294 Chin J Clin Oncol (2008) 5: 294~298 DOI 10.1007/s11805-008-0294-x Current Status of Studies on Targeted Therapy for Renal Cell Carcinoma Shaoqi Wang 1 Shaoxiang Wang 2 Juan Wang 1 1 Department of Oncology, Hebei People s Hospital, Shijiazhuang 050051, Hebei Province, China. 2 Shenzhen People s Hospital, Shenzhen 518020, Guangdong Province, China. Correspondence to: Shaoqi Wang E-mail: hackerwsq@163.com ABSTRACT Renal cell carcinoma (RCC) is regarded as one of the most refractory malignancies. A further study of the molecular mechanism of RCC formation has led to a series of successful examples for treatment of patients with advanced RCC. Over the past 20 years, a nonspecific immunotherapy, with cytokines, has been employed as the gold standard for therapy of metastatic RCC. However, with scientific development and clinical testing of new drugs, targeted molecular cancer therapy has become a focus of interest. At the same time, with a be er understanding of RCC, the treatment method has converged on anti-vascular endothelial growth factor (VEGF) and related molecular-targeted pathways. A large amount of research and numerous clinical trials have demonstrated the clinical efficacy of the targeted molecular therapies in patients with metastatic RCC. For example sorafenib and sunitinib were approved, in 2005 and 2006 respectively, by the U.S. FDA for treating advanced RCC. In this report, issues such as the importance of VEGF in RCC and the studies of bevacizumab, sunitinib and sorafenib in treating metastatic RCC etc., are reviewed. KEY WORDS: targeted molecular therapy, renal cell carcinoma, vascular endothelial growth factor. Copyright 2008 by Tianjin Medical University Cancer Institute & Hospital and Springer Introduction Received January 12, 2008; accepted June 2, 2008. CJCO http://www.cjco.cn E-mail: 2008cocr@gmail.com Tel (Fax): 86-22-2352 2919 Based on statistics from 2007, about 51,190 people are diagnosed with a renal carcinoma or a renal pelvic carcinoma in the U.S. each year. Most of the patients had renal cell carcinoma (RCC). Each year worldwide a total of 12,890 people die from the disease [1]. Over the past 20 years, the incidence of renal carcinoma has increased progressively at a rate of approximate 2% per year. The 5-year survival only reaches up to 5%~10% because of the insensitivity of RCC to radiotherapy and chemotherapy. For RCC therapy, an application of nonspecific immune supportive treatment has had a reasonable curative effect [2]. At present, recombinant interleukin 2 (ril-2) and recombinant Hu-interferon-α (IFN-α) are the main agents for immunotherapy [3], however, the application of these drugs has been severely restricted owing to factors such as toxicity and low efficacy etc. A series of retrospective studies has demonstrated that vascular endothelial growth factor (VEGF) is a potential target for treating metastatic RCC. Depression of VEGF expression by various methods has proven to produce a better anticancer effect and clinical benefit, which has significantly improved the overall treatment of RCC.
