VOTRIENT FOR THYROID CANCER

September 21, 2010 — The targeted therapy pazopanib (Votrient, GlaxoSmithKline) has produced the "highest response rate yet" in patients with a rare form of advanced thyroid cancer, according to American researchers.

In a phase 2 trial, 18 of 37 patients (49%; 95% confidence interval, 35 - 68) with radioiodine-refractory progressive differentiated thyroid cancer had a partial response with pazopanib. In other words, nearly half of the patients had their tumor shrink in size by 30% or more.

The study, published online September 17 in the Lancet Oncology, also found that it is estimated that two thirds of patients have a response lasting longer than 1 year.

"In this group of patients, we would have expected the cancer to have progressed in everyone within 6 months, but instead the median time to progression was almost a year in response to pazopanib therapy," said lead author Keith Bible, MD, PhD, from the Mayo Clinic in Rochester, Minnesota, in a press statement.

It's not the first time that a kinase inhibitor has been tested in this setting, notes an editorial accompanying the study.

"Since 2005, kinase inhibitors have been tested in phase 2 trials, and motesanib, axitinib, sunitinib, and sorafenib have yielded higher response rates than cytotoxic chemotherapy, but responses have been observed in only a few patients," writes Martin Schlumberger, MD, from the Institut Gustave-Roussy in Villejuif, France.

The study authors acknowledge the lesser activity of these other kinase inhibitors, but cannot explain why pazopanib stands out. That question "remains unanswered."

All of the kinase inhibitors have strong antiangiogenic effects, achieved through the inhibition of vascular endothelial growth factor (VEGF). However, these drugs also each have "a distinct profile of kinase inhibition," note the study authors.

"Kinases other than VEGF receptor might be targeted more effectively by pazopanib than by other agents in differentiated thyroid," speculate the study authors.

In his editorial, Dr. Schlumberger points out that pazopanib is more effective in certain patients in the study. A higher proportion of patients with follicular than with papillary carcinoma (73% vs 33%) attained partial responses to pazopanib therapy and received treatment for at least 12 months, he notes.

Adverse Effects Frequent

The study authors point out that only about 5% of patients with advanced thyroid cancer develop life-threatening progressive disease. Nevertheless, the condition resulted in about 1600 deaths in 2009 in the United States, they note.

All 37 patients assessed in the study had this rapidly progressive form of thyroid cancer, which was also metastatic, radioiodine-refractory, and differentiated.

Most of the patients treated were enrolled at Mayo Clinic campuses in Minnesota and Florida.

They received 800 mg of continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred.

Up to 2 previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrollment was a requirement for inclusion.

The primary end point was any tumor response, according to the Response Evaluation Criteria in Solid Tumors (RECIST).

Maximum concentration of pazopanib in plasma during the first cycle of treatment was significantly correlated with response (P = .021), report the authors.

Adverse effects were "frequently seen," said Dr. Schlumberger. However, no "unexpected" toxic effects occurred. A total of 16 (43%) patients required dose reductions because of adverse events, say the study authors.

The most frequent adverse events of any grade were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhea (27), and nausea (27). Two patients who died during treatment had "pre-existing contributory disorders," the authors report.

What's Next?

The study authors, who are from the Mayo Clinic and a couple of other American centers, including the University of Wisconsin in Madison, note that they are currently undertaking further investigations. These include an expanded cohort of patients with differentiated thyroid cancers and separate cohorts of patients with medullary or anaplastic thyroid cancers.

The Mayo Clinic press statement notes that "plans are underway for a larger phase 3 clinical trial with aggressive differentiated thyroid cancer patients." The trial will be centered in Europe, but will have some sites in the United States.

The study was funded by the National Cancer Institute. The study authors have disclosed no relevant financial relationships, and note that the manufacturer of pazopanib (GlaxoSmithKline) did not provide funding or other material support to the researchers and did not have access to the data. Dr. Schlumberger reports receiving grant support and payment for board membership from AstraZeneca, Bayer, Exilixis, Esai, and Genzyme; receiving grant support from Amgen; and being on the speakers' bureau for Genzyme.

Lancet Oncol. Published online September 17, 2010. Abstract, Abstract