Recent Progress in the Management of Advanced Renal Cell Carcinoma†
Dr. Jorge A. Garcia MD,
Garcia is Associate Staff, Departments of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Center; and Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
Rini is Staff, Departments of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Center; and Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH.
Disclosures: Jorge A. Garcia receives research funding from Genentech, Pfizer, and Celgene; Brian I. Rini received research funding from Genentech, Bayer, and Pfizer, and is a paid consultant to Genentech, Bayer, and Pfizer.
A better understanding of the molecular biology of renal cell carcinoma (RCC) has led to a dramatic paradigm shift in the treatment of patients with metastatic disease. Historically, a nonspecific immune approach using cytokines was employed, but recently this has transitioned to a molecularly-targeted approach against vascular endothelial growth factor (VEGF) and related pathways. Several anti-VEGF agents, including ligand-binding agents such as bevacizumab and the small molecule inhibitors of VEGF and related receptors such as sunitinib and sorafenib, have demonstrated clinical activity in patients with metastatic RCC. Other agents that inhibit alternative targets such as the mammalian target of rapamycin (mTOR) have also demonstrated activity. This generation of novel molecular targeted therapies continues to show great promise. The purpose of this review is to summarize the current management and to discuss potential future directions in the management of metastatic RCC.
In 2007, it is estimated that 51,190 people will be diagnosed with and 12,890 deaths will be attributed to cancers of the kidney and renal pelvis (the vast majority of which are renal cell carcinoma [RCC]) in the United States.1 During the past 2 decades, the incidence of these cancers has increased by approximately 2% per year.2 RCC represents the third leading cause of death among genitourinary malignancies and the twelfth leading cause of cancer death overall in the United States.1 The lack of demonstrable efficacy of chemotherapy and radiation therapy in Stage IV RCC has led to a 5-year survival ranging from 5% to 10%.3,4 Historically, the known immunogenicity of RCC has been the basis supporting the use of immunotherapy in metastatic RCC.5 Current immunotherapeutic regimens use recombinant human interleukin-2 (IL-2) and recombinant human interferon α-2b (IFN-α), either alone or in combination.6, , , , , , –13 The use of these cytokines, however, is limited by their toxicity and generally poor overall response rates.
Recent progress in understanding the biology of RCC has led to the identification of vascular endothelial growth factor (VEGF) as a potential therapeutic target in patients with metastatic clear-cell RCC. VEGF is the most potent proangiogenic protein, leading to increased tumor vasculature and metastatic growth. Several studies using different strategies to inhibit VEGF signaling have demonstrated significant antitumor effects and meaningful clinical benefits. The comprehensive management of the metastatic RCC patient has thus been refined.
ROLE OF CYTOREDUCTIVE NEPHRECTOMY IN ADVANCED DISEASE
An initial consideration in the management of metastatic RCC is the value of removing the primary tumor (cytoreductive nephrectomy). Retrospective series of metastatic RCC patients consistently identified prior nephrectomy as a favorable feature.14, –16 Similarly, retrospective data indicating that patients with metastatic RCC and prior nephrectomy treated with cytokines had improved outcomes compared with patients without prior nephrectomy led to the concept of cytoreductive nephrectomy as advantageous before the initiation of immunotherapy. Based on these observations, two identically designed, prospective randomized clinical trials were initiated in Europe and the United States (Table 1). Eligibility for both trials included biopsy-proven Tany, Nany, M1 RCC with a primary tumor amenable to resection as determined by the operating surgeon. Additional eligibility included Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, no prior radiotherapy or systemic treatment of any kind, and adequate end-organ function. Overall survival was the primary endpoint for both trials, with analysis based on intent-to-treat criteria using a Kaplan-Meier analysis for survival duration. The Southwest Oncology Group (SWOG) randomized 241 metastatic RCC patients to either IFN-α alone or nephrectomy followed by IFN-α therapy. Although the objective response rate (ORR) observed with IFN-α therapy was quite low (3.3% and 3.6%, respectively) when compared with other contemporary series, patients undergoing surgery followed by IFN-α therapy had a survival advantage over those who received IFN-α alone (8.1 versus 11.1 months, respectively; P = 0.012).17 Coincidently, the European Organization for Research and Treatment of Cancer trial18 randomized 85 patients with advanced RCC to either IFN-α alone or nephrectomy followed by IFN-α. By intent-to-treat analysis, the time to disease progression (TTP) favored the surgery arm (5 versus 3 months; hazard ration [HR] 0.60, 95% confidence interval [CI], 0.36 to 0.97). Furthermore, the median survival was significantly better for the surgery arm (17 versus7 months; HR 0.54, 95% CI, 0.31 to 0.94). When the data from these two studies are combined, they provide strong support favoring the use of nephrectomy before immunotherapy. Of the 341 total randomized patients, an overall survival advantage for the nephrectomized group is observed (13.6 months mean survival versus 7.8 months for the IFN-α-alone arm, P = 0.002). Not surprisingly, the benefit was most pronounced in performance status 0 patients, but was not dependent on site of metastasis or disease measurability. The combined results in 253 patients with measurable disease revealed a 6.9% response rate in the nephrectomy arm versus a 5.7% response rate in the IFN-α-only arm (P = 0.60). Surgical morbidity and mortality were acceptable and did not prevent subsequent administration of IFN-α in 95% of nephrectomized patients at a median of 19 days after surgery.19
Table TABLE 1. Summary of Randomized Trials Evaluating the Benefit of Cytoreductive Radical Nephrectomyin Metastatic Renal Cell Carcinoma
These trials provide convincing evidence of an overall survival benefit when advanced RCC patients undergo nephrectomy before the initiation of systemic therapy with IFN-α. Furthermore, the lack of response rate benefit on the IFN-α-containing arm implicates removal of the primary tumor itself as advantageous, independent of effect on subsequent therapy. The biologic mechanisms for such an effect remain unclear. Cytoreductive nephrectomy has thus been translated into routine clinical practice in the United States. Although there are no prospective data regarding the role of nephrectomy followed by antiangiogenic therapy, cytoreductive nephrectomy is routinely performed in metastatic RCC patients initially if the primary tumor is still in place. Proper patient selection is essential to maximize the benefits of cytoreductive nephrectomy. The optimal candidates include those with (1) good performance status; (2) a resectable primary tumor representing the majority of tumor burden; (3) no evidence of central nervous system metastasis; (4) no evidence of rapidly progressing extrarenal disease; and (5) no prohibitive medical comorbidities.
Similarly, resection of solitary (or limited number of) metastases may lead to long-term survival in 30% of such patients.20,21 Best results are obtained if the metastases are pulmonary, metachronous, with a long disease-free interval, and completely resected.22 Other small series have reported encouraging results following the excision of hepatic, adrenal, brain, and pancreatic metastases,23, , , –27 or of isolated local recurrences in the nephrectomy bed.28,29 Circumstances where patients can undergo resection of residual disease after response to systemic therapy may indeed become more common with the higher tumor shrinkage rates of novel agents described herein. A reevaluation of the efficacy and safety of metastasectomy in this setting is warranted. Systemic therapy in patients with no evidence of disease after undergoing metastasectomy is not of proven benefit.
THE CYTOKINE ERA
Over the past 2 decades, immunotherapeutic approaches implementing biologic response modifiers like IFN-α and IL-2 alone or in combination have been the standard treatment for patients with advanced RCC. Table 2 summarizes relevant trials evaluating cytokines in advanced RCC. Two large randomized trials have examined the benefit of high-dose (HD) IL-2 and low-dose cytokine regimens. The Cytokine Working Group randomized 193 cytokine-naïve metastatic RCC patients to either HD IL-2 (600,000 units/kg intravenous [IV] every 8 hours × 14 doses; maximum 3 cycles) or subcutaneous (SC) low-dose IL-2 at 5 million units (MU)/m2 5 days/week in combination with SC IFN-α at 5 MU/m2 3 days/week.6 The primary endpoint of this trial was progression-free survival (PFS) at 3 years. The overall response rate observed was 26% for HD IL-2 versus 11% for low-dose cytokines (P = 0.01), with no significant difference in 3-year PFS (5% versus 0%) or overall survival (17.5 months versus 13 months; P = 0.12). There were a substantially increased number of Grade 3/4 toxicities in the HD IL-2 arm. Similarly, the National Cancer Institute trial randomized 283 mostly untreated metastatic RCC patients to 1 of 3 treatment regimens: HD IL-2 (720,000 units/kg IV every 8 hours) or low-dose IV bolus IL-2 (72,000 units/kg IV every 8 hours) or low-dose SC IL-2 (125,000 units/kg SC 5 days/week × 6 week cycles).7 The reported overall response rate was 21% for HD IL-2 versus 13% for low-dose IV IL-2 versus 10% for low-dose SC IL-2 (P = 0.033), with no significant difference in overall survival (P = 0.34). There was a substantial increase in Grade 3/4 toxicities in the HD IL-2 arm. Taken together, these data suggest that HD IL-2 has a higher overall and complete response rate compared with low-dose therapy, with the majority of benefit realized in the durability of complete responses. There is no proven benefit, however, in disease-free or overall survival with HD IL-2 for the entire cohort. Toxicity is substantial with HD IL-2 and highlights the need for stringent patient selection.
