Pazopanib for Sarcoma Approved in Europe

Zosia Chustecka

August 08, 2012

August 8, 2012 — Pazopanib (Votrient, GlaxoSmithKline) has been approved by the European Medicines Agency for the treatment of adults with advanced soft tissue sarcoma. The indication covers more than 20 subtypes of sarcoma, but excludes gastrointestinal stromal tumors (GISTs) and adipocytic sarcomas, and is for second-line use in patients who have received previous chemotherapy for metastatic disease or who have progressed within 12 months of (neo)adjuvant therapy.

Approval for this indication was granted in the United States in April.

Pazopanib, an oral targeted agent, is already marketed for use in the treatment of kidney cancer.

The drug inhibits angiogenesis and tumor cell proliferation through its action on several factors, including vascular endothelial growth-factor receptors (VEGFR-1, 2, and 3), platelet-derived growth-factor receptors (PDGFR-α and β), fibroblast growth-factor receptors (FGFR1 and 3), stem cell factor receptors (c-Kit), interleukin-2-inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein-receptor tyrosine kinase (c-Fms).

Alternative to Chemotherapy

"I am delighted that we will now have another systemic treatment option for patients with soft tissue sarcoma," said Ian Judson, MD, head of the sarcoma unit and professor of cancer pharmacology at the Royal Marsden Hospital in London, United Kingdom. "This is a welcome and much needed addition to the treatments currently available, and good news for sarcoma patients," he stated in a GlaxoSmithKline press release.

Soft tissue sarcomas are rare cancers that develop in the supporting or connective tissues of the body, such as muscle, nerves, cartilage, blood vessels, and fat, the release notes. The prognosis for these patients is poor; from diagnosis of advanced disease, median survival is around 12 months, and 5-year survival rates are less than 20%.

This approval for pazopanib is based on the results of the recently published pivotal phase 3 PALETTE (Pazopanib Explored in Soft Tissue Sarcoma) study (Lancet. 2012;379:1879-1886).

Pazopanib is the first active oral agent for patients with non-GIST and nonadipocytic soft tissue sarcomas, and is "a meaningful addition to the treatment armamentarium for patients with this rare group of tumors," the PALETTE authors note.

In that trial, pazopanib showed a significant improvement in progression-free survival, compared with placebo (4.6 vs 1.6 months; P < .001). Half the patients who received pazopanib showed some degree of tumor shrinkage, whereas only 12% of the patients who received placebo did. Pazopanib also doubled the percentage of patients who experienced disease stabilization, compared with placebo (54% vs 27%).

However, there was no significant difference in overall survival between the pazopanib and placebo groups (12.5 vs 10.7 months; P = .25).

In an editorial that accompanied the PALETTE study (Lancet. 2012;379:1854-1856), Vivien Bramwell, MBBS, PhD, from the Tom Baker Cancer Center in Calgary, Alberta, Canada, questioned whether a significant improvement in progression-free survival but not overall survival is a clinically significant benefit in advanced soft tissue sarcoma.

However, in an interview with Medscape Medical News, George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, and lead author of PALETTE, suggested that using an oral agent in these patients could be preferable to the alternative.

The standard treatment for sarcoma is aggressive intravenous chemotherapy, he explained, which is accompanied by the usual toxic effects, such as hair loss, nausea and vomiting, low white blood counts, and immune suppression.

In PALETTE, the most common adverse events with pazopanib (experienced by 30% of patients or more) were fatigue, diarrhea, nausea, weight decrease, hypertension, decreased appetite, hair color changes, and vomiting. The majority of events were mild to moderate.

But the real problem with chemotherapy is that "it doesn't work that well," Dr. Demetri 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.... 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."

When it works in sarcoma, chemotherapy shrinks the tumor, whereas targeted agents such as pazopanib do not — they arrest the tumor and stop it from growing, he explained. Given the serious toxic effects associated with aggressive chemotherapy (usually an anthracycline such as doxorubicin, either alone or in combination with ifosfamide), arresting the disease with an oral drug with less toxicity would be doing patients who have a small tumor or tumors that are not causing many symptoms "a favor," he said.


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