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Originally published as JCO Early Release 10.1200/JCO.2009.21.8461 on May 18 2009 © 2009 American Society of Clinical Oncology.
Targeting Renal Cell CarcinomaMemorial Sloan Kettering Cancer Center, New York, NY Recent discovery and clinical development of targeted agents have expanded treatment options in renal cell carcinoma (RCC) and have improved prognosis for patients with RCC metastases. Because RCC displays nearly universal resistance to chemotherapy, it has long been considered a model tumor for studying drug resistance. Cytokine therapy has been the mainstay of RCC systemic treatment for the past two decades. However, few patients respond to interferon-alfa or interleukin-2, and median overall survival with these agents ranges from 10 to 15 months.1 Recently, an improved understanding of RCC biology, combined with targeted drug-directed research, has contributed to dramatic progress. Clear cell is the predominant RCC cell type, characterized by mutations in the von Hippel-Lindau gene, which plays a key role in regulating angiogenesis through a hypoxia-driven pathway. Targets for drugs within this pathway include vascular endothelial growth factor (VEGF) and its receptor (VEGFr), and hypoxia inducible factor (HIF). Therefore, early drug research with sorafenib and other targeted agents focused on RCC. In this issue of Journal of Clinical Oncology, Escudier et al2 report the survival analysis of a phase III randomized trial of sorafenib versus placebo as second-line therapy for metastatic clear cell RCC. At a preplanned interim independent assessment, progression-free survival was significantly longer in patients treated with sorafenib versus patients randomly assigned to placebo.3 The median interim progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio [HR], 0.44; P < .0001).3 After interim analysis, patient treatment was unblinded, and those on the placebo arm were offered sorafenib. In the final analysis, the median overall survival was comparable in both arms. However, treatment with sorafenib was associated with an improved survival when censoring patients randomly assigned to placebo who crossed over to sorafenib (17.8 v 14.3 months; HR, 0.78; P = .0287).2 The prolongation of progression-free survival observed with sorafenib is the relevant outcome. This phase III trial by Escudier et al, as well as five other trials, has established a benefit for targeted agents in metastatic RCC (Table 1).2,4–8 Sunitinib, temsirolimus, and bevacizumab (combined with interferon-alfa) have been compared with interferon-alfa alone in first-line therapy. Everolimus was compared with placebo after progression to VEGFr tyrosine kinase inhibitors (TKI) therapy (sunitinib and/or sorafenib).
The eligibility criteria for sunitinib and bevacizumab phase III trials allowed inclusion of all three Memorial Sloan-Kettering Cancer Center (MSKCC) risk groups, but trial accrual largely comprised patients with an intermediate or favorable prognosis.4 In an interim analysis, patients treated with sunitinib showed significant improvement in progression-free survival compared with interferon-alfa, meeting the primary end point of the trial.4 Overall survival was assessed as a secondary end point, and was longer with sunitinib than with interferon-alfa.9 The degree of difference in overall survival between the two arms was influenced by the number of patients in the interferon-alfa arm who crossed over to sunitinib at the time of progression. Nevertheless, the trial outcome resulted in a paradigm shift from cytokine therapy to targeted agents in first-line treatment of metastatic RCC. Moreover, the median survival of more than 2 years in the sunitinib arm is a milestone for RCC treatment, compared with the short survival previously achieved with cytokine therapies. Likewise, significant improvements in progression-free survival were observed in European and US cooperative group phase III trials with a combination of bevacizumab plus interferon-alfa compared to interferon-alfa alone.5,6 The targeted agent temsirolimus, a mammalian target of rapamycin inhibitor, was compared with interferon-alfa in a phase III trial of first-line therapy, where it was shown to prolong overall survival.7 Only patients with poor-prognosis features (expanded from MSKCC risk criteria)7,10 were eligible for this trial. Objective responses were infrequent with temsirolimus (< 10%) in this group of patients with a poor prognosis. However, the trial showed a statistically significant improvement for targeted therapy over interferon-alfa in an analysis of overall survival as a primary end point. Recently, everolimus, an orally administered mTOR inhibitor, was studied in patients who progressed on therapy with VEGFr TKI.8 The outcome of this trial indicated an advantage in progression-free survival. Everolimus was the first and only agent to show benefit in a phase III trial of patients who had progressed on VEGFr TKI therapy. As a result of these trials, the US Food and Drug Administration approved sorafenib (December 2005), sunitinib (January 2006, with phase II trial),11 and temsirolimus (May 2007) for the treatment of advanced RCC. Bevacizumab plus interferon-alfa has been approved by regulatory agencies in Europe (December 2007); the US outcome of a review by the US Food and Drug Administration is pending. Everolimus was recently approved (March 2009) by the US Food and Drug Administration for patients with advanced RCC after progression to treatment with sunitinib or sorafenib.
