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Journal of Clinical Oncology, Vol 26, No 20 (July 10), 2008: pp. 3469-3471 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.7410
Efficacy of Sunitinib and Sorafenib in Non–Clear Cell Renal Cell Carcinoma: Results From Expanded Access StudiesDepartment of Hematology and Medical Oncology, Marienhospital Herne, University of Bochum, Herne, Germany To the Editor: We refer to a recent report by Choueri et al1 regarding the efficacy of sunitinib and sorafenib, respectively, in metastatic papillary renal cell carcinoma (PRCC) and chromophobe renal cell carcinoma (ChRCC). Although published as an Original Report, the study was not a clinical trial but a retrospective multicenter review of 53 patients with advanced PRCC and ChRCC. The rationale for this report was the lack of data on the activity of sunitinib and sorafenib in advanced PRCC and ChRCC, because recent trials were mostly restricted to patients with clear cell (CCRCC) histologies. The most noteworthy aspects of the report were that both drugs may also prolong progression-free survival (PFS) in patients with non–clear cell histologies, and that sunitinib-treated patients had a statistically significant longer PFS compared with sorafenib-treated patients, especially in PRCC, even after adjusting for other clinical parameters. This article, however, raises some questions: Are oral tyrosine kinase inhibitors in general less active in non–clear cell RCC than in CCRCC patients? Within the heterogeneous group of non–clear cell RCC, is the histologic subtype predictive for clinical activity of either sunitinib or sorafenib? Renal cortical tumors have distinct histologic subtypes with varying degrees of metastatic potential. Conventional clear cell RCC, which comprises more than 80% of renal cortical tumors, has a less favorable outcome when compared with PRCC and ChRCC.2 Metastatic non–clear cell histologies including papillary, chromophobe, collecting duct, and unclassified cell types, respectively, are characterized by a resistance to systemic therapy and poor survival, with the survival for patients with chromophobe tumors being longer than that for patients with metastatic collecting duct or PRCC.3 Papillary carcinoma does not constitute a single morphologic, clinical, or genetic entity. Some variants are highly aggressive, whereas others are quite indolent. ChRCCs exhibit more indolent behavior than clear cell or papillary carcinomas.4 Both sorafenib and sunitinib have been approved by both the US Food and Drug Administration and the European Medicines Agency for the treatment of metastatic RCC, and have meanwhile largely replaced cytokines as the standard of care in this disease. However, randomized trials that have shown significant clinical activity of these drugs enrolled only patients with advanced CCRCC.5,6 Our understanding of clinical activity of sunitinib and sorafenib in advanced CCRCC is largely based on the inhibition of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases. ChRCC and PRCC overexpress c-Kit,7,8 which is also a target of both drugs and could therefore provide a therapeutic target for non–clear cell subtypes of RCC. It is questionable whether response rates in patients with ChRCC or PRCC who were treated with either sorafenib or sunitinib are the result of c-Kit inhibition.1 Historical survival data associated with metastatic RCC of non–clear cell histology showed a median overall survival (OS) of 9.4 months (95% CI, 8 to 14 months). The median OS for patients with papillary and chromophobe tumors was 5.5 months (95% CI, 4 to 12 months) and 29 months (95% CI, 19 to 59 months), respectively.3 Therefore, activity of oral tyrosine kinase inhibitors such as sunitinib and sorafenib in non–clear cell histologies is an unresolved issue of clinical relevance. In addition to a published registration-study database, a number of expanded-access trials on both drugs have been performed in North America and also in Europe.9-11 The primary aim of these nonrandomized, open-label trials was to make both drugs available to patients before regulatory approval. Nevertheless, analyses of this enormous database comprising thousands of patients are of great value. They contain a large, unselected population and therefore reflect the real world more closely than a highly selected patient population enrolled onto randomized phase III trials, which are carried out for registration purposes. Therefore, expanded-access trials are especially suitable for subpopulation analyses. Regarding sunitinib, a total number of 750 patients had been enrolled onto the first-line phase III trial,6and an additional 169 patients had been previously enrolled onto two phase II trials. Moreover, as of April 1, 2007, a total of 4,423 patients have been enrolled onto the sunitinib expanded-access study: data have been published for 2,341 patients, the majority (78%) of whom received prior therapy with cytokines.9 Subgroup analyses including patients with non–clear cell histology were reported in 11.8% of patients (n = 276), all of whom had received prior cytokines. The overall response rate (ORR) for the entire group was 9.3%, and clinical benefit was documented in 52.3% of the patients. In patients with non–clear cell histologies, the ORR was 5.4%, and clinical benefit was reported in 47%. The estimated median PFS was 8.8 months (95% CI, 8.3 to 9.9 months) for all patients. Furthermore, PFS was longer in patients with clear cell versus non–clear cell histologies (9.2 v 6.7 months). The authors concluded that PFS was consistent with previous data and deducted sunitinib activity also in subgroups of non–clear cell RCC, which had not previously been studied.9 Detailed data on papillary or chromophobe histologies were not reported. Response data on the Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded-access trial in North