Chin J Clin Oncol (2008) 5: 294~298 295 Expression of VEGF in RCC VEGF is a glycoprotein dipolymer, and is a member of the platelet-derived growth factor (PDGF) family that includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placenta growth factor (PlGF). VEGF is of great importance to normal or tumor-related angiogenesis, and at the same time it can induce endothelial cell division, cellular transplantation, thus enhancing the survival rate of endothelial cells, reducing apoptosis, and reversing endothelial cell aging [4]. VEGF exerts its own biological action via receptors on the cell surface. These transmembrane protein tyrosine kinase (PTK) receptors include VEGFR-1 and VEGFR-2, which are selectively expressed in vascular endothelial cells (VEC), the VEGFR-3 in lymphatic vessels and blood vessel endothelium, and the neural receptors on the blood vessel endothelium and neurons [5]. VEGF is expressed in most RCC cases, and the VEGF protein can be differentiated from RCC tissues [6]. The other proteins that relate to the biological characteristics and treatment of RCC include PDGF, fibroblast growth factor, erythropoietin, and α-type transforming growth factor. Development of RCC treatment by targeting VEGF Over-expression of VEGF in RCC has stimulated interest in targeting VEGF and its correlated pathway for RCC therapy, especially, in cases of metastatic or advanced RCC. Table 1 summarizes the clinical progress in treating RCC, with VEGF as the therapeutic target. Bevacizumab Bevacizumab (or Avastin) is a recombinant humanized anti-vegf monoclonal antibody. It can be conjugated with the VEGF receptor (VEGFR) and can inhibit the bioactivity of all VEGF subtypes. Studies on bevacizumab monotherapy Phase-II clinical trial using bevacizumab for treating metastatic RCC [7] : a total of 116 patients with metastatic water-clear cell renal carcinoma were randomized into bevacizumab and control groups (n = 40). Then the bevacizumab group was subdivided into a low-dose (3 mg/kg, n = 37) and high-dose group (10 mg/kg, n = 39), with i.v. administration, once every 2 weeks. Among the patients, 108 (93%) also received IL-2 therapy. The clinical trial showed that the median time of tumor progression (mttp) was doubled in the high-dose group compared to the control group (4.8 and 2.5 months, respectively, P = 0.001), whereas the mttp was 3.0 months in the low-dose group. A portion of the cases in the high-dose group (10%, 4/39) achieved partial remission (PR). No life-threatening reactions occurred, and there were no deaths related to bevacizumab medication. Frequent toxic reactions included hypertension, asymptomatic proteinuria, chest pain, or other various complaints etc., in the high-dose group. All reactions disappeared after the drug was withdrawn. Hemoptysis of Grade-I to II was found in only 4 cases, i.e. 1 in each of the high and low-dose groups, and 2 in the controls. Also one pulmonary embolism occurred in the control group. It was shown that bevacizumab can significantly prolong the TTP of RCC patients. Joint study of bevacizumab In a multi-centrally cooperative and jointly completed phase-ii clinical trial [8], the EGFR inhibitor, erlotinib, combined with bevacizumab, was used to treat metastatic RCC. All patients received bevacizumab (10 mg/kg, i.v., once every 2 weeks) and erlotinib (150 mg, peroral, once a day). A total of 63 patients were involved in the trial, all of whom underwent nephrectomy, but 68% of them did not receive a systematic treatment. The objective response rate (ORR) was 25% (15/63), and 36 patients maintained stable disease (SD) following an 8-week treatment. Two patients withdrew because a skin rash, but all other remained in the study. The rash of Grade-1 to 2 and diarrhea were the most frequent toxic reactions. Owing to a reasonable target in various tumors, the study showed that a combination of drugs for targeted therapy will be the direction of future development. In another phase-ii clinical trial of combined drug therapy, the results were not satisfactory [9]. Comparison of the curative effect between bevacizumab plus placebo Table 1. Clinical trials and results of targeted treatment of RCC patients. Subjects Targeted drugs Targets Cases Plan of clinical trials Previous treatment records Response rate (%) Time (months) Yang et al. [7] Bevacizumab VEGF ligand 116 Bevacizumab; placebo Immunotherapy 10; 0 4.8; 2.5 Bukowski et al. [9] Bevacizumab VEGF ligand 150 Motzer et al. [12] Motzer et al. [13] Sunitinib VEGFR 63 106 Bevacizumab + placebo; Bevaqcizumab + erlotinib Sunitinib No 13.7; 14 8.5; 8.9 Immunotherapy Motzer et al. [14] Sunitinib VEGFR 750 Sunitinib; IFN-α No 31; 6 11.1; 5.0 Escudier et al. [19] Sorafenib VEGFR and Raf kinase pathway 40 34 8.7 8.3 903 Sorafenib; placebo Immunotherapy 2; 0 5.5; 2.8
