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Motesanib Diphosphate Provides Anticancer Activity Among Patients with Progressive Thyroid Cancer


The investigative agent motesanib diphosphate (AMG 706) produces a regression of cancer among patients with thyroid cancer that is progressing despite standard therapies. These results were recently published in the New England Journal of Medicine.
The thyroid is a gland in the throat that produces hormones mostly related to metabolic processes in the body. According to the American Cancer Society, approximately 37,340 new cases of thyroid cancer will be diagnosed in 2008 in the United States. Nearly two-thirds of all thyroid cancers occur in people between the ages of 20 and 55. Overall, thyroid cancer is considered to be a highly curable cancer, with 97% of individuals alive at least five years following diagnosis. Nearly 95% of all thyroid cancers are classified as differentiated thyroid cancers, which refers to the type and characteristics of the cancer cells.
Standard therapy for thyroid cancer includes the removal of the thyroid, which is followed by drugs to suppress certain hormone levels related to the thyroid and radiation plus iodine (radioiodine) therapy, which is targeted to eliminate any remaining thyroid cancer cells. Patients whose thyroid cancer progresses or fails following standard therapy have a 10-year survival rate of less than 15%. Thus, novel agents targeting progressive thyroid cancers are needed.
The vascular endothelial growth factor (VEGF) is a protein that is an important component to cellular growth and replication. Often, cancer cells will have an overexpression or mutation of VEGF. Targeted therapies, including those targeted against VEGF, have recently demonstrated anticancer activity in certain types of cancers. Research into blocking VEGF continues in clinical trials.
Researchers from the M.D. Anderson Cancer Center recently conducted a clinical trial to evaluate motesanib diphosphate, a VEGF inhibitor, for the treatment of differentiated thyroid cancers that progress following standard therapies. This trial included 93 patients whose cancer had progressed following standard radioiodine therapy.
Anticancer responses were achieved in 14% of patients.
Disease stabilization was achieved in 67% of patients.
35% of patients achieved disease stabilization for at least six months.
The median duration of anticancer responses was 32 weeks.
Median progression-free survival was 40 weeks.
The most common side effects of therapy were diarrhea, increased blood pressure, fatigue, and weight loss.
The researchers concluded that motesanib diphosphate appears to provide significant anticancer activity, as well as long-lasting disease stabilization, in advanced thyroid cancer that progresses following standard therapies. Patients with progressive thyroid cancers may wish to speak with their physician regarding their individual risks and benefits of participating in a clinical trial further evaluating therapies such as motesanib diphosphate or other novel therapeutic approaches. Two sources of information regarding ongoing clinical trials include the National Cancer Institute (www.cancer.gov) and www.eCancerTrials.com.
Reference: Sherman S, Wirth L, Droz J-P, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. New England Journal of Medicine.

Nexavar® Provides Anticancer Activity in Advanced Thyroid Cancer


Nexavar® (sorafenib) provides cancer control among patients with thyroid cancer that has progressed following standard therapy. These results were recently published in the Journal of Clinical Oncology.
The thyroid is a gland in the throat that produces hormones mostly related to metabolic processes in the body. According to the American Cancer Society, approximately 37,340 new cases of thyroid cancer will be diagnosed in 2008 in the United States. Nearly two-thirds of all thyroid cancers occur in people between the ages of 20 and 55. Overall, thyroid cancer is considered to be a highly curable cancer, with 97% of individuals alive at least five years following diagnosis. Nearly 95% of all thyroid cancers are classified as differentiated thyroid cancers; the distinction refers to the type and characteristics of the cancer cells.
Standard therapy for thyroid cancer includes the removal of the thyroid, which is followed by drugs to suppress certain hormone levels related to the thyroid, and radiation plus iodine (radioiodine) therapy, which is targeted to eliminate any remaining thyroid cancer cells. Patients whose thyroid cancer progresses or fails following standard therapy have a 10-year survival rate of less than 15%. Thus, novel agents targeting progressive thyroid cancers are needed.
Researchers from the University of Pennsylvania recently conducted a clinical trial to evaluate Nexavar in the treatment of patients with advanced thyroid cancer who had stopped responding to iodine-based therapy. This trial included 30 patients who were treated with Nexavar for at least 16 weeks.
Partial anticancer responses occurred in 23% of patients.
Stabilization of cancer occurred in 53% of patients.
Total disease control (partial anticancer responses plus disease stabilization) occurred in 76% of patients.
Median progression-free survival was 79 weeks.
The researchers concluded that Nexavar provides significant anticancer activity among patients with thyroid cancer who have progressed following standard therapy, and that the results appeared to be improved compared with that of chemotherapy for patients with this disease. Patients with advanced thyroid cancer may wish to speak with their physician regarding their individual risks and benefits of participation in a clinical trial further evaluating Nexavar or other promising therapeutic agents. Two sources of information regarding ongoing clinical trials include the National Cancer Institute (www.cancer.gov) and www.eCancerTrials.com.
Reference: Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advaced thyroid cancer. Journal of Clinical Oncology [early online publication]. June 9, 2008.