America are available for a total of 1,871 patients (935 first-line and 936 second-line patients).10 Response rates for the first- and second-line patients were 4% and 3% partial response, respectively; and 83% and 84% had at least tumor stabilization, and thus clinical benefit, respectively. The estimated median PFS was 8.1 months (95% CI, 7.5 to 9.9 months) for all patients. Furthermore, in patients with non–clear cell histologies (n = 136), the ORR was 4% (n = 116) for patients with papillary and 1% (n = 18) for chromophobe histologies. Disease stabilization for at least 3 months was reported in 80% of patients with papillary and 95% of chromophobe patients, respectively. A median PFS of 8.0 months is reported for 23 of 224 patients with non–clear cell histologies who received first-line therapy.10 Data are also available on the European ARCCS Study (EU-ARCCS), which enrolled a total of 1,155 patients (118 patients with papillary histology, and another 118 patients with other non–clear cell RCCs).11 The majority of patients received prior therapy (72%), predominantly with cytokines (91%). A total of 1,031 patients were assessable for response: ORR was noted in 1.8% of patients, and 71% of patients had disease stabilization. The median PFS for all assessable patients was 6.9 months (95% CI, 6.2 to 7.5 months). Subgroup analyses revealed a median PFS for clear cell and non–clear cell histologies of 7.5 and 5.2 months, respectively. In addition, data on papillary histology showed a PFS of 5.8 months. The rates of patients presenting at least with disease stabilization were 75.7% for clear cell, 64.5% for all non–clear cell, and 66.4%, for papillary cell histologies.11 In addition to the limitations due to the small number of patients, the conclusions from the report of Choueiri et al1 are doubtful in the respect that the study was not randomized. Consequently, risk factors may not be distributed evenly between treatment groups. To account for treatment allocation bias, matched analyses would have been more appropriate. Response assessment was performed unblinded and retrospectively. Also, differences in tumor evaluation schedules may also affect PFS. Finally, in the corresponding abstract presentation at the 2007 American Society of Clinical Oncology Annual Meeting, the authors reported that OS was not different across the histologies and type of tyrosine kinase inhibitor received.12 Consequently, PFS in the presence of OS data should not have been the primary end point for this analysis. In conclusion, although the molecular mechanisms of pathogenesis between clear cell and non–clear cell RCC seem rather distinct, expanded-access trials of both sunitinib and sorafenib support clinical activity of both drugs in patients with non–clear cell histologies. Whether activity is based on inhibition of the vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases or inhibition of c-Kit or other molecular targets is not clear as yet. Current data are consistent with the notion that compared with CCRCC, clinical activity of both drugs expressed in ORR and PFS seems to be reduced in patients with non–clear cell histologies. Still, due to the limited number of patients and lack of controlled trials, none of the current data are conclusive. In contrast to the article from Choueiri et al, the expanded-access trial data on both sunitinib and sorafenib do not support the previous finding that the histologic subtype might be predictive in case of preferred or differential activity of either sunitinib or sorafenib. Given that no comparative, randomized study has been reported yet, one should not prematurely draw conclusions from nonrandomized data which are derived from different studies. AUTHOR'S 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: Dirk Strumberg, Bayer Healthcare (C) Stock Ownership: None Honoraria: Dirk Strumberg, Bayer Healthcare Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Choueiri TK, Plantade A, Elson P, et al: Efficacy of sunitinib and sorafenib in metastatic papilarry and chromophobe renal cell carcinoma. J Clin Oncol 26:127-131, 2008 2. Beck SD, Patel MI, Snyder ME, et al: Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma. Ann Surg Oncol 11:71-77, 2004[CrossRef][Medline] 3. Motzer RJ, Bacik J, Mariani T, et al: Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 20:2376-2381, 2002 4. Reuter VE: The pathology of renal epithelial neoplasms. Semin Oncol 33:534-543, 2006[CrossRef][Medline] 5. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma: N Engl J Med 356:125-134, 2007 6. 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 7. Yamazaki K, Sakamoto M, Ohta T, et al: Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene 22:847-852, 2003[CrossRef][Medline] 8. Lin ZH, Han EM, Lee ERS, et al: A distinct expression pattern and point mutation of c-kit in papillary renal cell carcinoma. Mod Pathol 17:611-616, 2004[CrossRef][Medline] 9. Gore ME, Porta C, Oudard S, et al: Preliminary assessment in an expanded access trial with subpopulation analysis. J Clin Oncol 25:237s, 2007 (suppl; abstr 5010) 10. Knox JJ, Figlin RA, Stadler WM, et al: The advanced renal cell carcinoma sorafenib (ARCCS) expanded access trial in North America: Safety and efficacy. J Clin Oncol 25:237s, 2007 (suppl; abstr 5011) 11. Beck J, Bajetta E, Escudier B, S et al: A large open-label, non-comparative phase III study of the multi-targeted kinase inhibitor sorafenib in European patients with advanced renal cell carcinoma. Eur J Cancer Suppl 7:244, 2007 (abstr 4506) 12. Plantade A, Choueiri T, Escudier B, et al: Treatment outcome for metastatic papillary and chromophobe renal cell carcinoma patients treated with tyrosine-kinase inhibitors sunitinib and sorafenib. J Clin Oncol 25:244s, 2007 (suppl; abstr 5037),[CrossRef]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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