Walter M. Stadler, MD1; Robert A. Figlin, MD2; David F. McDermott, MD3; Janice P. Dutcher, MD4; Jennifer J. Knox, MD5;Wilson H. Miller, Jr, MD, PhD6; John D. Hainsworth, MD7; Charles A. Henderson, MD8; Jeffrey R. George, MD9;Julio Hajdenberg, MD10; Tamila L. Kindwall-Keller, MD11; Marc S. Ernstoff, MD12; Harry A. Drabkin, MD13;Brendan D. Curti, MD14; Luis Chu, MD15; Christopher W. Ryan, MD16; Sebastien J. Hotte, MD17; Chenghua Xia, PhD18;Lisa Cupit, MD19; Ronald M. Bukowski, MD20, and on behalf of the ARCCS Study Investigators
BACKGROUND: The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval. METHODS: In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months.
RESULTS: The most common grade 2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups.
CONCLUSIONS: Sorafenib400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020). Cancer 2010;116:1272–80. V 2010 American Cancer Society.
Corresponding author: Walter M. Stadler, MD, Department of Medicine, University of Chicago Medical Center, 5841 S Maryland Avenue, MC 2115, Chicago, IL 60637; Fax: (773) 834-0188; email@example.com
1Department of Medicine, University of Chicago Medical Center, Chicago, Illinois; 2Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California; 3Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 4Division of Hematology/Oncology, New York Medical College, Bronx, New York; 5Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Ontario, Canada; 6Segal Cancer Centre, McGill University, Montreal, Quebec, Canada; 7Department of Oncology, Sarah Cannon Research Institute, Nashville, Tennessee; 8Department of Hematology/Oncology, Peachtree Hematology Oncology Consultants, Atlanta, Georgia; 9Department of Hematology/Oncology, Southern Cancer Center, Mobile, Alabama; 10Department of Medical Oncology and Hematology, M. D. Anderson Cancer Center, Orlando, Florida; 11Department of Hematology/Oncology, University Hospitals of Cleveland, Case Medical Center, Cleveland, Ohio; 12Section of Hematology/Oncology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire; 13Division of Hematology/Oncology, Department of Medicine and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina; 14Department of Genitourinary Oncology Research, Earle A. Chiles Research Institute, Portland, Oregon; 15Division of Hematology/Oncology, Florida Cancer Specialists, Sarasota, Florida; 16Division of Hematology/Oncology, Oregon Health and Science University, Portland, Oregon; 17Department of Medical Oncology, Juravinski Cancer Centre, Hamilton, Ontario, Canada; 18Pharmaceutical Division, Bayer HealthCare Pharmaceuticals, Montville, New Jersey; 19Medical Science/Oncology, Bayer HealthCare Pharmaceuticals, Wayne, New Jersey; 20Division of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio
Presented in part at the following meetings: 5th International Symposium of the Kidney Cancer Association, Chicago, Illinois, September 22-23, 2006; 22nd Annual Congress of the European Association of Urology, Berlin, Germany, March 21-24, 2007; 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, June 1-5, 2007; European Cancer Conference ECCO 14, Barcelona, Spain, September 23-27, 2007; 6th International Symposium of the Kidney Cancer Association, Chicago, Illinois, October 12-13, 2007; 1st European Multidisciplinary Meeting on Urological Cancers, Barcelona, Spain, November 2-4, 2007; 23rd Annual Congress of the European Association of Urology, Milan, Italy, March 26-29, 2008; 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, May 30-June 3, 2008; 33rd European Society for Medical Oncology Congress, Stockholm, Sweden, September 12-18, 2008; and 7th International Symposium of the Kidney Cancer Association, Chicago, Illinois, September 26-27, 2008.
We thank the patients who enrolled in this study and their families. We acknowledge the critical review provided by Sarah Guadagno, PhD and James Partyka, PharmD; Onyx Pharmaceuticals, Inc; and the medical writing assistance of Meenakshi Subramanian, PhD, Envision Pharma, Inc.
