Pazopanib: First Drug for Sarcoma in Decades

Zosia Chustecka

May 03, 2012

May 3, 2012 — Pazopanib (Votrient), approved last week in the United States for the treatment of advanced soft tissue sarcomas, is the first new drug option for these patients in decades.

Pazopanib, which targets VEGF, PDGF, and several tyrosine kinases, is already approved for the treatment of kidney cancer.

As an oral molecular targeted agent now approved for sarcoma, it offers an alternative for an orphan disease that is treated with aggressive intravenous chemotherapy, "sometimes in vain," said George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts.

This approval will stimulate further research into sarcoma, Dr. Demetri predicted. One line of investigation is whether pazopanib can be used earlier, before chemotherapy. However, Dr. Demetri noted that chemotherapy, when it works, shrinks the tumor, whereas the molecular targeted agents do not — they arrest the tumor and stop it from growing. These agents might be useful in patients who have small tumors, or several small tumors, that are not causing many symptoms. In such cases, arresting the disease with an oral drug with fewer toxic effects "would be doing them a favor," he told Medscape Medical News in an interview.

The 2 most common types of sarcoma — gastrointestinal stromal tumors (GIST) and liposarcomas — account for about 60% (30% each) of all sarcomas, but they are not covered by this approval of pazopanib. The approval covers the remaining 40% of soft tissue sarcomas, Dr. Demetri explained.

Rare Tumors of Connective Tissue

Sarcomas are rare, affecting an estimated 10,980 people in the United States in 2011, according to the American Cancer Society. They arise in mesenchymal cells, which are found in soft tissue such as fat, muscle, nerves, blood vessels, and other connective tissue.

"If the body was a house, these are the tumors that make up the 2 × 4s, as opposed to the plasterboard and the finishing touches, where most other cancers are found," Dr. Demetri said.

GIST was excluded because it has its own spectacular success story; the molecular targeted agent imatinib (Gleevec) has revolutionized the treatment of this disease, Dr. Demetri explained in an interview. "We now have patients who are alive after 12 years taking imatinib for a disease that would have killed them in 6 weeks back in 2002," he said.

"But there are many other different types of sarcoma," he continued, "and we haven't had a new drug for sarcoma since the early 1970s, when the ancient drug doxorubicin (Adriamycin) was grandfathered in as a treatment." It is still the only drug that has been technically approved for sarcoma in the United States, he added.

The standard treatment for sarcoma is aggressive intravenous chemotherapy, which is accompanied by the usual toxic effects, such as hair loss, nausea and vomiting, low white blood counts, and immune suppression. "The real problem is that it doesn't work that well," he said.

"If you have a patient with advanced incurable sarcoma, it almost seems unfair to give a treatment that will make them sick when you know that you aren't going to cure them.... That being said, where the sarcoma is large and is causing pain and suffering, the chemotherapy can shrink the tumor and give some relief, but at a sizeable human cost in terms of side effects."

The care of these patients has not changed much in 30 years, Dr. Demetri said. Having seen the revolutionary benefits of imatinib, and later sunitinib, in the treatment of GIST, there has been a hunt for molecular targeted drugs that could be useful in the remaining sarcomas. Researchers from the European Organiastion for Research and Treatment of Cancer (EORTC) sarcoma group started screening small groups of patients with new drugs, and found responses to pazopanib in many types of sarcoma. However, GIST patients were excluded from these screening studies, and the responses in patients with liposarcoma in this small screen were considered insufficient to warrant further study, Dr. Demetri explained.

Hence, the global phase 3 study, which was the basis of approval, excluded these 2 types of patients, he explained. Dr. Demetri was lead investigator for this study, known as PALETTE (Pazopanib Explored in Soft Tissue Sarcoma), conducted in collaboration with the EORTC and the manufacturer, GlaxoSmithKline. It involved 369 patients with advanced soft tissue sarcoma who had been treated with chemotherapy.

Positive Phase 3 Trial

The trial was positive, Dr. Demetri said. "For the first time, we could show that after chemotherapy had been tried and failed, this pill could stabilize the disease and give the patient some reprieve from the inexorable progression of the disease."

In it's approval, the US Food and Drug Administration (FDA) noted that pazopanib demonstrated a statistically significant and clinically meaningful increase in progression-free survival, the primary end point of the study. Median progression-free survival was 4.6 months with pazopanib and 1.6 months with placebo (hazard ratio [HR], 0.35; P < .001).

The results for overall survival trended toward pazopanib (12.6 vs 10.7 months), but the difference was not statistically significant (HR, 0.87; P = .256).

"We had to justify the benefits to an FDA advisory committee meeting," Dr. Demetri recalls, because "there was no statistically significant improvement in overall survival."

"Most of us believe that people live longer when they take this drug," he said. He suspects that the reason the trial did not show an overall survival benefit hinges on a technical detail. At the time the trial was being conducted in Europe, there was an increase in the use of another drug, trabectedin (Yondelis). Trabectedin was approved for use in advanced sarcomas in Europe in 2007, but has just recently received reimbursement (halfway through the study); this led to an increase in its use in Europe, he explained. Dr. Demetri said that many patients in the PALETTE trial were given trabectedin, which is effective, and this confounded the impact of pazopanib. (Trabectedin is not approved in the United States, although a large phase 3 trial in sarcoma is ongoing.)

There were also other confounders, he said. Patients could have gone on to receive other drugs, such as sunitinib and sorafenib; together, these factors "dampened the ability of the trial to show a survival benefit," he said.

Despite this, the trial showed that there was a benefit to controlling the disease, which was statistically proven, and that was enough for the FDA, he said. The FDA advisory committee, which met in March, voted 11 to 2 in favor of recommending the drug, and the agency approved the drug last week.

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