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New vascular endothelial growth factor inhibitor motesanib may slow disease progression in some patients with metastatic differentiated thyroid cancer

The new vascular endothelial growth factor inhibitor motesanib diphosphate may slow disease progression in some patients with metastatic differentiated thyroid cancer, according to an article in the July 3 issue of the New England Journal of Medicine.

Lead author Steven I. Sherman, MD, chair and professor of M. D. Anderson Cancer Center's Department of Endocrine Neoplasia and Hormonal Disorders noted there is strong evidence suggesting that vascular endothelial growth factor (VEGF) receptors play an important role in metastatic thyroid cancer, a disease with few current treatment options.

"There is no standard accepted chemotherapy for advanced metastatic differentiated thyroid cancer, and response rates have typically been 25 percent or less," Sherman said. "Most patients are not treated with systemic chemotherapy because the limited benefit rarely justifies the side effects. Treatment of thyroid cancer has been a completely unmet need."

Forty-two institutions internationally participated in the phase II clinical trial, including an important collaboration with the Institut Gustave Roussy, M. D. Anderson's sister institution in Villejuif, France. The study enrolled patients with progressive, locally advanced or metastatic, radioiodine-resistant thyroid cancer.

Study participants took 125 mg oral motesanib diphosphate once daily for 48 weeks or until they experienced unacceptable side effects or disease progression. The primary treatment outcome was radiographic evidence of tumor shrinkage as determined by an independent review. The researchers also analyzed the duration of tumor response, progression-free survival, and drug safety.

The researchers monitored tumor response with computed tomography or magnetic resonance imaging scans of the neck, chest, and abdomen every eight weeks or in response to signs of disease progression. Partial or complete responses to the drug were evaluated by independent review and confirmed with repeat scans four or more weeks later.

Of the 93 patients, 32 completed the full 48 weeks of treatment. Motesanib diphosphate was discontinued in 35 patients because of disease progression and in 12 patients because of drug-related adverse events. Five patients died, and nine withdrew for various administrative or personal reasons.

Thirteen patients (14 percent) achieved an objective partial response to the drug. Sixty-two patients (67 percent) experienced stable disease during the study; 33 of these (35 percent) achieved durable stable disease for at least 24 weeks. Nine patients (10 percent) had unconfirmed partial responses, which were classified as stable disease. Seven patients (8 percent) experienced only disease progression, and no response information was available for 11 patients (12 percent) because of incomplete or uninterpretable radiographic scans. A total of 67 percent of patients were considered to have stable disease.

Eighty-seven patients (94 percent) experienced at least one treatment-related adverse event. The most common events were diarrhea, hypertension, fatigue, and weight loss. In 51 patients, the adverse events were classified as severe (grade 3). Five patients had grade 4 (life-threatening) adverse events, including low calcium levels, high levels of uric acid, low potassium levels, cerebral hemorrhage, mental confusion, agitation, or decreased urine production. Two patients whose disease had progressed died of pulmonary hemorrhage.

Of the 93 patients with rapidly progressing cancer who were enrolled in the study, 49 percent had a positive response. From that group 14 percent had tumor shrinkage and 35 percent had tumor stabilization for more than 24 weeks. Median progression-free survival was estimated to be 40 weeks.

Genetic analyses of 25 patients indicated that patients with a specific mutation known as BRAF V600E in their tumor cells had a better response to motesanib diphosphate than patients without the mutation. Additional research is needed on this genetic connection, but the early results are a good start, Sherman said.

"Finding that patients whose tumors bear a particular mutation were more likely to respond to the drug is an example of where we would like to head in our research," Sherman said. "This is the first of the various thyroid cancer trials to identify specific mutations that might allow us to individualize or personalize therapy."

In the Phase I trial led by Roy Herbst, MD, PhD, professor in M. D. Anderson's Department of Thoracic/Head and Neck Medical Oncology, two out of five study patients with metastatic differentiated thyroid cancer responded to the drug, which was then taken directly to Sherman's phase II study. Other therapies are being rapidly transitioned from Kurzrock's program to Sherman's or other groups to establish efficacy as soon as evidence of response is seen in the phase I trial.


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