DOI: 10.1002/cncr.24864, Received: March 25, 2009; Revised: June 23, 2009; Accepted: July 6, 2009, Published online January 15, 2010 in Wiley InterScience (http://www.interscience.wiley.com/)
In 2008, 54,390 new cases of cancer of the kidney or re-nal pelvis were estimated to be diagnosed in the United States, with approximately 90% classified as renal cell carcinoma (RCC), and 13,010 patients were estimated to die of the disease.1,2 The traditional 5-year survival rate for patients with metastatic RCC is estimated to be <10%.2,3 At the time of diagnosis, 20% to 30% of RCC patients have metastatic disease, which is generally resistant to classic chemotherapy and radiation therapy.4Before the introduction of vascular endothelial growth factor (VEGF) pathwayand mammalian target of rapamycin (mTOR)-targeted therapy, recombinant human interleukin-2 and recombinant human interferon alpha2b (IFNa2b) either alone or in combination were the standard treatments.5However, these agents have limited efficacy and are associated with significant toxicity.6-12
Recognition of the essential role of VEGF in RCC pathogenesis led to the testing of angiogenesis inhibitors in this disease.13Sorafenib is a potent multikinase inhibitor of receptor tyrosine kinases VEGF receptors 1, 2, and 3 and platelet-derived growth factor receptors a and b, as well as the Raf/MEK/ERK pathway at the level of Raf kinase.14In xenograft models, sorafenib administered as a single agent had potent antiangiogenic activity and was found to inhibit the growth of RCC tumors.15,16
Sorafenib was investigated as monotherapy in 4 phase 1 trials 17-20 and had an acceptable toxicity profile. In a phase 2 randomized discontinuation trial, sorafenib prolonged progression-free survival (PFS) compared with placebo in patients with metastatic RCC in whom previous treatment was ineffective.21These positive results were subsequently confirmed in a large phase 3, randomized, placebo-controlled trial (Treatment Approaches in Renal Cancer Global Evaluation Trial [TARGET]) of sorafenib in 903 previously treated cytokine-refractory patients with metastatic RCC.22 Sorafenib therapy reduced the risk of disease progression by 56%; the median PFS with sorafenib (5.5 months) was twice that with placebo (2.8 months; P < .001).
The positive results in the TARGET trial substantiated the need to assess the use of sorafenib in patients who might benefit while it was under review by the US Food and Drug Administration (FDA) and not commercially available. The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access program was therefore instituted in North America to make sorafenib available to patients with advanced RCC who had no access to or did not qualify for other sorafenib clinical trials. We report here the safety and efficacy of sorafenib in this large group of patients representative of those with advanced RCC in the community setting.
MATERIALS AND METHODS
Eligible patients were ≥15 years old, had histologically confirmed advanced RCC, and an Eastern Cooperative Oncology Group performance status of 0 to 2, with waivers granted to selected patients with performance status 3 or 4. Unlike previous controlled clinical trials, this expanded access program included patients with nonclear cell pathology, patients with active or progressive metastatic brain disease despite previous treatment, those who had not received prior drug therapy for advanced RCC, and patients who had received therapy with bevacizumab at least 28 days before enrolling in this study (provided they had no grade ≥3 hemorrhagic episode during therapy, and no history of grade ≥2 hemorrhagic event within 6 months of bevacizumab therapy). Patients were excluded if they had treatment with other investigational drugs in the 4 weeks before enrollment, cardiac arrhythmias, active coronary artery disease or ischemia, uncontrolled hypertension, renal impairment requiring dialysis, recent or active bleeding diathesis, or life expectancy
All patients provided written informed consent. The study was approved by the institutional review board at each center and complied with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.