Table TABLE 2. Selected Trials of Immunotherapy for Advanced Renal Cell Carcinoma
3.8 months improvement compared with control (P = 0.0005)
Although similar randomized trials evaluating low-dose IL-2 have not been reported, a large randomized trial comparing continuous HD IL-2 with IFN-α or the combination of both regimens demonstrated similar clinical benefit for each cytokine.8 This trial failed to demonstrate an overall survival benefit for combination low-dose cytokines versus single-agent cytokine, with significantly more toxicity in the combination arm. No prospective randomized trial has demonstrated benefit to additional agents combined with cytokines. Thus, considering cytokine therapy in metastatic RCC, good performance status patients with access to experienced centers may appropriately receive HD IL-2 after careful consideration of the benefits and potential side effects of this agent. This remains true considering novel agents given the small, but real, durable complete response rate of high-dose IL-2. Clearly, however, refinement of patient selection and potential combination therapy of novel agents with cytokines is necessary for cytokine therapy to remain useful in the management of metastatic RCC.
Additional studies have investigated the benefit of low-dose IFN-α in patients with advanced RCC. One of the initial studies compared IFN-α versus medroxyprogesterone acetate (MPA). The study's intent-to-treat analysis demonstrated a median overall survival of 8.5 months for patients randomized to IFN-α and 6 months in the MPA arm (P = 0.017).9 With a similar design, Pyrhonen et al10 also randomized 160 patients with metastatic RCC to receive IFN-α 18 MU 3 times a week plus vinblastine 0.1 mg/kg IV every 3 weeks or the same dose and schedule of vinblastine alone. A significant overall survival advantage was demonstrated for the IFN-α-containing arm with a median overall survival of 15.8 months for the IFN-α/vinblastine arm versus 8.8 months for the vinblastine-alone arm (P = 0.0049). Significant differences in overall response rates (16.5% versus 2.4%; P = 0.0025), complete response rates (8.9% versus 1.2%), and median time to disease progression (3 months versus 2 months; P = 0.0001) were also observed, all favoring the IFN-α-containing arm. A recent meta-analysis reviewed 53 randomized controlled trials involving 4,216 patients treated between 1995 and 2004 with IL-2 or IFN-α in metastatic RCC.11 There were 4 trials (n = 644 patients) that randomized patients to IFN-α versus a non- IFN-α control arm, including the 2 largest trials noted above. The median survival improvement with IFN-α treatment versus control was 3.8 months (P = 0.007), with an odds ratio for death at 1 year of 0.56 for IFN-α (95% CI, 0.40 to 0.77). There was no evidence of dose-response relationship and no correlation between response rate and overall survival. More recently, Negrier et al reported the results of the Programme Étude Rein Cytokines (PERCY) Quattro and Duo trial. In the Quattro trial, 492 untreated advanced RCC patients were randomized to MPA (control group), IFN-α, SC IL-2, or the combination of IFN-α + IL-2. With overall survival as primary endpoint, the ORR at 3 months by World Health Organization criteria was 2.5%, 4.4%, 4.1%, and 10.9%, respectively. With a median follow up of 29 months, the overall survival did not differ between the groups (median 15 months, all P values = 0.5).12 To evaluate whether IV IL-2 was superior to SC IL-2 when given in combination with IFN-α, the Duo trial randomized 155 good-risk RCC patients to either treatment arm. As one would expect, more toxicities were noted in the IV treatment arm. Although the study was closed early due to poor accrual, the median PFS and ORR were similar in both arms. Similarly, no difference in the median overall survival was observed (37.7 months for IV versus 26.3 months for SC, P = 0.127).
This historical paradigm, however, must be interpreted in a new light given the robust activity of molecularly targeted therapy described below. Although cytokines retain modest antitumor activity in RCC, further use of these agents should occur in the context of clinical trials that investigate susceptible patient populations and/or combination therapy with anti-VEGF or other agents. For example, carbonic anhydrase IX (CAIX, also called G250) is an enzyme whose expression is upregulated in the vast majority of clear-cell RCC.30 This enzyme has been shown in retrospective series to be associated with an improved outcome and better response to IL-2-based therapy.31, –33 A prospective trial is now planned to select metastatic RCC patients based on CAIX expression and administer high-dose IL-2 to observe a higher response rate than historical controls.
