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Sunitinib Malate (Sutent) Provides Long-Lasting Responses in Imatinib Mesylate-Resistant GI Stromal Tumors: Presented at ICACT

By Jill Stein

PARIS, FRANCE -- February 2, 2006 -- The molecularly-targeted therapy sunitinib malate (SU11248, Sutent) is effective in patients with gastrointestinal stromal tumors (GIST) who have failed imatinib mesylate therapy, researchers reported here at the 17^th International Congress on Anti-Cancer Treatment (ICACT).

Their findings also show that sunitinib is associated with manageable adverse effects, the study's lead researcher said here on February 1^st.

Sunitinib is an oral highly selective, multi-targeted tyrosine kinase inhibitor with antiangiogenic and antitumor activities. The drug selectively inhibits vascular endothelial growth factor receptors, platelet-derived growth factor receptors, stem cell factor receptors, glial cell line-derived neurotrophic factor and FMS-like tyrosine kinase-3 receptor.

Lead author Jeffrey A. Morgan, MD, Chairman, Medical Oncology Division, Dana-Farber Cancer Institute, Boston, Massachusetts, United States, reported the results of the phase 2 study, which was designed to establish the optimal dose and evaluate clinical responses and safety of sunitinib at three different dosing schedules.

Their open-label, phase 1/2 study enrolled 97 patients, who were diagnosed with GIST and were refractory to the front-line drug imatinib or intolerant to imatinib.

"While first-line therapy for GIST is imatinib mesylate, secondary resistance usually develops after a year or two in patients who initially respond to the drug," Dr. Morgan observed. "In addition, nearly a fifth of imatinib-treated patients show primary resistance."

During the phase 2 portion of the study, sunitinib 50 mg/day was administered orally in 4-week cycles followed by 2 weeks off treatment.

Patients who demonstrated continued clinical benefit for more than 6 months were eligible to enter a continuation study in which additional measures of tumor progression and safety were obtained.

Dr. Morgan said that a partial response occurred in 8% of patients and stable disease in 70%, which included the 37% who had stable disease for 26 months.

Estimated time to progression was 7.8 months, and overall survival was 19.8 months.

Estimated time to progression was significantly longer in patients with pre-imatinib exon 9 versus exon 11 KIT mutations (P < .0003) and in patients with wild type KIT versus exon 11 mutations (P < .01).

Estimated time to progression was also significantly longer in patients with post-imatinib KIT exon 9 mutations only versus exon 11 mutations only (P = .002) or exon 11 plus secondary mutations (P < .003).

Overall survival was significantly longer in patients with pre-imatinib wild type KIT versus exon 11 mutations (P = .005) and in patients with KIT exon 9 versus exon 11 mutations (P = .01).

Sunitinib was generally well tolerated. Treatment-related adverse events were usually mild to moderate and included fatigue, diarrhea, skin discoloration, nausea, hand-foot syndrome, and stomatitis.

Thirty-two patients who achieved a partial response or stable disease for at least 6 months entered the continuation study and received additional sunitinib treatment.

When evaluated in April, 2005, 15 patients had no evidence of progressive disease with a median treatment time that exceeded 1.5 years.

The KIT mutational status of these 15 patients before imatinib treatment included three with the wild type gene, five with exon 9 mutations, two with exon 11-13 mutations, and five whose mutational status was not known.

Tolerability data in the continuation phase was similar to that seen in the phase 1/2 study.

Dr. Morgan said that the results of a recent phase 3 study support the efficacy of sunitinib in imatinib-resistant GIST.

The study was sponsored by Pfizer.


[Presentation title: Durable Responses to SU11248 (Sunitinib Malate) Are Observed Across All Genotypes of Imatinib Mesylate-Resistant GIST.]

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