This nonrandomized, open-label expanded access program was conducted at 319 centers in the United States and at 8 centers in Canada (clinicaltrials.gov identifier: NCT00111020). Enrollment in the United States started in June 2005 and ended in December 2005 when the FDA approved the use of sorafenib for the treatment of advanced RCC, and it became commercially available. In Canada, enrollment took place between June 2005 and July 2006. Patients received oral sorafenib 400 mg twice daily on a continuous basis. Sorafenib tablets were supplied by Bayer HealthCare Pharmaceuticals (West Haven, Conn). Therapy was discontinued if the patient developed unacceptable toxicity, if progression of disease occurred, or if, in the investigator’s judgment, the patient was unlikely to benefit from further treatment with sorafenib. Toxicity-related dose modifications of sorafenib were performed in accordance with protocol-specified guidelines.
Because there was no central pathologic review and the original case report forms included the choice ‘‘other’’ rather than ‘unclassified,’’ 1 member of the steering committee reviewed pathology reports from a total of 226 patients (162 other, 11 no subtype recorded, 50 nonclear cell, 3 clear cell). Among the nonclear cell reports reviewed, histologic coding was changed in 25, typically to unclassified (22 cases). Patients with ‘‘unclassified’’ histology or those coded as ‘‘other’’ in whom the pathology report could not be reviewed were not included in the nonclear cell category for analysis.
Initial study phase
A baseline radiologic assessment of tumor burden was completed within 28 days before enrollment. Radiologic and/or clinical assessment of the target tumor was repeated at 8-week intervals or in accordance with the local standard of care. Clinical assessments were used only if radiologic assessments were not available. There was no validation of the investigator’s assessment of disease progression by an independent radiologist or oncologist. When the expanded access program was discontinued, the protocol specified follow-up for overall survival (OS) every 3 months; however, compliance with this requirement was poor and, at the time of final data analysis, the median follow-up time was only 22.4 weeks. Patients who remained on sorafenib therapy when the program ended were switched to commercial product or enrolled into the extension phase.
Six-month extension phase
When the expanded access program ended in the United States with FDA approval of sorafenib, patients who had not received prior antineoplastic therapy for advanced RCC and/or who were diagnosed with nonclear cell RCC were eligible to enter a 6-month extension study. During the 6-month extension, visit procedures and reporting were the same as during the initial study phase. Tumor assessments and radiologic evaluations were performed every 8 weeks, as described. At the conclusion of the extension phase, patients were observed every 3 months for OS.
Table 1. Patient Characteristics
Safety and Efficacy Assessments
Assessment of adverse events was based on clinical and laboratory evaluations considered as standard of care, and any reported adverse events were graded with version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events. The best overall response rate was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.23 In this study, PFS was defined as the time from administration of the first dose of sorafenib to disease progression or death. OS was defined as the time from administration of the first dose of sorafenib to death and was calculated for all patients 18 months after FDA approval of sorafenib. Kaplan-Meier analyses were performed for PFS and OS.
Safety and efficacy data were evaluated separately for 2 prespecified patient groups: first-line patients with no prior antineoplastic therapy for advanced RCC and those who received prior therapy. In addition, post hoc analyses of safety and efficacy were completed for subgroups of patients who are typically not enrolled in sorafenib clinical trials: patients with nonclear cell RCC, brain metastases, or prior bevacizumab treatment, and patients 70 years of age.
Between June 2005 and July 2006, 2515 patients with advanced RCC were enrolled in the ARCCS program in North America; 2504 patients (2298 in the United States and 206 in Canada) received at least 1 dose of sorafenib and were included in safety and efficacy analyses. Of these patients, 328 participated in the extension phase of the program. Demographic and disease characteristics in firstline patients were similar to those with prior therapy (Table 1). Among patients with brain metastasis, 36 had no prior treatment for advanced RCC, and 34 had prior treatment. Patient disposition is shown in Figure 1.
