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Axitinib, an investigational drug, shrank tumors and stabilized advanced thyroid cancers in a small but groundbreaking phase II trial.
Median progression-free survival had reached 18.6 months as of May 2007. Of 60 patients who started the single-arm trial, 24 were still on axitinib, an oral antiangiogenesis agent that inhibits vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. Duration of treatment ranged from 6 to 744 days by the data cutoff point.
"This is a disease where literally in a span of months I went from offering patients almost nothing to being able to offer them a treatment [that] I believe is efficacious," Dr. Ezra E.W. Cohen, the study's lead author, said at a press briefing before his presentation.
No new drug has been approved for thyroid cancer in at least 30 years, according to Dr. Cohen, of the University of Chicago. Doxorubicin, the only chemotherapy drug indicated for refractory thyroid cancer, is highly toxic and its effect on survival has not been tested in a randomized trial. Only 30% of people who fail standard therapy with surgery and/or radioactive iodine live 5 years.
Pfizer Oncology, developer of axitinib, provided research support, and its employees participated in the study. The company has already started a second phase II trial in thyroid cancer patients who do not respond to doxorubicin. Other companies also have begun to test their VEGF inhibitors in thyroid cancer studies.
"I can't tell you that the other ones won't work. They probably will work," Dr. Cohen said, envisioning "a day when clinicians will have more than one agent that is active in this disease, and that we probably will ... have to compare them head to head."
All histologic subtypes of thyroid cancer were allowed in the multicenter trial reported by Dr. Cohen, and every subtype appeared to respond. The patients enrolled had a median age of 59 years; slightly more than half were men. Most had prior surgery and/or iodine treatment. Nearly half had had external beam radiation. Nine patients had tried chemotherapy. The protocol called for a starting dosage of one 5-mg axitinib pill twice a day with the option to escalate.
No patient had a complete response, but 18 patients (30%) had a partial response (defined as tumor shrinkage by 31%-68%). Duration of these responses ranged from 1 to 26 months.
Another 25 patients (42%) had stable disease that remained stable for 16 weeks or more. All but two of these patients had some tumor shrinkage as well.
Among 17 patients (28%) who did not respond to axitinib, seven patients had disease progression. Disease course was described as "indeterminate/unknown" in 10 nonresponders.
As of May, 36 patients in the trial had discontinued treatment with axitinib. Five dropped out because of treatment-related adverse events (one each for proteinuria, hypertension, fatigue, cerebral vascular accident, and unspecified toxicities). Nine stopped because of adverse events (including three deaths) that were not treatment related. Another 18 patients discontinued when their disease progressed; four others broke off for unspecified reasons.
At the time of data cutoff, Dr. Cohen reported that 37 patients (62%) were "alive and without evidence of progressive disease." No deaths were treatment related.
Axitinib was well tolerated with manageable side effects, according to Dr. Cohen. Hypertension was the most common grade 3 or higher toxicity (seven patients, 12%), followed by proteinuria (four patients, 7%), fatigue (three patients, 5%), and diarrhea (two patients, 3%).
A telling finding for drug developers was that blood tests showed reduced levels of VEGF receptor 2 in nearly all patients, regardless of response. "It does appear that patients who had the greatest degree of tumor shrinkage had the greatest decrease in soluble VEGF R2," Dr. Cohen said.
In a discussion of the trial, Dr. Barbara A. Burtness, of Fox Chase Cancer Center in Philadelphia, said it gave clear evidence that axitinib is active in thyroid cancer and "more than supports" further research. Although the investigators presented "pretty good results for iodine-refractory thyroid cancer," she noted that information on postprogression outcomes was limited because patients had remained enrolled in the study.
"Although posttherapy vascular regrowth may not be an issue when a patient is on an agent 744 days ... this has not been explored in the clinic and is something we should pay attention to," she said, citing a preclinical study that reported mice revascularized after axitinib was withdrawn.
Dr. Burtness also foresaw a need for future research to address whether antiangiogenesis agents can be used earlier in the course of thyroid cancer, what the risks and benefits of multitargeted kinase inhibitors are in thyroid cancer, and which of these agents "will be best for which histology."
Cohen E.E. et al. A phase II study of axitinib (AG-013736 [AG]) in patients (pts) with advanced thyroid cancers. Abstract 6008.
Commentary |
This study of the experimental agent axitinib—along with associated trials evaluating other anti-VEGF agents, such as sorafenib, sunitinib, and vandetanib (ZD6474)—has demonstrated that there is a major role for angiogenesis inhibitors in thyroid cancer. They are the first class of agents shown to be effective in this disease. The response rates in this tumor type appear to be relatively low, however, especially compared with combination therapy in colon cancer and single-agent treatment in renal cell cancer. Among the studies evaluating vascular endothelial growth factor (VEGF) receptor inhibitors in a variety of thyroid cancers, this particular trial showed axitinib to be the most effective. Vandetanib has demonstrated considerable efficacy as well in medullary thyroid cancer. In general, it appears that the VEGF receptor inhibitors and related small molecule tyrosine kinase inhibitors are effective in this disease, and, we hope, will improve outcomes for patients with aggressive thyroid carcinoma. Whether we will be able to cure any of the many types of thyroid cancers with these agents remains to be seen, however. Combination regimens with other cytotoxic agents may show enhanced results. It is likely that we will see genetic instability emerge, and tumors will find ways of escaping treatment. We know that we can rescue some patients with other cancers using bevacizumab, so it will be interesting to see how these agents can be combined, and whether they might be synergistic. — Marshall Posner, M.D.
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