TARGETED THERAPY FOR THYROID CANCER

August 10, 2009 (Toronto, Ontario) — Drug therapy has never figured largely in the treatment of thyroid cancer because traditional chemotherapy has little effect on the disease, but the new targeted therapies are making an impact. Several of these agents have shown activity in early clinical trials that has been hailed as "promising," and the accumulating data are generating considerable excitement among physicians treating these patients.

"These are the first drugs that have been shown to work and that have shown results," said Manisha Shah, MD, from Ohio State University Comprehensive Cancer Center in Columbus, who has headed one of these trials. "About 50% of patients benefit," she added.

At a session here at the World Congress on Thyroid Cancer 2009, Steven Sherman, MD, from the University of Texas MD Anderson Cancer Center in Houston, contrasted the situation now with the position 10 years ago, when there were no clinical trials at all in thyroid cancer. Even by 2005, no clinical trial in thyroid cancer had succeeded, mainly because of poor recruitment of patients.

The progress being seen now is because of close collaboration between endocrinologists and medical oncologists, a better understanding of the biology of the disease, and the emergence of the new targeted therapies, he told Medscape Oncology.

Sorafenib, sunitinib, axitinib, and motesanib have all shown activity in patients with differentiated thyroid cancer, as have vandetanib and XL184, which have shown activity in medullary thyroid cancer (MTC). There is also E7080, which is in clinical trials in both differentiated thyroid cancer and MTC, although no data have yet been reported with this agent, Dr. Sherman noted.

Many of these drugs are still under development, but sorafenib (Nexavar, Bayer/Onyx) and sunitinib (Sutent, Pfizer) are already marketed for use in several cancers, although not thyroid cancer.

All of these drugs are tyrosine kinase inhibitors, although they vary in their specific targets. However, a "common theme" is that they all inhibit the vascular endothelial growth-factor receptor, Dr. Sherman noted.

Although the data so far look promising, these drugs "are not curing patients," Dr. Sherman noted. There are no complete responses, he pointed out. They do seem to be effective in stabilizing patients with rapidly progressing cancer and they are prolonging progression-free survival, but whether this will translate into an increase in overall survival is unclear. For that, data from larger placebo-controlled trials are needed, he added.

Review of Results So Far

Dr. Shah reviewed the phase 2 data for differentiated thyroid cancer, summarized in the table below. She was involved in 1 of the 2 trials conducted with sorafenib, which is already on the market. Axitinib is under development by Pfizer and motesanib is being developed by Amgen.

Results from Phase 2 Trials

Results	Sorafenib, n = 58	Sorafenib, n = 30	Axitinib, n = 60	Motesanib, n = 93
Differentiated thyroid cancer (%)	93	90	75	95
Partial response (%)	15	23	30	14
Stable disease (%)	57	53	38	67
Median progression-free survival (months)	16	20	18	10

The results with axitinib and motesanib were highlighted as an advance in cancer research last year by the American Society of Clinical Oncology.

Dr. Shah cautioned against making direct comparisons because each trial had a slightly different patient population and different inclusion and exclusion criteria, but she told Medscape Oncology that the results seen in all of these trials were "in the same ball park."

At the same session, Dr. Sherman reviewed the data accumulating for MTC, which is much less common. Currently, the greatest interest is focused on XL184 and vandetanib, he told Medscape Oncology. Both of these drugs are now in phase 3 trials and the results are "eagerly awaited," he added.

A phase 2 trial with vandetanib (under development by AstraZeneca) showed a "slow and steady shrinkage of the tumor," with 33% of MTC patients achieving a partial response, and 63% achieving stable disease, Dr. Sherman noted.

Results for XL184 (under development by Exelixis) come from a phase 1 trial in which Dr. Sherman was involved; they were detailed at the meeting. The trial involved 85 patients, 34 of whom had MTC. A partial response was recorded in 14 of these 34 patients (41%), and the majority derived clinical benefit. This drug has gone straight from a phase 1 tril to a phase 3 international randomized trial, Dr. Sherman said.