Blood Vessel Inhibitor Shows Promise Against Metastatic Thyroid Cancer

Blood Vessel Inhibitor Shows Promise Against Metastatic Thyroid CancerResearchers also find evidence tying a genetic mutation to clinical outcomeThyroid cancer that has spread to distant sites has a poor prognosis, but an experimental drug that inhibits tumor blood vessel formation can slow disease progression in some patients, a research team led by investigators from The University of Texas M. D. Anderson Cancer Center reports in the July 3rd edition of The New England Journal of Medicine.The investigational drug, motesanib diphosphate, is a VEGF inhibitor, a biologic agent that targets receptors on a protein known as vascular endothelial growth factor (VEGF). VEGF is instrumental in angiogenesis (formation of new blood vessels), a process that allows tumors to grow and spread. Study lead author Steve Sherman, M.D., chair and professor of M. D. Anderson's Department of Endocrine Neoplasia and Hormonal Disorders, noted strong evidence that VEGF receptors play an important role in metastatic thyroid cancer, a disease with few 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."Sherman, colleagues in 10 countries, and scientists from Amgen, which is developing motesanib diphosphate (AMG 706), planned and conducted one of the largest clinical trials ever done for metastatic thyroid cancer. 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 their tumors shrink and 35 percent had their tumors stabilize for more than 24 weeks. Median progression-free survival was estimated to be 40 weeks.Genetic analyses of 25 patients indicated that those with a specific mutation known as BRAF V600E in their tumors had a better response to motesanib diphosphate than did those 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."Only 15 percent survive for 10 yearsFor most patients, papillary or follicular thyroid carcinomas are not lethal. Surgical removal of the thyroid-often followed by treatment with radioactive iodine-and lifelong thyroid hormone therapy are usually sufficient. But about 15 percent of patients will develop distant metastases, typically to the lungs. A small percentage of these patients will respond well to radioactive iodine treatment and survive for many years. But for others, the estimated median survival duration is two to four years, with a 10-year survival rate of less than 15 percent.Multinational trialForty-two institutions internationally participated in the 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 milligrams of oral motesanib diphosphate once a day 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.Stable Disease in 67 percent of patientsThe researchers monitored tumor response with computed tomography (CT) or magnetic resonance imaging (MRI) 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.Thirty-two patients 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.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.Phase I Program Revealed Drug's PotentialThe drug's potential benefit for advanced thyroid cancer was identified by researchers in M. D. Anderson's innovative Phase I Clinical Trials Program, led by Razelle Kurzrock, M.D., chair and professor of M. D. Anderson's Department of Investigational Cancer Therapeutics.The program typically has about 80 Phase I clinical trials under way, testing new targeted therapies for the first time in cancer patients. In addition to closely monitoring a new drug for safety, the program tests it against many different types of cancer."The molecular targets of new potential drugs are important for cancer in general, but at this stage the drugs aren't specific for any one type of cancer, so we include patients with different types on these early studies," Kurzrock said. "This gives us a unique opportunity to see response signals for the first time in specific cancers, flagging a drug for more extensive study in phase II or phase III clinical trials."In the Phase I trial led by Roy Herbst, M.D., Ph.D., 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.The phase II trial was funded by Amgen, Inc. Co-authors with Sherman are Lori J. Wirth, M.D., of the Dana-Farber Cancer Institute in Boston; Jean-Pierre Droz, M.D., of the Centre Leon Berard in Lyon, France; Michael Hofmann, M.D., Ph.D., of the Medical School Bern in Bern, Switzerland; Lars Bastholt, M.D., of Odense University Hospital in Odense, Denmark; Renato G. Martins, M.D., of the University of Washington in Seattle; Lisa Licitra, M.D., of the Istituto Nazionale dei Tumori in Milan, Italy; Michael J. Eschenberg, Yu-Nien Sun, Ph.D., Todd Juan, Ph.D., and Daniel E. Stepan, M.D., all of Amgen, Inc. in Thousand Oaks, Calif.; and Martin J. Schlumberger, M.D., of the Institut Gustave Roussy, University Paris Sud in Villejuif, France, on behalf of the Motesanib Thyroid Study Group. 07/02/08