The median duration of sorafenib treatment was 12 weeks (range,
Table 1. Patient Characteristics
Drug-related grade 2 and 3 adverse events reported in >2% of patients are presented in Table 2. The most common grade 2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). Rates in elderly patients were similar. Drug-related central nervous system hemorrhages occurred in <1% of the overall population and were not reported in the brain metastases subpopulation. Seizures occurred in 7% of patients with brain metastases and in 1% of the total population; none was attributed to sorafenib therapy. There were 189 (8%) on-study deaths. Incidence was similar across subgroups (range, 6%-8%), except in patients with brain metastases (17%). The most common nonfatal serious adverse events reported in all patients were dyspnea (3%) and dehydration (3%).
Figure 1. Patient disposition is shown. ARCCS indicates Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program; NCC, nonclear cell.
Overall best response per RECIST guidelines was available in 1891 (76%) patients (Table 3). The median PFS in the overall population was 24 weeks (95% confidence interval [CI], 22-25; censorship rate, 46%); it was similar among first-line and previously treated populations (Fig. 2, Top). For comparison with other clinical trials that typically exclude patients with nonclear cell RCC, PFS was also calculated without data from patients with nonclear cell RCC (n ¼ 202). Results were similar to that in the overall population with a median of 24 weeks (95% CI, 22-25; censorship rate, 46%).
Of the 328 patients enrolled in the extension protocol, 246 patients had data available for analysis of progression; the median PFS in these patients was 36 weeks (95% CI, 33-45; censorship rate, 56%). In the first-line patients from the extension population (n ¼ 220), the median PFS was 36 weeks (95% CI, 33-45; censorship rate, 58%). In the previously treated nonclear cell extension patients (n ¼ 26), the median PFS was 46 weeks (95% CI, 30-59; censorship rate, 38%) (Fig. 2, Bottom). The median OS in the entire population was 50 weeks (95% CI, 46-52; censorship rate, 63%); similar results were obtained for the first-line and previously treated patients (Fig. 3).
The phase 3 TARGET trial established the safety and efficacy of sorafenib in patients with advanced RCC22; the ARCCS expanded access program broadened the experience with sorafenib in this patient population. As the ARCCS program was conducted in hospitals and community practice centers in addition to academic sites and because inclusion criteria were more liberal than for clinical trials, the ARCCS program enrolled a large number of patients who were more representative of the general metastatic RCC population than those in the typical RCC clinical trial.
Sorafenib treatment in the ARCCS program demonstrated a clinically manageable safety profile, with types and severity of adverse events similar to those in the phase 3 TARGET trial. The most common adverse events in both TARGET and ARCCS were hand-foot skin reaction, rash, fatigue, diarrhea, and nausea. The severity of these adverse events was usually low to moderate grade. Incidence and severity of adverse events in different subgroups of patients (first-line patients, previously treated patients, patients with nonclear cell RCC, brain metastases, previous treatment with bevacizumab, and patients 70 years of age) were also similar to those in the overall ARCCS population.
Hypertension as a serious adverse event was reported in TARGET as well as other clinical trials with sorafenib.22,24 In ARCCS, grade 3 drug-related hypertension was reported in only 5% of patients. However, other studies indicate that the incidence of sorafenib-induced blood pressure elevation is on the order of 75%,25 and a metaanalysis suggests that the overall incidence of hypertension is about 23%.24
The ARCCS study also suggests that the tolerability profile of sorafenib is not worse in patients with previously treated active or progressive brain disease, although baseline data regarding the extent of brain disease and prior treatment were limited. Overall, the higher rate of seizures in those with brain metastases was not attributed to sorafenib, and there were no cerebral bleeding events reported in this subgroup. In the ARCCS program, 736 (29%) patients were ≥70 years of age, reflective of the age distribution of patients with advanced RCC. As with the overall ARCCS population, the adverse events were predictable and manageable in elderly patients.