296 Chin J Clin Oncol (2008) 5: 294~298 treatment and the drug combination was conducted. The results indicated that the ORR (13.7% and 14%) and the median progression-free survival (mpfs) (8.5 and 9.9 months) were the same in both groups. Although combined medication increases the anti-egfr targets, it does not improve the clinical efficacy. Bevacizumab combined with biotherapy: Rini et al. [10] have conducted a phase-iii clinical trial on a combination of bevacizumab with IFN-α treatment for advanced RCC. This combination has not been utilized before, with the results still being under analysis. This research will shed light on the efficacy of using bevacizumab along with immunotherapy for treating advanced RCC patients. Micromolecular inhibitors of the VEGF receptor The micromolecular substances that selectively inhibit VEGF activity include receptor tyrosine kinase (RTK) inhibitors. These micromolecular substances can not only depress the VEGFR, but also inhibit the plateletderived growth factor receptor (PDGFR). They are multi-targeting drugs. Sunitinib Sunitinib, is an oral multi-target micromolecular RTK inhibitor, which can depress the activity of VEGFR and PDGFR. In vitro experiments have demonstrated that sunitinib can inhibit endothelial cell proliferation induced by VEGF, and the proliferation of rat fibroblasts induced by PDGF [11]. There have been 2 large-scale phase-ii clinical trials for sunitinib. In Trial I [12], 63 metastatic RCC patients who had failed to respond to immunotherapy were studied. Most of these cases (87%) had been confirmed by histology as clear-cell carcinoma. Nephrectomy was not a requirement for inclusion in the trial, nevertheless 93% of the patients have undergone surgery. Recommended sunitinib dosage was given to all the patients (50 mg, peroral, once a day, over a 4 continuous weeks of administration, followed by 2 weeks of drug withdrawal; 1 cycle every 6 weeks). PR occurred in 25 cases (40%) and SD in 27% of the patients 3 months after medication. The mttp was 8.7 months, and median survival time was 16.4 months. In trial II, a total of 106 metastatic RCC patients, with a failure of a response to immunotherapy, were observed in another trial [13]. All were confirmed as clear-cell renal carcinoma by pathology and had received a surgical excision. PR was achieved in 36 cases (34%), and mttp was 8.3 months. In both the trials, frequent toxic reactions were as follows: fatigue (28%), diarrhea (20%), stomatitis (26%), dermatitis (12%) and hypertension (11%). These reactions can disappear after withdrawal, and can actively be prevented and treated during the treatment. These data show that sunitinib may have a reliable efficacy in the treatment of advanced RCC. Therefore in 2006, the U.S. FDA approved the use of sunitinib for treating advanced RCC patients. In 2007, Motzer et al. [14] published the results of phase-iii clinical trials for sunitinib medication. A total of 750 cases were shown to be clear-cell carcinoma. Systematic treatment had not been conducted previously in all the patients, who were randomized into a sunitinib group (recommended medication) and a IFN-α group (9 10 6 U hypo, 3 per week, 1 cycle every 6 weeks). The ORRs were respectively 31% and 6% (P = 0.000001), and the mpfss were 11 and 5 months (P = 0.00001). The toxic reactions in the phase-iii clinical trial was similar to the results in the phase-ii trial, the incidence rate of Grade-III and IV fatigue was significantly increased in the sunitinib group compared to the IFN-α group, and the incidence of diarrhea was also high. The curative effect of sunitinib in treating metastatic RCC was obviously superior to that of IFN-α therapy, indicating that sunitinib might be a favorable choice for treatment of advanced RCC patients. In another multi-center phase-ii clinical trial [15], the therapeutic efficacy of sunitinib in treating the patients, who failed to benefit from a treatment with bevacizumab as the cardinal remedy, was assessed. The recommended dosage of sunitinib was used in 61 patients who had undergone and failed bevacizumab treatment. In this trial the ORR was 16%, SD occurred in 61% of the patients and there was tumor reduction in 56%. Grade-III toxic reactions mainly included fatigue, hypertension, dermatitis, hand-foot-mouth syndrome and diarrhea, with the incidence of 31%, 15%, 5% and 5%, respectively. The