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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 127-131 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.3223 Efficacy of Sunitinib and Sorafenib in Metastatic Papillary and Chromophobe Renal Cell Carcinoma
From the Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Cleveland Clinic Taussig Cancer Center, Cleveland, OH; Institut Gustave Roussy, Villejuif; Centre Léon Bérard, Lyon; Centre Hospitalier Universitaire Bordeaux, Bordeaux; and Hopital Européen Georges Pompidou, Paris, France Corresponding author: Toni K. Choueiri, MD, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, DANA 1230, Boston, MA 02115; e-mail: Toni_Choueiri{at}dfci.harvard.edu
Purpose Sunitinib and sorafenib are novel tyrosine kinase inhibitors (TKIs) that have shown significant clinical activity in metastatic clear cell renal cell carcinoma (RCC). The activity of sunitinib and sorafenib in non–clear cell histologies has not been evaluated. Patients and Methods Clinical features at study entry and treatment outcomes were evaluated in patients with metastatic papillary RCC (PRCC) and chromophobe RCC (ChRCC) who received either sunitinib or sorafenib as their initial TKI treatment in five US and French institutions. Response rate and survival were documented. Fisher's exact test was used for categoric variables, and the Kaplan-Meier method was used to estimate survival. Results Fifty-three patients were included. The number of patients with papillary and chromophobe histologies was 41 (77%) and 12 (23%), respectively. Response rate, progression-free survival (PFS) time, and overall survival time for the entire cohort were 10%, 8.6 months, and 19.6 months, respectively. Three (25%) of 12 ChRCC patients achieved a response (two patients treated with sorafenib and one treated with sunitinib), and PFS was 10.6 months. Two (4.8%) of 41 PRCC patients achieved a response (both patients were treated with sunitinib). PFS for the whole cohort was 7.6 months. Sunitinib-treated PRCC patients had a PFS of 11.9 months compared with 5.1 months for sorafenib-treated patients (P < .001). Conclusion Patients with PRCC and ChRCC may have prolonged PFS from sunitinib and sorafenib, although clinical responses remain overall low in PRCC. Additional prospective trials with these agents in non–clear cell RCC will further clarify their use in the future.
Recent advances in understanding the biology and genetics of renal cell carcinoma (RCC) have led to major therapeutic implications. The role of the von Hippel-Lindau (VHL) gene in regulating proangiogenic factors has provided potential targets for novel agents. VHL gene inactivation, present in the majority of sporadic forms of RCC, leads to a defective VHL protein, followed by an active transcription of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others.1 Many of these gene products are involved in angiogenesis, tumor progression, and survival. However, the concept of VHL inactivation in RCC and the subsequent malignant phenotype is almost exclusively seen in patients with clear cell histology, a subtype constituting more than 80% of all RCCs.2 Trials with small-molecule VEGF and PDGF receptor inhibitors, such as sunitinib and sorafenib, have shown significant clinical activity in randomized trials in advanced clear cell RCC (CCRCC) and have largely replaced cytokines as standard of care in this disease.3,4 Both drugs have been approved by the US Food and Drug Administration for the treatment of metastatic RCC. Papillary RCC (PRCC) and chromophobe RCC (ChRCC) represent the most common remaining histologic subtypes with an incidence of 7% to 14% and 6% to 11%, respectively.5 Data are lacking regarding the activity of sunitinib and sorafenib in advanced PRCC and ChRCC because recent trials were mostly restricted to CCRCC patients. Earlier studies with cytokines and chemotherapy agents showed minimal activity in patients with chromophobe or papillary histologies. These studies were mostly based on small series and case reports. Moreover, less than 10% of patients with non–clear cell histologies were included on clinical trials of new investigational agents.6 We performed a retrospective multicenter review of patients with advanced PRCC and ChRCC treated with sunitinib and sorafenib to assess the clinical features and the treatment outcome of these particular RCC histologies.
Patients Patients had metastatic PRCC or ChRCC tumors and underwent clinical evaluation at four different cancer centers in France (Institut Gustave Roussy, Centre Léon Bérard, Centre Hospitalier Universitaire Bordeaux, and Hopital Européen Georges Pompidou) and one cancer center in the United States (Cleveland Clinic Taussig Cancer Center) from April 2002 to December 2006. Patients received sunitinib and sorafenib as their initial tyrosine kinase inhibitor (TKI) treatment. Patients were treated as part of extended access programs to sunitinib and sorafenib (compassionate use studies) or by direct access to the drug when it became available by medical prescription. At the time of start of TKI treatment, patients had a detailed history and physical examination, as well as baseline laboratory parameters. Also, pretreatment tumor status was evaluated with computed tomography scans of the brain, chest, abdomen, and pelvis. Data collected included standard pretreatment disease characteristics, baseline biochemical parameters, prior therapies, first date of treatment, best response to treatment including tumor measurement data when available, date of progression, and date of death or last follow-up. For response data collection, we first identified our population and then looked retrospectively at their radiologic examinations performed at baseline (before TKI initiation) and at each follow-up. We documented responses by Response Evaluation Criteria in Solid Tumors7 and confirmed responses on two consecutive measurements at least 4 weeks apart. Patients were seen by their physician with every cycle of therapy.