Sorafenib has also shown activity in MTC. A phase 2 study of 19 patients reported earlier this year showed partial responses in 11% of patients and stable disease in 84%, he noted.

Sorafenib is now being tested in combination with tipifarnib in a phase 1 trial by Dr. Sherman's team. Tipifarnib was developed by Johnson & Johnson (as Zarnestra) for acute myeloid leukemia, but failed to get approval in 2005. It was added to sorafenib in this trial because it blocks pathways, important in MTC, that are not inhibited by the tyrosine kinase inhibitors, Dr. Sherman explained.

Results with the combination from the first 9 evaluable patients, presented at the meeting, show that "virtually every patient had some shrinkage of their tumor," he said. "When you compare the progression of the tumor in the year before treatment with that seen during treatment, you get a gut sense that these drugs are having a beneficial effect in this cancer," he added.

However, 1 of the phase 2 trials in MTC had disappointing results. The MTC portion of trial with motesanib failed to achieve its primary end point; partial response was seen in only 2% of the 91 enrolled patients. However, 81% of patients showed stable disease, which suggests that they were responding to the drug, just not enough to reach the partial-response level, Dr. Sherman noted. He added that pharmacokinetic analysis suggested the blood levels of the drug were low, and that higher doses might be needed.

Toxicity With Targeted Therapies

Both researchers highlighted the toxicities that can occur with the targeted therapies, and emphasized the need to monitor these patients closely. Dr. Sherman noted, in particular, concern over the fact that squamous cell carcinoma has been reported as an adverse event in patients receiving sorafenib, as well as some of the other agents.

In 1 series of patients with renal cell carcinoma, 5% developed squamous cell carcinoma and another 5% were found to have precancerous lesions, he said. The mechanism is unclear, but in patients showing this toxicity with sorafenib, the lesions appeared within 2 months of therapy initiation and receded when the patients were switched to sunitinib, he told meeting attendees. When asked whether it was only the skin that was affected, Dr. Sherman replied that it might not be — 1 patient also had a suspicious lesion in the lung — and he urged monitoring of all epithelial surfaces.

The toxicity of these targeted agents is a particular worry in thyroid cancer patients, because they could be taking these drugs for a long time, maybe years, he told Medscape Oncology. Patients who have been diagnosed with thyroid cancer live for many years — the specific-cause mortality rate with differentiated thyroid cancer is only 2%, and although the prognosis is worse for MTC, the 5-year survival rates are around 50% to 60%, other speakers noted.

"These drugs are not suitable for all patients with thyroid cancer," Dr. Sherman emphasized. They are not useful for patients with stable disease or those with slow-growing cancers, as this is the end result of the therapy, so "it's not worth the toxicity," he said. But they might make a difference in patients who have rapidly progressing disease, with cancer growing at a rate of 20% to 40% each year, he said.

The best place for these patients is in clinical trials, he continued. In fact, clinical trials are often the only option; most of the drugs of interest for thyroid cancer are still under development. Neither of the 2 already on the market is officially approved for use in thyroid cancer, although they could be used off label in such patients. In the United States, the National Comprehensive Cancer Network and the American Thyroid Association have both recommended that they can be used in the treatment of advanced disease, and because of this, such a use may be covered by medical-insurance organizations such as Medicare, Dr. Sherman noted.

As previously reported by Medscape Oncology, the results with targeted therapies in thyroid cancer have been welcomed enthusiastically, and have even led some experts to suggest that a paradigm shift in the treatment of thyroid cancer is not far off.

Dr. Sherman reports receiving research funding from Amgen, AstraZeneca, Eisai, Genzyme, the National Cancer Institute, and the V Foundation; receiving honoraria from Exelixis and Genzyme; serving as a consultant for Bayer, Exelixis, Eisai, Oxygen, Plexicor, Semaphore, and Eli Lily; and serving as a speaker for Genzyme. Dr. Shah reports receiving honoraria from Exelixis, Bayer, and Novartis.

World Congress on Thyroid Cancer (WCTC) 2009: Abstract 052, presented August 8, 2009; Abstract 0153, presented August 9, 2009.