IMPORTANCE OF VEGF IN RENAL CELL CARCINOMA
VEGF is a dimeric glycoprotein and a member of the platelet-derived growth factor (PDGF) superfamily of growth factors that includes VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor (PlGF). VEGF is crucial for both normal and tumor-associated angiogenesis. The proangiogenic effects of VEGF have been well characterized and include induction of endothelial cell division and migration,34,35 promotion of endothelial cell survival through protection from apoptosis,36 and reversal of endothelial cell senescence.37 VEGF exerts its biologic effect through interaction with receptors present on the cell surface. These transmembrane tyrosine kinase receptors include VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), selectively expressed on vascular endothelial cells; VEGFR-3 (Flt-4), expressed on lymphatic and vascular endothelium; and the neuropilin receptor (NRP-1), expressed on vascular endothelium and neurons.38
The vast majority of patients with clear-cell RCC have overexpression of VEGF in tumor tissues, as demonstrated by the level of mRNA transcripts and VEGF protein identified in RCC tumor tissue.39 In patients with the clear-cell histologic subtype of RCC (approximately 80% to 85% of metastatic RCC patients), VEGF expression results from the inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene that occurs in 60% of patients and has been extensively reviewed elsewhere.40
Of note, other genes relevant to RCC biology and therapy are also VHL-mediated, including PDGF,41 basic fibroblast growth factor (bFGF),42 erythropoietin,43 and transforming growth factor alpha (TGF-a).44,45 Products of these genes may additionally serve as therapeutic targets in RCC.
EVOLVING THERAPIES IN RCC: TARGETINGTHE VEGF PATHWAY
The biology of VEGF overexpression in RCC has led to the development of several novel therapeutic strategies to inhibit this proangiogenic pathway required for tumor growth and proliferation in RCC. Figure 1 depicts the relevant biology of VEGF effects on endothelial cells and therapeutic targets within this pathway. Table 3 summarizes the clinical activity of VEGF-targeted agents in advanced RCC.
Table TABLE 3. Clinical Activity of Selected Vascular Endothelial Growth FactorTargeted Agents in Advanced Renal Cell Carcinoma
Randomized phase III versus IFN-α versus temsirolimus+IFN-α
9% versus 7% versus 11%
3.7 versus 1.9 (IFN-α)(P = 0.0001)
A recombinant human monoclonal antibody against VEGF (bevacizumab [Avastin]) binds and neutralizes all biologically active isoforms of VEGF.45
The clinical utility of bevacizumab in metastatic RCC was investigated in a randomized Phase II trial in which 116 patients with metastatic clear-cell RCC were randomized to receive placebo, low-dose (3 mg/kg) bevacizumab, or high-dose (10 mg/kg) bevacizumab given intravenously every 2 weeks.46 All patients had prior disease progression despite at least one systemic treatment regimen; the vast majority had received prior IL-2 (93%). Groups were balanced using established prognostic factors.53 The study was designed to detect a two-fold TTP increase with either dose of bevacizumab versus placebo (4.8 versus 2.5 months; P = 0.001 by log-rank test). There were 4 partial responses, all in the high-dose bevacizumab arm (4 of 39; 10% ORR). There were no life-threatening toxicities or deaths attributable to bevacizumab. Common toxicity included hypertension and proteinuria, more commonly seen in the high-dose bevacizumab arm. All toxicities were reversible with cessation of therapy. Grade 1 or 2 hemoptysis was observed in 2 patients receiving bevacizumab and 2 patients receiving placebo. No thromboembolic events were reported in any arm.
These results highlight the possibility that VEGF blockade may result in a low ORR, but could still lead to a delay in disease progression for the entire cohort. That is, tumor burden reduction not meeting criteria for objective response (defined in Response Evaluation Criteria in Solid Tumors [RECIST] as ≥30% tumor burden reduction) may translate into a prolongation of TTP. This phenomenon has also been observed with other VEGF-targeting agents described below and highlights the limitations of our ability to assess the antitumor effect and clinical benefit of a given drug by tumor measurements alone.
Bevacizumab and Erlotinib
Considering that the epidermal growth factor receptor (EGFR) also is overexpressed in RCC, a multicenter, Phase II study evaluated the addition of erlotinib (Tarceva), an EGFR inhibitor, to bevacizumab in metastatic RCC patients.54 Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally each day. Sixty-three patients were enrolled. All patients had had a nephrectomy, and 68% had received no previous systemic therapy. Fifteen (25%) patients had objective responses, and an additional 36 patients (61%) had stable disease after 8 weeks of treatment. Treatment was generally well tolerated; only two patients discontinued treatment because of toxicity (skin rash). Grade 1/2 skin rash and diarrhea were the most frequent treatment-related toxicities.
