Accessed January 22, 2014.
2. Corless CL, Heinrich MC. Molecular pathology of gastrointestinal stromal sarcomas. Ann Rev Pathol Mech Dis. 2008;3:557-586.
3. Reichardt P, Blay J-Y, Boukovinas I, et al. Adjuvant therapy in GIST: state of the art. Ann Oncol
4. DeMatteo RP, Ballman KV, Antonescu CR, et al. Long-term results of adjuvant imatinib mesylate in localized, high-risk primary gastrointestinal stromal tumor: ACOSOG Z9000 (Alliance) Intergroup phase 2 trial. Ann Surg. 2013;258(3):422-429.
5. Demetri GD, Garrett CR, Schöffski P, et al. Complete longitudinal analyses of the randomized, placebo-controlled, phase 3 trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clin Cancer Res. 2012;18(11);3170-3179.
6. George S, Wang Q, Heinrich MC, et al. 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. J Clin Oncol. 2012;30(19):2401-2407.
7. Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib: and international, multicenter, prospective, randomized, placebo-controlled phase 3 trial (GRID). Lancet. 2013;381(9863):295-302.
8. Demetri GD, Jeffers M, Reichardt P, et al. Mutational analysis of plasma DNA from patients in the phase III GRID study of regorafenib versus placebo in tyrosine kinase inhibitor–refractory GIST: correlating genotype with clinical outcomes. J Clin Oncol. 2013;31(suppl): Abstract 10503.
9. Montemurro M, Gelderblom H, Bitz U, et al. Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumor and pretreatment including both imatinib and sunitinib: a retrospective analysis. Eur J Cancer. 2013;49(5):1027-1031.
10. Reichardt P, Blay J-Y, Gelderblom H, et al. Phase 3 study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol. 2012;23(7):1680-1687.
11. Zhou A, Zhang W, Chang C, et al. Phase I study of the safety, pharmacokinetics, and antitumor activity of famitinib. Cancer Chemother Pharmacol. 2013;72(5):1043-1053.