trials indicated that sunitinib can inhibit the signaling pathway in cases when there is bevacizumab resistance. Sorafenib Sorafenib is a stretch serine threonine protein kinase (Raf) and tyrosine kinase inhibitor. It was shown, by a xenogeneic graft modeling of a human tumor, that sorafenib can depress the expression of the Ras gene [16], which can activate the RAF-MEK-ERK pathway and promote cell proliferation. It has been demonstrated that sorafenib can directly inhibit the VEGFR-2, VEGFR-3 and PDGFR-β [17]. In December 2005, sorafenib was approved by the U.S. FDA to be used in treating advanced RCC patients. In phase-ii clinical trials [18], 202 advanced RCC patients were enrolled. All received sorafenib treatment (400 mg, peroral, b.i.d). A double-blind randomized test was conducted in patients with SD following a 12-week treatment, and then another 12-week sorafenib or placebo treatment was conducted. Sorafenib medication was continued with 73 patients achieving tumor size reduction of over 25%. The drug treatment was ceased in 64 patients who showed tumor enlargement of 25%. The other 65 SD patients were randomized into a sorafenib (32) or placebo group (33). At the 24th week of drug
Chin J Clin Oncol (2008) 5: 294~298 297 treatment, the progression-free survival (PFS) occurred in 50% of the patients receiving sorafenib treatment, a significant increase compared to the control group (18%, P = 0.0077). The mpfs was respectively 24 and 6 weeks in the 2 groups (P = 0.0087), with an mpfs of 29 weeks in all patients. The main toxic reactions included skin rash or desquamation, hand-foot cutaneous reaction and fatigue. The drug had to be withdrawn in 9% of the patients because of toxic reactions. The results of successive phase-iii sorafenib clinical trials were serially reported at the ASCO Meetings from 2005 to 2007. The findings were mainly in relation to patients with refractory RCC after immunotherapy [19-21]. PR was achieved in 7 of the total patients (2%) during the trial. SD was seen in a 78% of the patients from the sorafenib-treated group, and only 55% from the control group. In the group receiving sorafenib, tumor reduction to various degrees occurred in a 74% of the patients. The mpfs was 24 weeks in the sorafenibtreated group, while in the control group it was 12 weeks (P = 0.0000001), with an improvement of the survival rate in 39% of the patients. The mpfs was significantly increased in the sorafenib-treated group. Then the initial plan of the test was changed, so the patients of the control group were diverted to a drug-treatment group to receive sorafenib administration. A total of 216 patients from the control group later were diverted to the sorafenib group. Six months after conducting the inversion program, the median overall survival (mos) was 19.3 months in the sorafenib-treated group, and 14.3 months in the control group (P = 0.015), with an improvement of the survival rate in 30% of the treated patients. Based on the end-results of the trial reported at the 2007 ASCO Meeting, there were 561 deaths up to September 2006. The mos was respectively 17.8 and 15.2 months in the 2 groups, with no statistical difference between the 2 groups (P = 0.116). Improvement of the survival rate was achieved in 13.5% of the cases. The toxic reactions mainly included Grade-I and II hypertension, fatigue, and the symptoms related to the GI tract, skin and nervous system. The test suggested that the sorafenib treatment failed to significantly improve the mos, but the therapeutic efficacy of the sorafenib treatment was obvious in the 1st and the 2nd phases of the tests. The curative effect of sorafenib combined with IFN-α on new RCC cases, without any previous treatment, was assessed in 2 tests in which all 31 patients were given 400 mg sorafenib peroral, b.i.d., and IFN-α, 100,000 U hypo, t.i.d. [22] Twenty-four of the cases were worthy of appraisement. The ORR was 42% (38% PR, 4% CR), with a SD of at least 8 weeks in 46% of the patients, among which a 20% reduction of tumor size occurred in 8% of these patients. The toxic reactions mainly included Grade-I and II fatigue (78%), anorexia (74%), skin rash (70%, 11% Grade III), diarrhea 67%), nausea (56%), neutropenia (48%, 19% Grade III), alopecia (44%) and stomatitis or oral mucositis (26%). Based on the report of another trial [23], 62 metastatic RCC patients, without any previous treatment, were treated with the above-mentioned medication. The ORR was 19%, SD 31%, mpfs 7 months, and toxic reactions were basically similar in the patients. The results of the trial showed