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Regulatory Issues: FDA

Food and Drug Administration Drug Approval Summary: Sunitinib Malate for the Treatment of Gastrointestinal Stromal Tumor and Advanced Renal Cell Carcinoma

^a Division of Drug Oncology Products, ^b Office of Biostatistics, and ^c Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

Key Words. Sunitinib • Sutent • Gastrointestinal stromal tumor • Renal cell carcinoma

Correspondence: Edwin P. Rock, M.D., Ph.D., Food and Drug Administration, Division of Drug Oncology Products, 10903 New Hampshire Avenue, Bldg. 22, Rm. 2133, Silver Spring, Maryland 20903, USA. Telephone: 301-796-2330; Fax: 301-796-9845; e-mail: edwin.rock{at}fda.hhs.gov

Received April 25, 2006; accepted for publication September 23, 2006.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Gastrointestinal Stromal Tumor Renal Cell Carcinoma Safety Marketing Authorization Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Discuss the mechanism of action of the newly approved targeted cancer drug sunitinib.
   
2. List the current approved oncology indications for this agent.
   
3. Describe the pharmacology, metabolism, and side effect profile of sunitinib.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Gastrointestinal Stromal Tumor Renal Cell Carcinoma Safety Marketing Authorization Disclosure of Potential... References

 
On January 26, 2006, sunitinib (Sutent) received regular approval as monotherapy for the treatment of patients with gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate (Gleevec). Time-to-tumor progression (TTP) of sunitinib-treated patients was superior to that of placebo-treated patients. Median TTP of sunitinib-treated patients was 27.3 weeks, compared with 6.4 weeks for placebo-treated patients (p < .0001). Partial responses were observed in 6.8% of sunitinib-treated patients and no placebo-treated patients. Sunitinib also received accelerated approval on January 26, 2006, as monotherapy for treatment of advanced renal cell carcinoma (RCC). In two single-arm trials of sunitinib in patients with metastatic RCC, partial responses were observed in 25.5% (95% confidence interval [CI], 17.5, 34.9) and 36.5% (95% CI, 24.7, 49.6) of patients. Median response durations in the two trials were 27.1 weeks (95% CI, 24.4, incalculable) and 54 weeks (95% CI, 34.3, 70.1). Treatment-emergent adverse events in sunitinib-treated patients included diarrhea, mucositis, skin abnormalities, altered taste, electrolyte abnormalities, hypertension, and diminution in left ventricular ejection fraction. Cardiac safety of sunitinib in patients with preexisting cardiac abnormalities remains unknown. Based on nonclinical findings, physicians prescribing sunitinib should monitor for adrenal insufficiency in patients who undergo stressors such as surgery, trauma, or severe infection. Caution should be exercised when administering sunitinib in combination with known CYP3A4 inducers or inhibitors.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Gastrointestinal Stromal Tumor Renal Cell Carcinoma Safety Marketing Authorization Disclosure of Potential... References

 
Sunitinib (N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide) is an orally administered small molecule that inhibits multiple receptor tyrosine kinases (RTKs). Sutent (Pfizer, Inc., New York) is the malate salt of sunitinib. Targets of sunitinib include vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor receptors (PDGFR and PDGFRß), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Some of these RTKs have been implicated in tumor growth, pathologic angiogenesis, and metastatic progression.

Sunitinib is metabolized predominantly by the hepatic cytochrome P450 enzyme CYP3A4. Cotreatment with the potent CYP3A4 inhibitor ketoconazole doubled the sunitinib area under the concentration-time curve (AUC). Cotreatment with the potent CYP3A4 inducer rifampin reduced the AUC by half. There are no clinically relevant effects of age, body weight, creatinine clearance, race, gender, or Eastern Cooperative Oncology Group (ECOG) score on the pharmacokinetics of sunitinib or its primary active metabolite. Pharmacokinetic studies have not been conducted in pediatric patients. Food has no effect on sunitinib bioavailability.