findings. The OS of 12 months observed in the ARCCS program was lower than that in the TARGET study (19 months); however, the patient population was less selective in the former. Furthermore, efficacy results from the ARCCS program are not directly comparable to those from randomized, controlled trials because of inherent limitations in study design and methods of an expanded access program. First, data collection and monitoring were not as rigorous as for a controlled clinical trial. A key limitation was that investigator assessments were not validated by an independent, centralized reviewer. In addition, radiologic assessments were preferred but not always obtained; in such cases, clinical assessments of tumor response were used. Perhaps most importantly, FDA approval of sorafenib for treatment of advanced RCC terminated the expanded access program. This limited the duration of on-study therapy (median, 12 weeks) and precision in the estimate of PFS because of the high rate of censorship (46%-73% of this was because of switching to commercial drug). In a large proportion of cases, confirmatory radiologic assessments of a partial response could not be performed on study.
The extension phase was added as a protocol amendment to allow for longer treatment and follow-up of patients who had not received prior therapy and those with nonclear cell RCC, thus providing additional information about efficacy of sorafenib in these patient types. However, the censorship rate in the extension subset was also quite high (56%-91% of this was because of switching to commercial drug). Nonetheless, within the limits of the program design, these results suggest that sorafenib is effective regardless of prior therapy status. Recently, first-line therapies for advanced RCC with other multikinase inhibitors (sunitinib) and angiogenic inhibitors (combination of bevacizumab and interferon) were shown to be more effective than IFN-a alone. There are no direct comparisons between these treatments and sorafenib.27,28
The majority (80%) of metastatic RCC is clear cell; therefore, most prior efficacy data, including those obtained with sorafenib, are from patients with this histologic diagnosis. In fact, in many trials, patients with nonclear cell RCC were excluded. Although the extension phase of this protocol was designed in part to assess PFS in patients with nonclear cell disease, the number of patients with nonclear cell enrolled in the extension population was too small (n ¼ 202) to provide meaningful estimates. Nevertheless, the 127 patients with valid response data represent the largest experience with this drug in nonclear cell RCC to date. Within the limitations of local pathology evaluation, albeit with central pathology report review, sorafenib appears to have antitumor activity in papillary and probably chromophobe cancers.
Finally, emerging data suggest that there is not an absolute cross-resistance between different VEGF pathway targeting agents. In fact, a previous study demonstrated activity of sorafenib or sunitinib in patients with advanced RCC with prior therapy with antiangiogenic agents.29 In ARCCS, 290 patients had prior therapy with bevacizumab, and their response to sorafenib was similar to that of other subgroups. Thus, similar to sunitinib, sorafenib has clinical activity after bevacizumab treatment.30
In conclusion, the ARCCS expanded access program provided additional information on sorafenib for the treatment of advanced RCC in a more representative patient population, extending the experience with sorafenib beyond the clinical trial setting in patients who had not been previously examined. This confirms that sorafenib, along with other VEGF and mTOR pathwaydirected agents, is an appropriate addition to the therapeutic armamentarium for this disease. This study does not address current controversies regarding relative value or appropriate sequence of the various agents now available. The data generated from the ARCCS program supported results from the TARGET trial and extended the findings to other subsets of patients who had not been previously examined. The tolerability of sorafenib was similar to that observed in previous clinical trials, with the majority of adverse events clinically manageable. Furthermore, these findings were supportive of previous trials demonstrating that sorafenib therapy delays disease progression in patients with advanced RCC. Additional studies are currently underway to investigate how best to combine or sequence sorafenib with other therapeutic agents in a variety of treatment settings.
