An Update on Sunitinib as First-Line Therapy for Metastatic RCC

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Special Issue 2009

An Update on Sunitinib as FirstLine Therapy for Metastatic RCC Data demonstrate that treatment-na誰ve patients with metastatic renal-cell carcinoma, or mRCC, who received sunitinib malate had longer progressionfree survival and higher response rates than those receiving interferon alfa with a median overall survival of 2 years.

Kidney cancer accounts for approximately 2% of all new cancer cases throughout the world.1 According to the National Cancer Institute, there were about 54,390 new cases of kidney cancer in the United States in 2008.2 Renal cell carcinoma (RCC), which arises primarily from the proximal tubular epithelium, accounts for approximately 85% of all kidney cancers; the remainder consists of renal pelvis cancer and other rare malignancies. Many patients with RCC are asymptomatic and cannot be palpated until relatively late in the

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course of the disease. More than half of RCC cases are detected incidentally as a result of imaging tests which are performed for other reasons. It has been estimated that between 25% and 30% of all patients with RCC are initially diagnosed with the disease due to symptoms of metastases.1 Sunitinib malate is an orally administered inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).3,4 These receptor tyrosine kinases play a key role in the pathogenesis of clear-cell carcinoma—the predominant type of RCC—because of involvement of the von Hippel-Lindau (VHL) gene. Robert J. Motzer, MD, explains that “VHL is inactivated in up to 80% of sporadic cases of clear-cell carcinoma by deletion, mutation, or methylation. This tumor-suppressor gene encodes a protein that is involved in the regulation of the production of

vascular endothelial growth factor [VEGF], platelet-derived growth factor [PDGF], and other hypoxia-inducible proteins. Inactivation of the VHL gene causes overexpression of these agonists of VEGFR and PDGFR. The resulting persistent stimulation of the receptors may promote tumor angiogenesis, tumor growth, and metastasis.5 All of these considerations make the receptors for VEGF and PDGF rational targets in the treatment of clear-cell RCC.”

First-Line Data In the January 11, 2007, New England Journal of Medicine, Dr. Motzer and colleagues reported the results of a randomized phase 3 trial of sunitinib malate as compared with interferon alfa in treatmentnaïve patients. The study assessed patients (n=750) with mRCC who were randomized in a 1:1 ratio to receive either sunitinib or interferon alfa. In addition to a confirmed clear-cell histology, other key eligibility criteria included the presence of measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate hematologic, coagulation, hepatic, renal, and cardiac function. Patients were stratified according to baseline levels of lactate dehydrogenase (>1.5 vs ≤1.5 times the upper limit of the normal range), ECOG performance status (0 vs 1), and previous nephrectomy (yes vs no). Each treatment group was also balanced with respect to baseline demographic and disease characteristics.6 Sunitinib malate was administered orally as a once-daily dose at 50 mg in 6-week cycles. These cycles consisted of 4 weeks of treatment followed by 2 weeks without treatment. Interferon alfa was given as a subcutaneous injection three times per week on nonconsecutive days at 3 MU per dose during the first week, 6 MU per dose the second week, and 9 MU per dose thereafter. Treatment in both groups was continued until the disease progressed, unacceptable adverse events occurred, or there was a withdrawal of consent.6

Progression-Free Survival As reported in the New England Journal of Medicine, singleagent sunitinib malate significantly prolonged progression-free survival (PFS) vs interferon alfa. The median PFS was 11 months for those treated with sunitinib compared with just 5 months for the interferon-alfa group (hazard ratio [HR]=0.42, P<.000001) (Figure 1).6 According to the trial findings, sunitinib treatment was also associated with a 5-fold higher objective response rate (ORR) than interferon alfa as assessed by blinded central review of imaging studies (28% vs 5%).7 During independent central review in a second interim analysis, sunitinib was associated with a 39% ORR compared with an 8% ORR with interferon alfa (Figure 2).8 ORR is a secondary endpoint.

The most common adverse reactions (ARs) occurring in 20% or more of patients receiving sunitinib for treatment-naïve mRCC (all grades, vs interferon alfa) were fatigue (58% vs 55%), diarrhea (58% vs 20%), nausea (49% vs 38%), altered taste (44% vs 14%), mucositis/stomatitis (43% vs 4%), anorexia (38% vs 40%), bleeding, all sites (30% vs 8%), hypertension (30% vs 4%), vomiting (28% vs

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14%), dyspepsia (28% vs 4%), rash (27% vs 11%), abdominal pain (22% vs 12%), asthenia (21% vs 24%), and hand-foot syndrome (21% vs 1%). The most common grade 3/4 ARs (occurring in 5% or more of sunitinib patients) were hypertension (10% vs <1%), fatigue (9% vs 14%), asthenia (7% vs 6%), diarrhea (6% vs 0%), and hand-foot syndrome (5% vs 0%). Most sunitinib-related adverse events were ameliorated by interruption or modification of the dose. Sunitinib treatment was discontinued in less than 10% of patients because of adverse events (9% vs 12% for interferon alfa).6 In the study, 38% of patients on sunitinib had a dose interruption compared with 32% of patients on interferon alfa, and 32% of patients in the sunitinib group had a dose reduction compared with 21% for the interferon alfa-treated group. Sunitinib was escalated back to the previous dose level in the next cycle if the adverse reaction grade was reduced to an acceptable level.