This article summarizes efficacy and safety data supporting the approval of sunitinib by the U.S. Food and Drug Administration (FDA). Two indications were sought. Regular approval was sought for treatment of gastrointestinal stromal tumor (GIST) following progression on or resistance to imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corporation, East Hanover, NJ). In addition, accelerated approval was sought for the treatment of advanced renal cell carcinoma.

	GASTROINTESTINAL STROMAL TUMOR

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Historically, limited treatment options were available for patients with malignant GIST because conventional cytotoxic chemotherapy and palliative radiation have generated low response rates with a significant burden of toxicity. However, after a transmembrane RTK encoded by the c-kit gene was recognized as a pathologic hallmark of GIST, the tyrosine kinase inhibitor imatinib was tested in this disease [1–3]. Gleevec received accelerated approval in February 2002 for the treatment of patients with KIT (CD117)-positive unresectable and/or metastatic malignant GIST. Efficacy was based on durable objective radiographic responses in a phase II trial [4].

The study supporting the approval of sunitinib for second-line treatment of GIST is a randomized, double-blind clinical trial performed in 56 centers in Asia, Europe, and North America, including 22 centers in the United States. Eligible patients were adults with radiographically measurable GIST following either documented progression on or intolerance to imatinib. Imatinib intolerance was defined as either any grade 4 toxicity on imatinib or persistent, unacceptable toxicity induced by a moderate dose (e.g., 400 mg/day). Patients with clinically significant cardiac, hematopoietic, hepatic, or renal dysfunction were excluded, as were patients with an ECOG performance status 2. Tumoral expression of the c-kit gene product was not required, and there was no requirement for a minimum prior dose of imatinib.

Treatment was administered in repeated 6-week cycles. Patients received either oral sunitinib malate (50 mg) or placebo daily for 4 weeks followed by 2 weeks of rest (schedule 4/2). Doses were to be reduced for nonhematologic or hematologic toxicities. Patients in both treatment arms received best supportive care in addition to study treatment. Following Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression, patients on the placebo arm who met crossover eligibility criteria were offered the opportunity to receive open-label sunitinib.

The primary endpoint was time-to-tumor progression (TTP). This was defined as the time from random assignment to first documentation of objective tumor progression. Patients were assessed radiographically every 6 weeks for progression by RECIST criteria [5]. Independent, blinded review of radiographic images was performed to eliminate potential bias in the interpretation of progression. In the absence of documented progression, TTP data were censored on the day after the last tumor assessment. Secondary endpoints included overall survival, progression-free survival (PFS), and confirmed objective response rate (ORR).

Three hundred twelve patients randomly assigned 2:1 to sunitinib versus placebo comprised the intent-to-treat population. Baseline characteristics are shown in Table 1. Overall, the groups were well balanced. After 149 progression events had occurred, the first interim analysis for efficacy revealed that patients receiving sunitinib experienced a more than four-fold increase in median TTP from 6.4 to 27.3 weeks (hazard ratio, 0.33; 95% confidence interval [CI], 0.23, 0.47; log-rank p < .0001; Fig. 1). This result went beyond the O’Brien-Fleming stopping boundary of p < .0042, the nominal significance level for 149 events. The trial was then unblinded, and patients receiving placebo were offered treatment with sunitinib. PFS results were similar. Fourteen patients receiving sunitinib and none receiving placebo experienced partial responses, for an ORR of 6.8%. Survival data were not mature.

View larger version (19K): [in this window] [in a new window]   Figure 1. Kaplan-Meier curves of time-to-tumor progression in the intent-to-treat population of the randomized trial of sunitinib in malignant gastrointestinal stromal tumor. Abbreviation: CI, confidence interval.

	RENAL CELL CARCINOMA

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Metastatic renal cell carcinoma (MRCC) is typically unresponsive to chemotherapy [6]. High-dose interleukin-2 (IL-2) was approved by the FDA in May 1992 for the treatment of MRCC based on a 15% response rate in 255 patients from seven studies submitted for review. This included 17 (7%) complete and 20 (8%) partial responses. Median response duration was 54 weeks. IL-2 treatment carries a substantial burden of toxicity, most notably the capillary leak syndrome. Less than 10% of the 255 patients completed all planned treatment [7].