CONFLICT OF INTEREST DISCLOSURES
Sponsored by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals, Inc. Dr. Stadler has acted in a compensated consultant/advisory role for Bayer, Onyx, Pfizer, Genentech, Novartis, and Wyeth, and has received research support from Bayer and Onyx. Dr. Figlin has acted in a compensated consultant role for Bayer and Onyx. Dr. McDermott has acted in a compensated consultant/advisory role for Bayer, Onyx, Genentech, Wyeth, and Novartis and has received research funding from Novartis. Dr. Dutcher has acted in a consultant role for Bayer/Onyx, has received honoraria and research grant from Bayer/Onyx. Dr. Knox has received honoraria from Bayer, Pfizer, and Novartis, and research funding from Bayer and Pfizer. Dr. Henderson has acted in a consultant role for Amgen, Genentech, Bristol, ImClone, GlaxoSmithKline, Abraxis, and Pfizer. Dr. Drabkin has received honoraria as a member of the advisory board for Nexavar. Dr. Curti has acted in an uncompensated consultant/advisory role for Zymogenetics and has received honoraria from Novartis and Bayer/Onyx. Dr. Ryan has received honoraria and speaking fees from Bayer/Onyx. Dr. Xia is an employee of Bayer HealthCare. Dr. Cupit is an employee of Bayer HealthCare. Dr. Bukowski has acted in a compensated consultant/advisory role for Pfizer, Bayer, Novartis, Wyeth, and Genentech, and has received honoraria from Pfizer, Wyeth, Genentech, Bayer, and Novartis.
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2007;58:71-96.
2. Garcia JA, Rini BI. Recent progress in the management of advanced renal cell carcinoma. CA Cancer J Clin. 2007;57:112-125.
3. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335:865-875.
4. Yagoda A, Petrylak D, Thompson S. Cytotoxic chemother apy for advanced renal cell carcinoma. Urol Clin North Am. 1993;20:303-321.
5. Escudier B. Advanced renal cell carcinoma: current and emerging management strategies. Drugs. 2007;67:1257 1264.
6. Motzer RJ, Russo P. Systemic therapy for renal cell carci noma. J Urol. 2000;163:408-417.
7. Atkins MB, Regan M, McDermott D. Update on the role of interleukin-2 and other cytokines in the treatment of patients with stage IV renal carcinoma. Clin Cancer Res. 2004;10:6342S-6346S.
8. Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13:688-696.
9. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med. 1998;338:1272-1278.
10. Collaborators MRCRC. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet. 1999;353:14-17.
11. Negrier S, Maral J, Drevon M, et al. Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. Cancer J Sci Am. 2000;6(suppl 1):S93-S98.
12. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21:3127 3132.
13. Rini BI, Small EJ. Biology and clinical development of vas cular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028-1043.
14. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhib its broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099-7109.
15. Chang YS, Adnane J, Trail PA, et al. Sorafenib (BAY 43 9006) inhibits tumor growth and vascularization and indu ces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2007;59:561-574.
16. Levy J, Pauloski N, Braun D. Analysis of transcription and protein expression changes in the 786-O human renal cell carcinoma tumor xenograft model in response to treatment with the multi-kinase inhibitor sorafenib (BAY 43-9006). Proc Am Assoc Cancer Res. 2006;47:213-214.
17. Moore M, Hirte HW, Siu L, et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, adminis tered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol. 2005;16: 1688-1694.
18. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vas cular endothelial growth factor receptor inhibitor BAY 43 9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005;23:965-972.
19. Awada A, Hendlisz A, Gil T, et al. Phase I safety and phar macokinetics of BAY 43-9006 administered for 21 days on/ 7 days off in patients with advanced, refractory solid tumours. Br J Cancer. 2005;92:1855-1861.
20. Clark JW, Eder JP, Ryan D, et al. Safety and pharmacoki netics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res. 2005;11:5472-5480.
21. Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:2505-2512.
22. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134.
23. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guide lines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Can cer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216.
24. Wu S, Chen JJ, Kudelka A, et al. Incidence and risk of hyper tension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol. 2008;9:117-123.
25. Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006;24:1363-1369.
26. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med. 2005;353:2477-2490.
27. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.
28. 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. Lan cet. 2007;370:2103-2111.
29. Tamaskar I, Garcia JA, Elson P, et al. Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol. 2008;179:81-86.
30. Rini BI, Michaelson MD, Rosenberg JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3743-3748.