that the curative effect of sorafenib combined with IFN-α in treating RCC patients is superior to either sorafenib or IFN-α monotherapy, and that the toxic reactions are tolerable. Discussion A further understanding of the molecular pathogenesis of RCC, and development and application of drugs designed for targeted molecular therapy, both have greatly influenced previous concepts and modes of RCC therapeutics. Although the mttp and mos have not been remarkably improved from the tests, it is encouraging that tumor reduction occurred in a 70% to 75% of the patients in the trials, and that the ORR reached 2% to 40% of the cases. The therapeutic efficacies of bevacizumab, sunitinib and sorafenib are equivalent, so it is difficult to say which drug produced the best efficacy in these clinical trials. The availability of several drugs with equal curative effects raises questions, as to the drug choice, risk-benefit ratio of a drug combination versus monotherapy, drug tolerance and the sequence of drug administration. These questions need to be answered from further clinical trials. The growth of tumor cells is the result of a common effect on multiple pathways. All patients can not benefit from targeted molecular therapy that solely inhibits VEGF and the related pathways. So a variety of drugs are needed to concurrently inhibit the pathways in relation to the pathogenesis of RCC. Multiple clinical trials to address this concept are under way, which hopefully will explain the theoretical prospect of multi-target therapy for RCC patients. References 1 Jemal A, Siegel R, Ward E, et al. Cancer Statistics 2007. CA Cancer J Clin 2007; 57: 43-66. 2 Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 2005; 25: CD001425. 3 Li CF, Yan QZ, Kong XB, et al. Clinical observation of long-term efficacy of bio-chemotherapy in the treatment of metastatic lesions of renal carcinoma. Zhongguo Zhong Liu Lin Chuang 2007; 34: 26-28 (Chinese). 4 Benjamin LE, Golijanin D, Itin A, et al. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999; 103: 159-165. 5 Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20: 4368-4380. 6 Rini BI, Small EJ. Biology and clinical development
298 Chin J Clin Oncol (2008) 5: 294~298 of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 2005; 23:1028-1043. 7 Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349: 427-434. 8 Hainsworth JD, Sosman DR, Spigel RC, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and Erlotinib. J Clin Oncol 2005; 23: 7889-7896. 9 Bukowski RM, Kabbinavar F, Figlin RA, et al. bevacizumab with or without erlotinib in metastatic renal cell carcinoma (RCC). J Clin Oncol 2006; 24: 4523. 10 Rini BI, Halabi S, Taylor J, et al. Cancer and Leukemia Group B 90206: A randomized phase III trial of interferon-alpha or interferon-alpha plus anti-vascular endothelial growth factor antibody (bevacizumab) in metastatic renal cell carcinoma. Clin Cancer Res 2004; 10: 2584-2586. 11 Mendel 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. 12 Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multi-targeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006; 24: 16-24. 13 Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006; 295: 2516-2524. 14 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. 15 Rini BI, George DJ, Michaelson MD, et al. Efficacy and safety of sunitinib malate (SU11248) in bevacizumabrefractory metastatic renal cell carcinoma (mrcc). J Clin Oncol 2006; 24: 4522. 16 Lyons JF, Wilhelm S, Hibner B, et al. Discovery of a novel Raf kinase inhibitor. Endocr Relat Cancer 2001; 8: 219-225. 17 Wilhelm S, Carter C, Tang L, et al. BAY 43-9006 exhibits 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. 18 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. 19 Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of sorafenib (BAY 43 9006)-an oral multi-kinase inhibitor-in patients with advanced RCC. J Clin Oncol 2005; 23: 4510. 20 Eisen T, Bukowski RM, Staehler M, et al. Randomized phase III trial of sorafenib in advanced renal cell carcinoma (RCC): Impact of crossover on survival. J Clin Oncol 2006; 24: 4524. 21 Bukowski RM, Eisen T, Szczylik C, et al. Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysis. J Clin Oncol 2006; 24: 5023. 22 Gollob JA, Rathmell KR, Richmond TM, et al. Phase II trial of sorafenib plus interferon-alpha 2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol 2007; 25: 3288-3295. 23 Ryan CW, Goldman BH, Lara PN, et al. Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: a phase II study of the Southwest Oncology Group. J Clin Oncol 2007; 25: 3296-3301.