Pathology Review
Statistical Analysis
Patient Characteristics Median age for the 53 patients was 59 years (range, 24 to 83 years). Sixty-six percent of patients were male. PRCC was present in 41 patients (77%), and ChrCC was present in 12 patients (23%). All but three patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, 16 (30%) of 53 patients had more than two metastatic sites, and 33 (62%) of 53 patients had received prior systemic therapy. Prior therapies included cytokines (49%), chemotherapy (23%), bevacizumab (4%), and hormonal therapy (1%). Nephrectomy was performed in 46 patients (87%). The most common sites of metastatic disease included lymph nodes (37 of 53 patients, 70%), lung (28 of 53 patients, 53%), bone (15 of 53 patients, 28%), and liver (12 of 53 patients, 23%). One patient (2%) had brain metastases. The majority of patients (33 of 53 patients, 62%) were treated with sorafenib (Table 1).
The overall response rate for the whole cohort was 10% (five patients; 95% CI, 3% to 21%), with all patients having partial responses. Stable disease (SD) was achieved in 36 patients (68%). Median PFS time for the whole cohort was 8.6 months (95% CI, 5.3 to 11.9 months). Median follow-up time for the patients who remained progression free was 9 months. Estimated OS time is 19.6 months, but only 40% of patients have died; therefore, this result should be viewed cautiously because of the heavy censoring in addition to the small number of patients. Toxicities from sunitinib and sorafenib were overall comparable to studies in CCRCC and included mainly fatigue, rash, and diarrhea.
Treatment Outcome per Histologic Subtype PFS time was 7.6 months for PRCC patients. Clinical factors associated with PFS (P < .05) included hemoglobin and time from diagnosis to therapy (Table 2). Additionally, patients with papillary tumors tended to have a better PFS with sunitinib than sorafenib (PFS: 11.9 v 5.1 months, respectively; P < .001; Fig 1). This statistical significance persisted even adjusting for the other significant clinical prognostic factors.
Chromophobe tumors. Among the 12 ChRCC patients, seven were treated with sunitinib, and five were treated with sorafenib. Two patients treated with sorafenib and one patient treated with sunitinib achieved a partial response, corresponding to a response rate of 25% (three of 12 patients). SD of more than 3 months was achieved in all nine patients who did not have a response. Four of nine patients achieved minor responses ranging from –11% to –27%. PFS time for ChRCC patients was 10.6 months. Sorafenib-treated patients tended to have a prolonged median PFS time (27.5 months). Time from diagnosis to treatment was the only factor that correlated with PFS (P = .02; Table 3).
Outcome of Patients With Sequential Use of Sorafenib and Sunitinib or Other Anti-VEGF Agents Two patients, both with ChRCC, were previously treated with bevacizumab and subsequently received sunitinib. Both patients achieved SD, with 19% overall tumor shrinkage in one of the patients. Thirteen PRCC patients, initially treated with sorafenib, subsequently received sunitinib after progression. Twelve patients were assessable; six (50%) of 12 patients experienced progression after two cycles of sunitinib, one patient achieved partial response and experienced progression after 6.5 months of therapy, and five patients achieved SD. Among the five patients who achieved SD after two cycles of sunitinib, two patients experienced progression after 7 and 9.5 months. Three patients are still progression free at 3, 6, and 7 months of follow-up. One patient with PRCC who experienced progression on sunitinib and subsequently received sorafenib achieved SD after two cycles of therapy.