Two single-arm, multicenter studies of single-agent sunitinib for the treatment of MRCC were submitted. Both trials were conducted entirely within the United States in patients who had experienced failure of prior cytokine-based therapy. In study 1006, eligible patients had MRCC following nephrectomy, clear cell histology, and radiographic evidence of disease progression within 9 months of completion of one cytokine therapy treatment (interferon- [IFN-], IL-2, or IFN- plus IL-2). By contrast, study 014 enrolled patients with MRCC of any histology with either disease progression or unacceptable treatment-related toxicity following from prior cytokine therapy. Both studies excluded patients with clinically significant cardiac, hematopoietic, hepatic, or renal dysfunction; ECOG performance status 2; or evidence of central nervous system involvement.

Patients received 50 mg of sunitinib orally on schedule 4/2. Therapy was continued until documentation of progressive disease, intolerable adverse events, or withdrawal of consent. Dose reductions were allowed.

The primary endpoint for both studies was overall ORR by RECIST criteria [5]. Study 1006 results were generated by independent, blinded review of radiographic images, whereas those from study 014 were from investigators. Secondary endpoints included duration of response, time to response, PFS, TTP, and overall survival.

Study 1006 enrolled 106 patients, and study 014 enrolled 63. The pooled study populations were approximately 90% white and 65% male. Pooled median age was 57 years with a range of 24–87 years. Ninety-five percent had at least some component of clear-cell histology, and 97% had undergone nephrectomy. All patients had received one prior cytokine regimen. Baseline metastatic disease included lung metastases in 81% of patients. Liver metastases were more common in study 1006 (27% vs. 16%); bone metastases were more common in study 014 (51% vs. 25%). Overall, 52% of patients had at least three metastatic sites.

ORR and response duration are summarized in Table 2. In study 1006, the core radiology laboratory found 27 PRs, for an ORR of 25.5%, whereas in study 014 investigators found 23 PRs, for an ORR of 36.5%. Most (>90%) responses were observed during the first four cycles; the latest reported response was observed in cycle 10. Response duration data from study 1006 are premature in that only 4 (15%) of 27 patients responding to treatment had experienced disease progression at the time of analysis. As of the data cutoff, study 1006 was ongoing, with 44 (41.5%) of 106 patients continuing treatment. Eleven (17.5%) of 63 patients enrolled on study 014 continued to receive sunitinib on a continuation protocol.

	SAFETY

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Common (>10%) treatment-emergent adverse events for patients receiving sunitinib versus those on placebo are presented in Table 3. Diarrhea, mucositis, altered taste, skin abnormalities, and grade 3/4 hypertension were more common in patients receiving sunitinib. In addition, oral pain other than mucositis/stomatitis occurred in 12 patients (6%) receiving sunitinib versus three (3%) receiving placebo. Hair color changes occurred in 15 patients (7%) receiving sunitinib versus four (4%) receiving placebo. Alopecia was observed in 10 patients (5%) receiving sunitinib versus two (2%) receiving placebo. Most treatment-emergent adverse events in both study arms were grade 1 or 2 in severity.

View this table: [in this window] [in a new window]   Table 3. Treatment-emergent adverse events reported in 10% of GIST patients who received sunitinib or placebo

View this table: [in this window] [in a new window]   Table 4. Treatment-emergent laboratory abnormalities reported in 10% of GIST patients who received sunitinib or placebo

Incidence of declines in LVEF to less than 50% was 11% in patients receiving sunitinib versus 3% in those receiving placebo. The clinical significance of these findings remains unknown, as there was no difference in clinical heart failure observed between the two study groups. Patients with baseline cardiac abnormalities were excluded. Thus, cardiac safety of sunitinib in patients with preexisting cardiac abnormalities also remains unknown.