The 2009 National Comprehensive Cancer Network (NCCN) treatment recommendations offer guidelines for management of metastatic clear cell RCC. According to these guidelines, a category 1 recommendation is based on high-level evidence (eg, randomized controlled trials) and uniform NCCN consensus.12 Sunitinib and bevacizumab plus interferon-alfa have a category 1 recommendation for first-line treatment of metastatic clear cell RCC. Temsirolimus has a category 1 recommendation for first-line treatment of metastatic clear cell RCC (and non–clear cell RCC) in patients with poor-prognostic features (based on For second-line (subsequent) treatment, sorafenib and sunitinib are recommended at the category 1 level after progression on cytokine therapy. Sorafenib does not carry a category 1 level of recommendation for first-line treatment, since the phase III trial by Escudier et al2 compared sorafenib with placebo as second-line therapy after progression on cytokine therapy. Also, a large randomized phase II trial in first-line treatment failed to show improvement in progression-free survival with sorafenib (median, 5.7 months) compared with interferon-alfa (median, 5.6 months).13 2009 NCCN guidelines were revised based on phase III trial outcome8 to provide a level 1 recommendation for everolimus following progression to treatment with TKIs such as sunitinib or sorafenib. Fortunately, treatment options and outcomes for metastatic clear cell RCC have improved dramatically as a result of targeted therapy. This has also led to new research questions. Phase III trials are currently under way to determine optimal sequencing of targeted agents and their role in adjuvant therapy, along with studies to determine the molecular signature of responses. Newer drugs in the process of development may add therapeutic benefit or improved safety profile. Pazopanib and axitinib are two promising VEGF-TKIs. Both showed favorable objective response rates and progression-free survival in phase II trials.14,15 A multicenter, international phase III trial is under way comparing pazopanib to standard sunitinib therapy in first-line, metastatic clear cell RCC.16 In addition, a phase III trial comparing axitinib to sorafenib as second-line therapy in metastatic RCC is ongoing.16 RCC, once highlighted as a model of drug resistance, now represents a tumor model for the study of new antiangiogenesis targeted agents. Clinical challenges in RCC targeted-drug treatment include development of resistance and lack of complete response, adverse events, cost of treatment, and maintenance of therapy. The treatment of patients with metastatic RCC continues to evolve, with ongoing and future trials seeking answers on individualizing treatment and optimizing patient outcomes. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Robert J. Motzer, Bayer Onyx, GlaxoSmithKline, Novartis Research Funding: Robert J. Motzer, Pfizer, GlaxoSmithKline, Wyeth, Novartis, Genentech Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Robert J. Motzer, Ana M. Molina Manuscript writing: Robert J. Motzer, Ana M. Molina Final approval of manuscript: Robert J. Motzer, Ana M. Molina Acknowledgment We thank Carol Pearce, Memorial Sloan-Kettering Cancer Center Department of Medicine writer/editor, for her review of this manuscript. REFERENCES
1. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 335:865–875, 1996. 2. Escudier B, Eisen T, Stadler WM, et al: Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. J Clin Oncol 27:3312–3318, 2009. 3. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134, 2007. 4. Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124, 2007. 5. Escudier B, Pluzanska A, Koralewski P, et al: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal-cell carcinoma: A randomised, double-blind phase III trial. Lancet 370:2103–2111, 2007.[CrossRef][Medline] 6. Rini BI, Halabi S, Rosenberg JE, et al: Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26:5422–5428, 2008. 7. Hudes G, Carducci M, Tomczak P, et al: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281, 2007. 8. Motzer RJ, Escudier B, Oudard S, et al: Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456, 2008.[CrossRef][Medline] 9. Figlin RA, Hutson TE, Tomczak P, et al: Overall survival with sunitinib versus interferon (IFN)-alfa as first-line treatment of metastatic renal cell carcinoma (mRCC). J Clin Oncol 26:256s; 2008 (suppl) abstr 5024. 10. Motzer RJ, Bacik J, Murphy BA, et al: Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20:289–296, 2002. 11. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516–2524, 2006. 12. National Comprehensive Cancer Network. NCCN Practice Guidelines. http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. 13. Szczylik C, Demkow T, Staehler M, et al: Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: Final results. J Clin Oncol 25:241s; 2007 (suppl) abstr 5025.[CrossRef] 14. Hutson TE, Davis ID, Machiels JP, et al: Pazopanib (GS786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT). J Clin Oncol 25:242s; 2007 (suppl) abstr 5031. 15. Rixe O, Bukowski RM, Michaelson MD, et al: Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: A phase II study. Lancet Oncol 8:956–957, 2007.[CrossRef][Medline] 16. National Cancer Institute. http://www.cancer.gov.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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3 defined, poor-prognostic, pretreatment clinical features).