At the time when results from the phase 3 study were published, the median overall survival (OS) data had not matured for either treatment group, but results from this study were updated at the American Society of Clinical Oncology annual meeting in 2008.1 Median PFS was unchanged from that previously reported in the New England Journal of Medicine by Dr. Motzer and colleagues (11 vs 5 months; P<.000001).1

Overall Survival According to Dr. Motzer, median OS values in the phase 3 trial were greater than 2 years for patients in the sunitinib group (26.4 vs 21.8 months in the interferon alfa group; HR=.821; log-rank

P=.051) (Figure 3).1 “This is the first time OS longer than 2 years has been achieved with any phase 3 trial of a first-line therapy in mRCC,” says Dr. Motzer.1 “This is a testimony to the fact that the prognosis is improved for patients with metastatic RCC over the past 3 years.”

Median OS exceeded 2 years whether the data were unstratified or stratified according to the pre-specified characteristics of baseline ECOG performance status, lactate dehydrogenase levels, and prior nephrectomy.1

Crossover Data & Subsequent Therapy Patients involved in the phase 3 study were not allowed to cross over from the interferon alfa arm to the sunitinib arm until late in the study.9 When the option became available, 6% were crossed over to the sunitinib arm.

In an exploratory analysis, when the data were censored for the 25 patients who crossed over to sunitinib during the study, the median OS was 26.4 months for those who crossed over to the agent compared with 20.0 months for patients in the interferon alfa group (HR=.808; log-rank P=.0362).1 More than 56% in both groups received post-study treatment; 33% of patients in the interferon alfa arm received sunitinib as subsequent therapy.9 “Additional therapies for RCC emerged during the study time frame,” explains Dr. Motzer, “and some patients taking interferon alfa who experienced disease progression gained access to sunitinib or other therapies.”

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The Landscape for Treatment for mRCC RCC had long been considered to be resistant to traditional cancer treatment and was associated with a poor prognosis as recently as 5 years ago. “Few treatment options were available,” says Dr. Motzer, “but there has been significant progress as new treatment options have emerged within the past few years. There has been a paradigm shift in the treatment for advanced RCC.”

According to the most recent clinical guidelines from the National Comprehensive Cancer Network, sunitinib has been given a category 1 recommendation based on recent clinical data for firstline treatment of patients with relapsed or medically unresectable stage IV renal cancer with predominant clear-cell histology. It is the only single-agent therapy with category 1 evidence for all Memorial Sloan-Kettering Cancer Center risk groups.10 Dr. Motzer says, “We now have data establishing sunitinib as a standard of care for firstline treatment of patients with advanced RCC.”

References 1. H utson TE. Sunitinib (SUTENT) for the treatment of metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2008;8:1723-1731.

Abstract at: www.expert-reviews.com/doi/abs/10.1586/14737140.8.

11.1723?prevSearch=allfield%3A%28Hutson+TE%29.

2. National Cancer Institute. Kidney Cancer Homepage. Available at: www.cancer.gov/cancertopics/types/kidney. Accessed February 2, 2009.

3. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor ß in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471-478. Available at: http://mct.aacrjournals.org/cgi/reprint/2/5/471.

4. M endel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/ pharmacodynamic relationship. Clin Cancer Res. 2003;9:327-337.

5. I liopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996;93:10595-10599.

6. M otzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.

Available at: http://content.nejm.org/cgi/reprint/356/2/115.pdf.

7. S UTENT® Prescribing Information. Available at: www.pfizer.com/files/ products/uspi_sutent.pdf. Accessed February 2, 2009.

8. M otzer RJ, Figlin RA, Hutson TE, et al. Sunitinib versus interferon-alfa (IFN-a) as first-line treatment of metastatic renal cell carcinoma (mRCC): updated results and analysis of prognostic factors. J Clin Onc. 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2007;25:18S. Abstract No. 5024.

9. D ata on file. Pfizer Inc. 10. N ational Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. V.1.2009. Available at: www.nccn.org/professionals/physician_gls/ PDF/kidney.pdf. Accessed February 2, 2009.

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