SILVER SPRING, MD. – A Food and Drug Administration advisory panel supports approval of the angiogenesis inhibitor pazopanib as a treatment for advanced soft-tissue sarcoma, despite some concerns about the degree of response in the main study considered for approval.
At its March 20 meeting, the Oncologic Drugs Advisory Committee (ODAC) voted 11-2 that pazopanib (Votrient) has a favorable risk-benefit profile as a treatment for advanced soft-tissue sarcoma (STS) in patients who have received prior chemotherapy, the new indication proposed by the manufacturer, GlaxoSmithKline.
In the pivotal placebo-controlled PALETTE study, the gain in median progression-free survival was 3 months, which was significant. The difference in median overall survival, a secondary end point, was 1.9 months, however, and this was not statistically significant.
Although panelists agreed that the effects of the drug were marginal, those voting in favor of approval said that they believed the effect was real. They reasoned that a 3-month benefit was meaningful to patients, as there are few options available for this rare tumor.
Several were encouraged by the fact that 14% of patients in the study remained still on treatment after 1 year (compared with 1% of those on placebo). Panelists also said that having a noncytotoxic treatment option for soft-tissue sarcomas would be beneficial.
Pazopanib, a tyrosine kinase inhibitor, targets the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and stem cell growth factor. It was approved in 2009 for the treatment of advanced renal cell carcinoma.
In the double-blind, phase III study, patients with soft-tissue sarcoma who had progressed during or following prior chemotherapy (including anthracyclines) were randomized to pazopanib, 800 mg daily, in tablet formulation (246 patients) or placebo (123 patients). They were examined every 4 weeks during a 12-week period and then every 8 weeks until evidence of progression, death, excessive toxicity, or patient withdrawal.
A little more than half the patients were female, their median age was 51-56 years; most were from the European Union, 12% were from the United States. The most common histologies were leiomyosarcoma (40% on placebo and 44% on pazopanib) and synovial sarcoma (11% and 10%, respectively).
Median progression-free survival, the primary end point, reached 4.6 months among those on pazopanib, compared with 1.6 months among those on placebo, a statistically significant difference that represented a 65% reduced risk.
Treatment was not associated with a statistically significant improvement in overall survival, however. It reached 12.6 months among those on pazopanib and 10.7 months among those on placebo, for a reduced risk of 13%.
With a few exceptions, the safety profile in sarcoma trials was similar to the safety profile of patients in renal cell carcinoma studies, with adverse effects that included hepatoxicity, hypothyroidism, and hemorrhagic events.
"From my own experience of treating many sarcoma patients, this is a drug I would like to have in my armamentarium," panelist Dr. Lee J. Helman, scientific director for clinical research, at the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.
While he would have liked to see a greater impact on progression-free survival, he said, "It’s a little step ... but it’s a little step in a field that has had nothing."
The company has proposed that the indication include the statement "Important limitations of use: The phase [III] STS trial population excluded patients with adipocytic STS or gastrointestinal stromal tumors."
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.
Occasionally, a panelist may be given a waiver and at this meeting, Dr. Deborah K. Armstrong was granted a waiver to participate in the meeting, because of her expertise in STS. The conflict pertained to study grants received by her employer, the Sidney Kimmel Comprehensive Cancer Center in Philadelphia, according to the FDA.