GIST

Regorafenib Active in Refractory Gastrointestinal Stromal Tumors.

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Progression-free survival was significantly longer with regorafenib versus placebo after disease progression with imatinib and sunitinib.

For patients with metastatic gastrointestinal stromal tumors (GISTs), the use of tyrosine kinase inhibitors (TKIs) that target KIT and PDGFR improves disease control and survival. Adjuvant therapy with these TKIs after resection of high-risk primary disease also improves survival. However, despite the success of the TKIs imatinib as first-line therapy and sunitinib as second-line therapy, virtually all patients with metastatic GISTs ultimately develop resistance to these agents.

Investigators now report the results of an industry-supported, global, double-blinded, placebo-controlled, phase III trial of the novel, multitargeted TKI regorafenib in patients with GISTs that were refractory to both imatinib and sunitinib. A total of 199 patients were randomized 2:1 to receive oral regorafenib (160 mg daily) or placebo. Most patients had received >18 months of prior imatinib therapy (67% and 83%), most had received two prior lines of therapy (56% and 59%), and many had received more than two lines of therapy (44% and 41%).

Regorafenib recipients achieved longer progression-free survival (the primary endpoint) than placebo recipients (4.8 months vs. 0.9 months; hazard ratio, 0.27; P<0.0001) as well as higher rates of response (4.5% vs. 1.5%) and disease control (52.6% vs. 9.1%; P<0.0001). Overall survival was similar in both groups, because placebo patients were allowed to crossover to regorafenib at disease progression. Grade 3 or 4 toxicities of regorafenib included hypertension in 23% of recipients, hand-foot skin reactions in 20%, and diarrhea in 5%.

Comment: Regorafenib, a TKI with a broader spectrum of tyrosine kinase blockade than imatinib, represents an important new addition to the group of agents that are active in patients with GISTs. Studies of the molecular mechanisms of response in GISTs that are refractory to both imatinib and sunitinib are eagerly awaited.

Source:Journal Watch Oncology and Hematology

Clinical Experience to Date With Nilotinib in Gastrointestinal Stromal Tumors

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Nilotinib, a novel tyrosine kinase inhibitor (TKI) that inhibits BCR-ABL, the stem cell factor receptor (KIT), and platelet-derived growth factor receptor-alpha (PDGFRα), is approved for the treatment of patients with newly diagnosed Philadelphia chromosome–positive chronic myelogenous leukemia (CML) and those with CML that is imatinib-resistant or -intolerant. Due to its potent inhibition of KIT and PDGFRα—the two tyrosine kinases that are the central oncogenic mechanisms of gastrointestinal stromal tumors (GIST)—nilotinib also has been investigated for potential efficacy and safety in patients with GIST who have progressed on other approved treatments. Initial results have been encouraging, as nilotinib has demonstrated clinical efficacy and safety in a phase I trial as either a single agent or in combination with imatinib, as well as in heavily pretreated patients with GIST in a compassionate use program. In addition, the phase III trial of nilotinib versus best supportive care (with or without a TKI at the investigator’s discretion) indicated that nilotinib may have efficacy in some third-line patients. Furthermore, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST g1 trial), a phase III randomized, open-label study comparing the safety and efficacy of imatinib versus nilotinib in the first-line treatment of patients with GIST, is currently under way. Other studies with nilotinib either have been initiated or are in development. Based on published and accruing clinical data, nilotinib shows potential as a new drug in the clinician’s armamentarium for the management of GIST.

source: science direct