New Agents Hold Promise for Patients With Advanced Thyroid Cancer
By Jill Delsigne
New agents are expanding treatment options for patients with advanced thyroid cancer—not only the papillary variant but also the less common medullary and differentiated variants of the disease.
“The new drugs provide hope for patients with metastatic thyroid cancer,” said Mouhammed Amir Habra, M.D., an assistant professor in the Department of Endocrine Neoplasia and Hormonal Disorders at The University of Texas MD Anderson Cancer Center. “Until recently, there were few options besides surgery and radioiodine treatment, which has limited efficacy. Now, we have promising and more efficacious treatment that is reasonably tolerated for patients with advanced disease.”
Metastatic disease is seen in a minority of thyroid cancer patients but constitutes a large proportion of cases at MD Anderson because of referral patterns.
Partial or total thyroidectomy remains the first treatment option for metastatic thyroid cancer. Surgery is sometimes followed by radioiodine therapy, which has been used since the 1940s and was the first reported treatment to cure any type of metastatic cancer. However, because thyroid cancer cells often lose their ability to absorb iodine, radioiodine therapy has limited effectiveness against most cases of metastatic thyroid cancer.
Other treatment options for metastatic thyroid cancer were limited until recently. Maria Cabanillas, M.D., an associate professor in the Department of Endocrine Neoplasia and Hormonal Disorders, said, “Cytotoxic chemotherapy is rarely effective in thyroid cancer, so 10 years ago we had little to offer patients with metastatic disease. There also were no effective targeted therapies for patients with advanced, progressive medullary thyroid cancer or radioiodine-refractory differentiated thyroid cancer.”
Dr. Habra recalled how helpless he felt when, as an endocrinology fellow at MD Anderson in 2002, he treated a thyroid cancer patient who had lung metastases: “The tumors did not respond to treatment, and he eventually died.”
Toward better therapy
The rarity of metastatic thyroid cancer has hampered the development of more effective therapy. Steven Sherman, M.D., a professor in and chair of the Department of Endocrine Neoplasia and Hormonal Disorders, explained that 10 years ago, pharmaceutical companies were resistant to drug development for thyroid cancer.
To overcome this challenge, Dr. Sherman said, “We made a strategic decision on how to engage the pharmaceutical industry in thyroid cancer research. If we could intelligently select a drug based on molecular abnormalities in the tumor and get early evidence of response to a drug, we felt we could leverage with a pharmaceutical company to advance it.”
This strategy led to the first successful international phase II trial of a targeted therapy for metastatic thyroid cancer. The study found motesanib, a vascular endothelial growth factor (VEGF) inhibitor, to be effective against progressive differentiated thyroid cancer. This success led to clinical trials of other agents for advanced thyroid cancer. “We now have two approved drugs, cabozantinib and vandetanib, for medullary thyroid cancer and one, sorafenib, for differentiated thyroid cancer,” Dr. Cabanillas said.
With these new agents, Dr. Habra said, “We can treat some thyroid cancers as chronic conditions that can be managed long-term. These patients used to go to hospice because we had no other treatment options. Not anymore.”
Recent research in the molecular pathogenesis of thyroid cancer has revealed several new pathways for targeted therapy. Dr. Sherman said, “As in many other forms of cancer, we are now identifying critical driver oncogenes that are important in the development of thyroid cancer. The MAP kinase pathway turns out to be particularly critical for both differentiated as well as medullary thyroid cancer. Eighty to ninety percent of patients with papillary thyroid cancer, the most common histology, will have an oncogenic mutation in BRAF, RAS, or RET. With the newest findings from studies like The Cancer Genome Atlas, we can also find less common mutations that might permit targeted therapy, like mutations in ALK.”
One of the most promising new agents for advanced thyroid cancer is lenvatinib (also called E7080). Lenvatinib selectively inhibits several tyrosine kinases that contribute to angiogenesis and cancer proliferation, including VEGF 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor-β, KIT, and RET.
Drs. Cabanillas and Habra were the local co-principal investigators on lenvatinib’s phase III trial, which enrolled nearly 400 patients with radioiodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression. More than 100 sites throughout Europe, Asia, and North and South America participated in the trial.
The results of the phase III trial were presented at the American Society of Clinical Oncology’s annual conference at the beginning of June. Patients treated with lenvatinib—even those whose disease previously did not respond to anti-VEGF therapies—had a significantly longer median progression-free survival duration (18.3 months) than placebo-treated patients did (3.6 months). Several patients treated with lenvatinib experienced a complete response to therapy. The drug’s most common side effects were hypertension, diarrhea, decreased appetite, weight loss, and nausea. Dr. Habra said the U.S. Food and Drug Administration is likely to approve the drug for differentiated thyroid cancer by the end of this year.
Other clinical trials are investigating drugs that target the BRAF protein kinase in papillary thyroid cancer. According to the American Thyroid Association, the V600E BRAF point mutation occurs in approximately 50% of papillary thyroid cancers and is associated with lymph node metastasis, distant metastasis, disease recurrence, and loss of radioiodine avidity, making the mutation a promising therapeutic target.
One such clinical study, led by Dr. Cabanillas, is investigating the effects of the BRAF inhibitor vemurafenib in patients with metastatic papillary thyroid cancer. According to the trial’s preliminary report, 9 of the 26 treatment-naïve patients in the study had a confirmed partial response to the therapy (a more than 30% reduction in tumor size). These results were presented at the 2013 European Cancer Congress.
Unfortunately, papillary thyroid cancer can become resistant to BRAF inhibitors, resulting in only a partial response to therapy. Another research group at MD Anderson is investigating the mechanism of this drug resistance. The group is led by Marie-Claude Hofmann, Ph.D., a professor in the Department of Endocrine Neoplasia and Hormonal Disorders. The group’s preclinical research focuses on the role that estrogen receptors play in drug resistance to BRAF inhibitors, and the findings may also explain why papillary thyroid cancer occurs predominantly in women.
Despite the advances made so far, more progress is needed. According to Dr. Cabanillas, “We need to focus on salvage therapy, mechanisms of resistance, and finding a cure.”
Fortunately, Dr. Habra said, “We are starting to understand the molecular pathways and genetics of thyroid cancer. We can pinpoint treatments that are based on molecular markers, not just pathologic results, to choose the best treatment for each individual patient.”
For more information, contact Dr. Maria Cabanillas at 713-792-2841, Dr. Mouhammed Amir Habra at 713-792-2841, or Dr. Steven Sherman at 713-792-2841.
Thyroid Cancer Facts and Figures
The number of patients diagnosed with thyroid cancer has been rising in recent years, perhaps because advances in imaging modalities (particularly ultrasonography) facilitate earlier detection of the disease.
The American Cancer Society estimates that nearly 63,000 patients will be newly diagnosed with thyroid cancer in 2014. Of these new patients, the vast majority—more than 47,000—will be women. Nearly 1,900 people will die of the disease.
The most common types of thyroid cancer are papillary carcinoma, which accounts for 80% of cases, and follicular carcinoma, which accounts for 10% of cases. Fortunately, these types of thyroid cancer usually grow very slowly. Medullary thyroid carcinoma accounts for approximately 4% of thyroid cancer cases. This type of cancer can spread to other tissues before a thyroid nodule is even detected. However, medullary thyroid carcinoma can often be detected early by blood tests for calcitonin and carcinoembryonic antigen. The most aggressive form of thyroid cancer, anaplastic carcinoma, constitutes only 2% of thyroid cancer cases.
OncoLog, June 2014, Volume 59, Issue 6