Pazopanib: New Drug for Advanced Soft-tissue Sarcoma


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

In April 2012, pazopanib (Votrient) was approved for the treatment of patients with advanced soft-tissue sarcoma who have received prior chemotherapy.1,2 The efficacy of pazopanib for the treatment of patients with adipocytic soft-tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated. Pazopanib has a prior indication in the treatment of advanced renal cell carcinoma.

Approval in advanced soft-tissue sarcoma was based on a multicenter trial in which 369 patients with metastatic soft-tissue sarcoma who had received prior chemotherapy including an anthracycline were randomly assigned (2:1) to receive double-blind oral pazopanib at 800 mg once daily (n = 246) or placebo (n = 123).2 Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Patients had a median age of 55 years, 59% were female, 72% were Caucasian, and 56% had received two or more prior systemic therapies. The proportions of patients in the three prespecified histologic subgroups of leiomyosarcoma, synovial sarcoma, and other soft-tissue sarcomas were 43%, 10%, and 47%, respectively.

Median treatment durations were 4.5 months in the pazopanib group and 1.9 in the placebo group. Median progression-free survival—the primary endpoint of the trial—was 4.6 months in the pazopanib group vs 1.6 months in the placebo group, representing a significant 65% reduction in risk of progression with pazopanib (HR = 0.35, 95% CI = 0.26–0.48, P < .001).

In the three histologic subgroups, risk of progression was significantly reduced with pazopanib by 63% (HR = 0.37, 95% CI = 0.23–0.60) among patients with leiomyosarcoma, 57% (HR = 0.43, 95% CI = 0.19–0.98) among patients with synovial sarcoma, and 61% (HR = 0.39, 95% CI = 0.25–0.60) among patients with other soft-tissue sarcomas. These improvements were consistent with the progression-free survival improvement observed with pazopanib treatment in the overall population.

The objective response rate was 4% for patients receiving pazopanib and 0% in the placebo group. Median overall survival was nonsignificantly increased in the pazopanib group (12.6 vs 10.7 months, HR = 0.87, 95% CI =0.67–1.12).

How It Works

Pazopanib is an antiangiogenic multi–tyrosine kinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor (PDGF) receptors, and c-kit, among other receptors.2,3 VEGF is expressed in many types of soft-tissue sarcoma, with increased expression being associated with higher malignancy grade and poorer metastasis-free and overall survival in localized disease. VEGF blood levels are elevated in patients with soft-tissue sarcoma compared with controls and are correlated with histologic grade of the primary tumor. PDGF is also believed to be involved in soft-tissue sarcoma angiogenesis.

How It Is Given

Pazopanib is given at 800 mg once daily without food, at least 1 hour before or 2 hours after a meal. Tablets should not be crushed. The dose should not exceed 800 mg. Dose changes should be performed in 200-mg steps based on individual tolerability.

Alternatives to pazopanib should be considered in patients with moderate hepatic impairment; in these patients, pazopanib should be started at 200 mg/d. Pazopanib is not recommended in patients with severe hepatic impairment. No dose adjustment is required in patients with mild hepatic impairment.

Concomitant use of strong CYP3A4 inhibitors (for example, protease inhibitors [ritonavir, idinavir], some macrolide antibiotics [clarithromycin], and some antifungals [ketoconazole, itraconazole]) increases pazopanib concentrations and should be avoided. If use of a strong CYP3A4 inhibitor is warranted, the pazopanib dose should be reduced to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. Strong CYP3A4 inducers may decrease pazopanib concentrations and should be avoided. Pazopanib should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers.

Safety Profile

The most common (≥ 20%) adverse reactions (any grade) in patients with soft-tissue sarcoma in the randomized, double-blind trial were fatigue (65% vs 48% in placebo group), diarrhea (59% vs 15%), nausea (56% vs 22%), weight loss (48% vs 15%), hypertension (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%).2

Grade 4 adverse events were infrequent. The most common grade 3 adverse events in pazopanib patients were fatigue (13%, 1% grade 4), tumor pain (8%; 7% grade 3 and 2% grade 4 in the placebo group), hypertension (7%), and decreased appetite (6%). Other significant adverse events reported in pazopanib-treated patients included hepatic toxicity, arterial and venous thrombotic events, hemorrhage, gastrointestinal perforation and fistula formation, pneumothorax, and left ventricular dysfunction.

The most common laboratory abnormalities (all grades) in pazopanib recipients were increased AST (51%), increased ALT (46%), increased glucose (45%), leukopenia (44%), and lymphocytopenia (43%). Other abnormalities that occurred in > 15% of pazopanib-treated patients and with at least 5% greater frequency than in the placebo group were (in order of decreasing frequency) thrombocytopenia, decreased albumin, neutropenia, decreased alkaline phosphatase, decreased sodium, increased total bilirubin, and increased potassium. The most frequent grade 3/4 abnormalities in pazopanib patients were lymphocytopenia (10%/0%), increased AST (8%/2%), and increased ALT (5%/3%).

Pazopanib carries a boxed warning for hepatotoxicity. Severe hepatotoxicity, including fatal hepatotoxicity, has been observed in clinical trials. Hepatic function must be assessed prior to starting treatment and monitored regularly during treatment, and evidence of hepatic toxicity requires dose reduction, interruption, or discontinuation. Pazopanib also carries warnings/precautions for QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial thrombotic events, venous thromboembolic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, wound healing, hypothyroidism, proteinuria, infection, and increased toxicity with other cancer therapy. Pazopanib may cause fetal harm. Interruption of pazopanib treatment is recommended in patients undergoing surgery. ■

References

1. U.S. Food and Drug Administration: Hematology/oncology (cancer) approvals & safety notifications. Pazopanib. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm302090.htm.

2. VOTRIENT (pazopanib) tablets, prescribing information. GlaxoSmithKline, April 2012. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022465s-010S-012lbl.pdf.

3. Sleijfer S, Ray-Coquard I, Papai Z, et al: Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: A phase II study from the European Organisation for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group (EORTC study 62043). J Clin Oncol 27:3126-3132, 2009.



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