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FDA Approval for Sunitinib Malate

 Brand name(s): Sutent®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

Pancreatic Neuroendocrine Tumors

On May 20, 2011, the Food and Drug Administration (FDA) approved sunitinib (Sutent® Capsules, made by Pfizer, Inc.) for the treatment of progressive well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable, locally advanced, or metastatic disease.

The approval was based on a randomized controlled trial of sunitinib, 37.5 mg by mouth daily (n=86), versus placebo (n=85) in patients with unresectable, locally advanced, or metastatic well-differentiated pNET. Treatment with somatostatin analogs was allowed. The median age of patients was 57 years; 59 percent of the patients were Caucasian, and 48 percent were male.

The trial’s primary endpoint was investigator-assessed progression-free survival (PFS). After documented radiological progression, patients treated with placebo were permitted to receive sunitinib. Of the 85 patients treated with placebo, 69 percent subsequently received sunitinib. Secondary endpoints included overall survival (OS) and overall response rate (ORR). Prior to the pre-specified interim analysis, an independent data monitoring committee recommended termination of the trial.

The median PFS for patients treated with sunitinib was 10.2 months, compared with 5.4 months for patients treated with placebo [HR 0.427 (95 percent CI: 0.271, 0.673), p 0.001]. An improvement in PFS was observed in multiple patient subgroups, including those with prior use of somatostatin analogs. OS data were not mature at the time of the analysis. There were no complete responses.

Safety was evaluated in 83 patients who received sunitinib during the double-blind portion of the trial. The most common (at least 30 percent) grade 1-4 adverse reactions were diarrhea, nausea, asthenia, vomiting, and fatigue. The most common (at least 5 percent) grade 3-4 adverse reactions were neutropenia, hypertension, palmar-plantar erythrodysesthesia syndrome, and leukopenia.

Five patients treated with sunitinib and nine patients treated with placebo died during the study. Of the five on-study deaths in patients treated with sunitinib, one was due to cardiac failure and four were due to disease progression. An additional patient treated with sunitinib was taken off study due to cardiac failure and died two months later.

Adverse events resulted in permanent discontinuation of treatment in 22 percent of patients treated with sunitinib and 17 percent of patients treated with placebo. Dose delays and/or reductions were necessary in 61 percent of patients treated with sunitinib and 23 percent of patients treated with placebo.

The recommended dose and schedule for sunitinib is 37.5 mg by mouth daily. Patients with severe or intolerable adverse reactions may require temporary dose reductions to 25 mg daily or dose interruption.

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Advanced Kidney Cancer

On January 26, 2006, the FDA granted approval for sunitinib malate (Sutent® capsules, made by Pfizer, Inc.), for the treatment of advanced (metastatic) renal cell carcinoma (kidney cancer) based on partial response rates and response duration under accelerated approval regulations. On February 2, 2007, the FDA converted the approval of sunitinib malate for advanced kidney cancer from accelerated approval to regular approval following confirmation of an improvement in progression-free survival.

Efficacy in advanced kidney cancer patients was demonstrated in a multicenter, international randomized trial enrolling 750 patients with treatment-naïve metastatic renal cell carcinoma. Patients were randomized to receive either sunitinib or interferon-α (IFN-α).

Sunitinib was administered at a starting dose of 50 mg orally once daily for four weeks, followed by two weeks off treatment. IFN-α was given subcutaneously on three nonconsecutive days/week at a starting dose of 3 MU per dose during the first week, 6 MU per dose the second week and 9 MU per dose thereafter.

The two treatment arms were balanced for baseline demographic characteristics. Patients were required to have a component of clear cell histology. Ninety percent had prior nephrectomy. The median number of disease sites was two. Common metastatic sites included lung, lymph nodes, bone and liver.

Efficacy data were based on an interim progression-free survival (PFS) analysis by an independent data review committee. There were 96 events (25.6 percent) of progression/death on sunitinib compared with 154 events (41.1 percent) on IFN-α. Median PFS was 47.3 weeks (95 percent CI 42.6, 50.7) for sunitinib-treated patients and 22.0 weeks (95 percent CI 16.4, 24.0) for patients treated with IFN; the hazard ratio was 0.415 (95 percent CI .320, 0.539, p<0.000001).

Objective response rate on the sunitinib arm was 27.5 percent (95 percent CI 23.0 percent, 32.3 percent) vs. 5.3 percent (95 percent CI 3.3 percent, 8.1 percent) on IFN-α. Overall survival data were not mature at the time of the second interim analysis.

Treatment-emergent adverse events occurring more commonly on sunitinib included gastrointestinal events (diarrhea, nausea, mucositis, vomiting, dyspepsia, abdominal pain, gastroesophageal reflux, oral pain, glossodynia, and flatulence); bleeding; hypertension; dermatologic events (rash, skin discoloration, dry skin, and hair color changes); hand-foot syndrome; limb pain; decreases in cardiac ejection fraction; and peripheral edema. Treatment-emergent hypothyroidism was also more common in patients receiving sunitinib.

Grade 3/4 adverse events more common on sunitinib included hypertension, diarrhea, hand-foot syndrome, nausea, vomiting, mucositis, and bleeding.

Grade 3/4 laboratory abnormalities more common in sunitinib-treated patients included hematologic abnormalities (neutropenia, thrombocytopenia, and leucopenia), increased lipase, increased amylase, hyponatremia, hyperuricemia, and hyperbilirubinemia.

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Gastrointestinal Stromal Tumor (GIST)

On January 26, 2006, the FDA granted approval for sunitinib malate (Sutent® capsules, made by Pfizer, Inc.), for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on, or intolerance to, imatinib mesylate (Gleevec®).

Like imatinib, sunitinib malate is a molecularly targeted therapy that binds to and inhibits tyrosine kinase proteins involved in a tumor’s growth and blood supply. However, sunitinib malate binds to different as well as more kinase proteins than does imatinib.

Efficacy and safety in GIST patients were evaluated in a randomized, double-blind placebo-controlled trial in patients who had disease progression during prior imatinib treatment or who were imatinib-intolerant. The primary endpoint was time-to-progression (TTP).

Randomization into the treatment arms was 2:1; 207 patients were randomized to sunitinib malate and 105 to placebo. Baseline age, gender, race and performance status were comparable between the two treatment arms. Most patients enrolled (96 percent in both arms) had progressed on or within six months of completing prior imatinib therapy. Approximately 30 percent of patients were > 65 years of age and more than 98 percent had an Eastern Cooperative Oncology Group (ECOG) performance score of 0/1.

A planned interim efficacy and safety analysis was performed after 149 TTP events had occurred. A significant advantage for sunitinib malate in TTP (median 27 versus six weeks with p<0.0001; hazard ratio = 0.33) and an advantage in progression-free survival (median 24 versus six weeks with p<0.0001; hazard ratio = 0.33) were observed. Survival data are not mature.

A single-arm study conducted in GIST patients following progression on or intolerance to imatinib enrolled 55 patients following identification of the recommended phase II regimen. Five partial responses were observed (response rate 9.1 percent, 95 percent C.I. 3.0, 20.0).

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This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

  • Updated: May 24, 2011