RCC treatment has been classically derived from clinical trials that incorporated all histologies, despite the fact that renal epithelial neoplasms encompass several histopathologic categories, based on different tumor morphology, histochemistry, cytogenetics, and molecular studies.5 This difference translates into an apparent therapeutic divergence. For example, patients with clear cell histology tend to have a much better response to immunotherapy compared with patients with other histologies.6,14 Most recently, novel anti-VEGF therapies (sunitinib and sorafenib) have shown significant clinical activity in advanced RCC and have changed the standard of care in this disease. However, pivotal studies with these drugs were exclusively performed in patients with clear cell histology. The optimal therapy for papillary and chromophobe histologies therefore remains unknown. Motzer et al6 suggested that patients with metastatic PRCC have the worst outcome of all RCC histologies. In their series of 18 metastatic PRCC patients, median survival time was 5.5 months, and no patients survived beyond 2 years. A recent large international study reported on the outcome of 1,001 patients with metastatic RCC (82 of whom had papillary histology).15 Five-year survival rate of papillary and clear cell subtypes was similar, in the range of 10%. Unlike CCRCC, no treatment has proven to be active in PRCC. Despite the fact that VHL inactivation and the subsequent overexpression of hypoxia-inducible genes are hallmarks of CCRCC, patients with papillary histology can still demonstrate high expression of VEGF16 and VEGFR-2,17 making VEGF-targeted therapy an attractive therapeutic option. One recently published case report illustrates a partial response from sunitinib and a PFS time of 8.5 months.18 Our experience illustrates the largest public series to date in PRCC with these new agents. We found a response rate of only 5% (two responders) in patients treated with these VEGF-targeted therapies. Both responders received sunitinib, corresponding to an overall response rate of 17% in sunitinib-treated patients. Similarly, PFS seemed to be longer in the 13 patients treated with sunitinib compared with the 28 patients treated with sorafenib (11.9 v 5.1 months, respectively). Although the number of PRCC patients in our study is too small to draw definitive conclusions, the prolonged PFS from sunitinib in PRCC is comparable to the data from a large phase III trial in newly diagnosed RCC patients with clear cell histology.3 Additionally, it is important to know that two distinct classes of PRCC exist, based on separate morphologic and molecular features.19,20 These two classes of PRCC have different outcomes. In our study, we did not stratify patients according to these two histologic subtypes, and therefore, we may not have accounted for the natural history of the disease in papillary histology. Regarding ChRCC, metastatic disease constitutes less than 5% of all cases and less than 1% of all metastatic RCC. Overall, advanced ChRCC carries a favorable prognosis. In a series of 12 patients with metastatic disease published by Motzer et al,6 the median survival time was 29 months, which is significantly longer than other histologic subtypes. However, only one patient with metastatic ChRCC responded to cytokine therapy. Our data suggest that this histologic subtype may be responsive to both sunitinib and sorafenib, with an overall clinical response rate of 25% and many patients achieving disease stabilization. ChRCC, like PRCC and CCRCC, can have upregulation of VEGF and its receptor mRNA, suggesting an active regulation of the VEGF-associated angiogenic pathway in this RCC subtype and potential antitumor activity with VEGF-targeted therapy.16 Additionally, the KIT oncogene was found specifically to be upregulated in ChRCC.21 Both sunitinib and sorafenib inhibit KIT in biochemical and cellular assays, suggesting another potential tumoral target. It is interesting to note that several patients who experienced progression on one anti-VEGF therapy and who were subsequently switched to another anti-VEGF therapy achieved SD and one patient achieved a partial response. Although the overall duration of follow-up was relatively short, the results support the clinical rationale for continued targeting of the VEGF and c-kit signaling pathway in non–clear cell RCC. One of our study limitations is the lack of central pathologic review, and it is possible that this has resulted in tumor misclassification. However, within each center, patients were often reviewed by a single pathologist experienced in the classification of RCC. Conversely, the lack of centralized pathologic review perhaps makes our results more applicable to general practice. Information about tumor grade was not present in the majority of patients and could not be accounted for when looking at different histologic subtypes. However, this is not likely to affect our results because it remains controversial whether these tumors should be graded and, if so, what system to use. One study found no association between Fuhrman nuclear grading system and survival in PRCC but found a significant association with the morphologic classification previously mentioned.22 Another limitation is the small number of patients included. However, despite this limitation and compared with older series,6 this study remains the largest to report on therapies in PRCC and ChRCC. A prospective study with a novel TKI restricted to non–clear cell histologies would be ideal. One of the strength of this data is the fact that we accounted for multiple known clinical prognostic factors in RCC when looking at the impact of both sunitinib and sorafenib. Although multivariate analysis could not be performed because of the small number of patients, an attempt was made to adjust for the impact of clinical prognostic factors when necessary. For example, sunitinib-treated patients were still noted to have a longer PFS than sorafenib treated patients, even after adjusting for other clinical factors. In summary, sunitinib and sorafenib seem to be active in metastatic chromophobe kidney cancer. Sunitinib seems to be more active than sorafenib in PRCC, although responses are overall low. Additional prospective studies and clinical experience with these two histologic non–clear cell subtypes are needed.
