Lake BUENA VISTA, FLA. – Pazopanib is an effective therapy for advanced thyroid cancer, but at present, there seems to be no way to predict which patients will respond to it.
An investigation into the predictive value of thyroglobulin found that the level during treatment did change, but it did so in parallel with response; there was no way to use the protein to parse out which patients would do well, Dr. Keith Bible said at the International Thyroid Congress.
Dr. Keith Bible
“We had hoped that it might be a predictor as early as 4 weeks, so we could assign patients into categories of response and perhaps stop treatment earlier,” said Dr. Bible of the Mayo Clinic, Rochester, Minn. “Unfortunately, there was no way to do that.”
Pazopanib (Votrient) is a tyrosine kinase inhibitor of vascular endothelial growth factor receptors. It is approved for advanced soft tissue sarcoma and advanced renal cell carcinoma. The Mayo Clinic Consortium has been investigating pazopanib in phase II trials for advanced differentiated and medullary thyroid cancers. In a 2010 report, it was shown to induce at least a partial response in about half of the patients who received it (Lancet Oncol. 2010 Oct;11[10]:962-72).
Last year, it was also shown to be effective in advanced medullary thyroid cancer. Five of 35 patients attained partial Response Evaluation Criteria In Solid Tumors (RECIST) responses (14%) (J Clin Endocrinol Metab. 2014 May;99[5]:1687-93).
The drug has not been successful in treating advanced anaplastic thyroid cancer, however.
Because of pazopanib’s proclivity to induce sometimes-severe hypertension, investigators were hoping for some way to stratify potential responders. Thyroglobulin levels could be one marker, Dr. Bible said at the meeting, which was held by the American Thyroid Association, Asia-Oceania Thyroid Association, European Thyroid Association, and Latin American Thyroid Society.
He and the consortium investigators examined how thyroglobulin levels correlated with RECIST scores in 60 patients with metastatic differentiated thyroid cancers. The patients received a median of 10 cycles, but the range was wide (1-53 cycles). Most of them (92%) had already received systemic therapy, including a tyrosine kinase inhibitor and/or radioactive iodine.
The most common side effect was hypertension, which occurred in 75% patients, and was severe in 23%. Of those with a severe reaction, 53% required a new prescription for an antihypertensive medication. No one left the study or required a pazopanib dose reduction because of a blood pressure elevation, however. “We responded with a aggressive treatment, but it was a prominent issue,” Dr. Bible said.
Other adverse events were fatigue (83%; 8% severe); decrease in neutrophils (47%; 8% severe); diarrhea (78%; 7% severe); hand-foot syndrome (17%; 7% severe); and elevations of liver enzymes (53%; 6% severe). There were no deaths related to the study drug.
Partial RECIST responses occurred in 22 patients (37%). Thyroglobulin change did not differ by response after cycle 1, although its nadir was lower among patients who attained a partial response than among those who maintained disease stability (–87% vs. –69%).
“There was this correlation of nadir with maximum RECIST response, but this occurred in parallel with the response, so it was not capable of providing a prediction of response,” Dr. Bible said.
Prior therapy also was not a response predictor, he added.
Genomic profiling was available for 16 patients; of these, 11 had mutations of BRAF, p53, JAK3 or HRAS. Thyroglobulin change and response to treatment was not significantly correlated with any of these mutations. Nor did it correlate with any type of prior tumor therapy.
The finding that pazopanib can benefit patients previously treated with a kinase inhibitor is an interesting one, Dr. Bible noted.
“Most kinase inhibitors are very promiscuous – they work on a number of pathways and have a footprint which is very messy. Most of them seem to have some activity in differentiated thyroid cancer, but we are still struggling to understand how that footprint varies. In theory they are all targeting VEGF receptors, but it’s striking that we can go from one kinase inhibitor to the next and still get a response.”
Dr. Bible had no financial declarations.
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