ASCO—Axitinib (AG-013736), an oral small molecule tyrosine kinase inhibitor (TKI), yielded a 30% response rate in a phase II study of patients with metastatic or unresectable thyroid cancer unresponsive to or not suitable for standard treatment with radioactive iodine. Ezra E.W. Cohen, MD, reported the results of the 60-patient single-arm multicenter trial at the 2007 meeting of the American Society of Clinical Oncology (abstract 6008). Dr. Cohen is director, Head and Neck Oncology Program, University of Chicago.
Referring to axitinib as a "potent and selective inhibitor of VEGF receptors 1, 2, and 3," he pointed out that the IC50's for inhibition of these three receptors by axitinib "are in the subnanomolar range."
Used with permission from Pfizer.
Malignant thyroid tissue has been found to contain elevated levels of VEGF, compared with normal tissue. Axitinib, in development by Pfizer, has activity not only against VEGFR 1, 2, and 3 (picomolar potency), but also against PDGF-beta receptor and KIT (nanomolar potency).
All study patients had failed treatment with radioactive iodine or were unsuitable for this therapy (ie, those with medullary thyroid cancer). All histologic subtypes of thyroid cancer were allowed. Most patients had undergone prior surgery (88%) and prior treatment with radioactive iodine (70%). Nearly half had received prior external beam radiotherapy. A few had received prior chemotherapy (15%).
Patients received axitinib at a starting dose of 5 mg orally twice a day. They were assessed radiographically at baseline and every 8 weeks. A total of 24 patients remained in the trial as of May 2007, and 36 patients had discontinued therapy, 18 because of disease progression. The most common treatment-related adverse events included hypertension, fatigue, diarrhea/nausea, stomatitis/mucositis, and proteinuria. There was a low incidence of grade 3-4 adverse events, and there were no treatment-related deaths.
At a median follow-up of just over 1 year, the partial response rate was 30% (18 patients), 42% (25 patients) had stable disease lasting 16 weeks or longer. Patients with the greatest degree of tumor shrinkage, he said, had the greatest decrease in levels of soluble VEGFR2. Median progression-free survival was 18.6 months. A pivotal trial of axitinib in patients with doxorubicin-refractory thyroid cancer is actively accruing patients, he said.
VantagePoint
Follicular Thyroid Cancer Is 'the Most VEGFR Rich'
BARBARA ANN BURTNESS, MD
— In discussing the trial by Cohen et al, Dr. Burtness, an attending physician at Fox Chase Cancer Center, commented on the treatment-refractory nature of thyroid cancer and the "excitement" about noncytotoxic agents such as the anti-VEGF axitinib, noting that follicular thyroid cancer in particular is "the most VEGF receptor rich" (Eur J Endocrinol 153:701-709, 2005). Results of the current trial, she emphasized, "are more than sufficient to support an ongoing phase III study."
While the shorter half-life of the small-molecule tyrosine kinase inhibitor axitinib may make it more potent than a monoclonal antibody such as bevacizumab (Avastin), she cautioned that there may be a "rebound effect" of rapid tumor vasculature regrowth when axitinib is discontinued. Results of a mouse study of axitinib (J Clin Invest 116:2610, 2006) "suggest that empty sleeves of basement membrane and pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGFR therapy," she said. This potential for vascular regrowth "may not be an issue after prolonged treatment, but it has not been explored in the clinic."
On the Cover
The binding of axitinib to the kinase domain of VEGF receptors stabilizes an inactive conformation of the kinase, thus inhibiting signal transduction by VEGF. As shown, from the x-ray crystal structure of the complex with VEGFR-2, axitinib fits tightly into a tunnel in the interior of the kinase and forms many stabilizing interactions.