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: Brian I. Rini, Pfizer Inc (C), Genentech (C), Bayer (C); Ronald M. Bukowski, Bayer (C), Pfizer Inc (C), Genentech (C), Celgene (C), Wyeth (C) Stock Ownership: None Honoraria: Toni K. Choueiri, Pfizer Inc; Brian I. Rini, Bayer; Ronald M. Bukowski, Bayer, Pfizer Inc, Genentech Research Funding: Brian I. Rini, Bayer, Pfizer Inc, Genentech; Ronald M. Bukowski, Bayer, Pfizer Inc, Genentech, Celgene, Wyeth Expert Testimony: None Other Remuneration: None
Conception and design: Toni K. Choueiri Financial support: Ronald M. Bukowski, Bernard Escudier Administrative support: Toni K. Choueiri, Anne Plantade, Ronald M. Bukowski, Bernard Escudier Provision of study materials or patients: Toni K. Choueiri, Anne Plantade, Sylvie Negrier, Alain Ravaud, Stephane Oudard, Ming Zhou, Brian I. Rini, Ronald M. Bukowski, Bernard Escudier Collection and assembly of data: Toni K. Choueiri, Anne Plantade, Paul Elson, Ming Zhou Data analysis and interpretation: Toni K. Choueiri, Anne Plantade, Paul Elson, Sylvie Negrier, Alain Ravaud, Stephane Oudard, Brian I. Rini, Ronald M. Bukowski, Bernard Escudier Manuscript writing: Toni K. Choueiri, Paul Elson, Sylvie Negrier, Alain Ravaud, Brian I. Rini, Ronald M. Bukowski, Bernard Escudier Final approval of manuscript: Toni K. Choueiri, Anne Plantade, Paul Elson, Sylvie Negrier, Alain Ravaud, Stephane Oudard, Ming Zhou, Brian I. Rini, Ronald M. Bukowski, Bernard Escudier
Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Choueiri TK, Bukowski RM, Rini BI: The current role of angiogenesis inhibitors in the treatment of renal cell carcinoma. Semin Oncol 33:596-606, 2006[CrossRef][Medline] 2. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 335:865-875, 1996 3. 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 4. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125-134, 2007 5. Reuter VE: The pathology of renal epithelial neoplasms. Semin Oncol 33:534-543, 2006[CrossRef][Medline] 6. 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 7. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 8. Lopez-Beltran A, Scarpelli M, Montironi R, et al: 2004 WHO classification of the renal tumors of the adults. Eur Urol 49:798-805, 2006[CrossRef][Medline] 9. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 10. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 11. Mekhail TM, Abou-Jawde RM, Boumerhi G, et al: Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 23:832-841, 2005 12. Choueiri TK, Rini BI, Garcia JA, et al: Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinoma. Ann Oncol 18:249-255, 2006[CrossRef][Medline] 13. Choueiri TK, Garcia JA, Rini BI, et al: Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. Cancer 110:543-550, 2007[Medline] 14. Upton MP, Parker RA, Youmans A, et al: Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother 28:488-495, 2005[Medline] 15. Patard JJ, Leray E, Rioux-Leclercq N, et al: Prognostic value of histologic subtypes in renal cell carcinoma: A multicenter experience. J Clin Oncol 23:2763-2771, 2005 16. Jacobsen J, Grankvist K, Rasmuson T, et al: Expression of vascular endothelial growth factor protein in human renal cell carcinoma. BJU Int 93:297-302, 2004[CrossRef][Medline] 17. Leppert JT, Lam JS, Yu H, et al: Targeting the vascular endothelial growth factor pathway in renal cell carcinoma: A tissue array based analysis. J Clin Oncol 23:386s, 2005 (suppl 16S; abstr 4536) 18. Ronnen EA, Kondagunta GV, Ishill N, et al: Treatment outcome for metastatic papillary renal cell carcinoma patients. Cancer 107:2617-2621, 2006[Medline] 19. Delahunt B, Eble JN: Papillary renal cell carcinoma: A clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 10:537-544, 1997[Medline] 20. Yang XJ, Tan MH, Kim HL, et al: A molecular classification of papillary renal cell carcinoma. Cancer Res 65:5628-5637, 2005 21. Yamazaki K, Sakamoto M, Ohta T, et al: Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene 22:847-852, 2003[CrossRef][Medline] 22. Delahunt B, Eble JN, McCredie MR, et al: Morphologic typing of papillary renal cell carcinoma: Comparison of growth kinetics and patient survival in 66 cases. Hum Pathol 32:590-595, 2001[CrossRef][Medline] Submitted June 30, 2007; accepted September 26, 2007.
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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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ABSTRACT
INTRODUCTION
2 tests were used to assess the relationship between patient characteristics and clinical response. Median survival time was defined as the time from initiation of treatment to the date of death or last follow-up. Progression-free survival (PFS) was defined from the initiation of treatment to the date of progression or death, whichever came first. Survival distributions were estimated using the Kaplan-Meier method.