Adrenal toxicity, represented as cortical congestion, hemorrhage, or necrosis, was seen in rats and monkeys. This occurred at doses as low as 0.7x the AUC observed in clinical trials at the maximum recommended dose. Although no overt clinically important adrenal suppression was observed in patients taking sunitinib, patients receiving sunitinib while undergoing physiologic stressors such as infection, trauma, or surgery may be unable to mount an appropriate adrenal response due to subclinical adrenal toxicity. Such subclinical toxicity may be difficult to detect without unmasking by physiologic stress [8]. Physicians prescribing sunitinib are advised to monitor for adrenal insufficiency in patients who undergo stressors such as surgery, trauma, or severe infection.

	MARKETING AUTHORIZATION

Top Learning Objectives Abstract Introduction Gastrointestinal Stromal Tumor Renal Cell Carcinoma Safety Marketing Authorization Disclosure of Potential... References

 
On January 26, 2006, the FDA approved sunitinib for the treatment of GIST after disease progression on or intolerance to imatinib mesylate. This was based on a statistically robust prolongation of time-to-tumor progression. Freedom from disease progression was considered to be an acceptable surrogate of clinical benefit in GIST following progression on or intolerance to imatinib in that there is no other therapy of documented clinical benefit in this disease setting.

In addition, accelerated approval was granted for the treatment of advanced renal cell carcinoma. The accelerated approval pathway allows for marketing authorization of agents that demonstrate an advantage over existing therapy for the treatment of serious and life-threatening diseases. Such approvals are based on demonstration of an effect of the product on a surrogate endpoint that is reasonably likely to predict clinical benefit. Subsequent confirmation of clinical benefit is required. Accelerated approval of sunitinib for the treatment of advanced renal cell carcinoma was based on durable partial responses observed in two studies. This is because the partial response rates and response duration seen would be unlikely to occur spontaneously in this disease. To confirm clinical benefit, the sponsor is conducting a randomized trial of sunitinib versus IFN- with progression-free survival as the primary endpoint. Post-marketing commitment studies are underway to delineate further the cardiac effects of more prolonged exposure to sunitinib and to assess pharmacokinetics of the drug in patients with impaired liver function.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Gastrointestinal Stromal Tumor Renal Cell Carcinoma Safety Marketing Authorization Disclosure of Potential... References

 
The authors indicate no potential conflicts of interest.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Gastrointestinal Stromal Tumor Renal Cell Carcinoma Safety Marketing Authorization Disclosure of Potential... References

 
The views expressed in this article are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration. We thank other members of the FDA Sutent review team, including Sophia Abraham, Brian Booth, Nallaperumal Chidambaram, Christy Cottrell, Joga Gobburu, Ravi Harapanhali, Shiew-Mei Huang, Glen Jones, Hsien Ju, Chengyi Liang, Lydia Martynec, George Mills, Carol Noory, Sarah Pope, Roshni Ramchandani, Rajeshwari Sridhara, Barbara Stinson, and Karen Weiss.

	REFERENCES

Top Learning Objectives Abstract Introduction Gastrointestinal Stromal Tumor Renal Cell Carcinoma Safety Marketing Authorization Disclosure of Potential... References

 

1. Miettinen M, Lasota J. Gastrointestinal stromal tumors–definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch 2001;438:1–12.[CrossRef][Medline]
2. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New Engl J Med 2002;347:472–480.[Abstract/Free Full Text]
3. Verweij J, Casali PG, Zalcberg J et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364:1127–1134.[CrossRef][Medline]
4. Dagher R, Cohen M, Williams G et al. Approval summary: Imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 2002;8:3034–3038.[Abstract/Free Full Text]
5. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–216.[Abstract/Free Full Text]
6. Cohen HT, McGovern HJ. Renal-cell carcinoma. New Engl J Med 2005; 353:2477–2490.[Free Full Text]
7. Eklund JW, Kuzel TM. Interleukin-2 in the treatment of renal cell carcinoma and malignant melanoma. Cancer Treat Res 2005;126:263–287.[Medline]
8. Rivers EP, Blake HC, Dereczyk B et al. Adrenal dysfunction in hemodynamically unstable patients in the emergency department. Acad Emerg Med 1999;6:626–630.[Medline]

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