A Phase II trial has shown that sorafenib (Nexavar? , Bayer Healthcare/Onyx Pharmaceuticals), an oral targeted tyrosine kinase inhibitor, may be an effective alternative for those patients with gastrointestinal stromal tumors (GIST) that are resistant to standard therapies. The study results were presented during the eighth annual Gastrointestinal Cancers Symposium, held January 20-22, 2011, at The Moscone West Building in San Francisco, Ca.

Patients with GIST, a type of soft tissue sarcoma that occurs in the stomach, small bowel, or other sites in the gastrointestinal tract, usually have a mutation in the KIT or PDGFRA gene. The tyrosine kinase inhibitor imatinib (Gleevec? , Novartis Oncology) targets those overactive genes, and is effective in more than 80 percent of patients with advanced GIST. But most eventually develop resistance, and the disease progresses. Another tyrosine kinase inhibitor, sunitinib (Sutent?, Pfizer), is approved for treating patients in whom imatinib is ineffective.

?There is an urgent need for additional agents to treat patients with imatinib- and sunitinib-refractory GIST, since there are no FDA-approved options for these patients other than resumption of imatinib,? said lead author and University of Chicago Oncology fellow Nicholas P. Campbell, MD.

In the Phase II prospective trial, researchers at six centers examined the effectiveness of sorafenib in 38 GIST patients whose disease continued to worsen, despite treatment with imatinib and sunitinib. Sorafenib inhibits a wide range of tyrosine kinase mutations, including many of the secondary mutations that develop in patients who become resistant to imatinib and sunitinib. Among the 38 patients, 6 were resistant to imatinib and 32 were resistant to both imatinib and sunitinib. The researchers found that sorafenib controlled tumors in 68% of the patients. Tumors shrank in 13% of patients (partial response) and the disease did not progress in an additional 55% of patients (stable disease). The one- and two-year overall survival was 44% and 21%, respectively.

Side effects from sorafenib included hypertension, fatigue and hand-foot syndrome, which involves dry, peeling skin. As a result, approximately 63 percent of the patients required dose reductions, though the drug was still effective at lower doses. Imatinib?s side effects tend to be relatively modest, while side effects from sunitinib ? especially fatigue ? can be worse than imatinib.

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?Most of these patients had received two lines of therapy and had nothing left to try. Despite this, more than two-thirds achieved stabilization of their disease or better. Many were maintained on sorafenib for extended periods ? up to three years ? and did quite well. These results give us hope that we can find additional treatment options for these patients,? said senior author Hedy Lee Kindler, MD, associate professor of medicine at the University of Chicago.

For more information:
Campbell NP, Wroblewski K, Maki RG, D’Adamo DR, Chow WA, Gandara DR, Final results of a University of Chicago phase II consortium trial of sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST) Abstract #4.

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