The additive or synergistic potential of thisregimen was further evaluated in a randomized Phase II trial of bevacizumab plus placebo versus bevacizumab plus erlotinib.47 This trial demonstrated identical response rates and PFS rates for the 2 arms (ORR: 13.7% versus 14%, respectively, and PFS of 8.5 versus 9.9 months, respectively; P = 0.58). Thus, it is not apparent from this trial that adding an EGFR-targeting agent increases the clinical activity of VEGF-targeting approaches. Additional combination trials targeting both VEGF and EGFR are underway and will further define the role, if any, of targeting EGFR in RCC.
Other Combinations with Bevacizumab
The addition of an antiangiogenic agent to standard cytokines has also been explored. Two randomized Phase III trials have evaluated bevacizumab plus IFN-α versus IFN-α alone in untreated advanced RCC patients.55 Both trials have completed accrual, and analysis is underway. Similarly, combinations of high-dose IL-2 and low-dose IL-2 plus bevacizumab are currently ongoing. These studies will further define the role of bevacizumab as frontline therapy in patients with advanced RCC.
Another rational approach currently under testing is to simultaneously target two steps within the VEGF pathway (ie, using a ligand binding agent with a small tyrosine kinase inhibitor [TKI]). Consequently, several Phase I trials evaluating the combination of sorafenib or sunitinib with bevacizumab are currently in progress.
SMALL-MOLECULE VEGF RECEPTOR INHIBITORS
An alternative approach to VEGF inhibition involves small-molecule TKIs. These agents inhibit not only the VEGFR, but also other receptors in the split kinase domain superfamily of receptor tyrosine kinases, including the platelet-derived growth factor receptor (PDGFR). PDGFR is expressed in pericytes, which serve as structural supporting cells for endothelial cells.
Sunitinib (Sutent) is an orally bioavailable oxindol small-molecule tyrosine kinase inhibitor of VEGFR-2 and PDGFR-β. In vitro assays have demonstrated inhibition of VEGF-induced proliferation of endothelial cells and PDGF-induced proliferation of mouse fibroblast cells.56 Investigation in mouse xenograft models demonstrated growth inhibition of various implanted solid tumors and eradication of larger, established tumors.
Sunitinib has been investigated in two sequentially conducted single-arm multicenter Phase II trials. Trial 1 enrolled 63 cytokine-refractory metastatic RCC patients. The majority of patients (87%) had clear cell histology. Although prior nephrectomy was not required, 93% of patients had undergone cytoreductive nephrectomy before enrollment. All patients had received prior cytokine-based therapy. Patients were treated with 50 mg of sunitinib orally daily on a 4-week-on/2-week-off cycle. Overall, 25 (40%) of 63 patients treated with sunitinib achieved partial responses. Stable disease lasting greater than 3 months was observed in 27% of patients. Median time to progression for the 63 patients was 8.7 months (95% CI, 5.5 to 10.7), and the median survival was 16.4 months (95% CI, 10.8 to NA).48
A confirmatory Phase II trial required clear cell histology and prior nephrectomy for all patients. In this trial, 106 cytokine-refractory metastatic RCC patients were enrolled.49 The ORR according to an independent third-party assessment resulted in 36 patients with partial response (34%; 95% CI, 25% to 44%) and a median PFS of 8.3 months (95% CI, 7.8 to 14.5 months). These data recently led to the US Food and Drug Administration (FDA) approval of this compound in January 2006 for the management of advanced RCC patients.
In both Phase II trials, the most common toxicities included fatigue/asthenia, observed in 28% of patients, diarrhea in 20%, stomatitis in 26%, dermatitis in 12%, and hypertension in 11%. Neutropenia, elevation of lipase, and anemia were the most common laboratory abnormalities observed in 45 (42%), 30 (28%), and 27 (26%) patients, respectively.
To evaluate the activity of sunitinib in previously untreated metastatic RCC patients, a randomized Phase III study was undertaken. This study was recently completed and presented in abstract form.50 Previously untreated metastatic RCC patients (n = 750) with clear cell histology were randomized 1:1 to receive sunitinib (6-week cycles: 50 mg orally once daily for 4 weeks, followed by 2 weeks off [4/2 schedule]) or IFN-α (6-week cycles: SC injection 9 MU given 3 times weekly). The primary endpoint was PFS. Secondary endpoints included ORR, overall survival, and adverse events. Patients were stratified based on lactate dehydrogenase (LDH), ECOG performance status, and the presence or absence of nephrectomy. The ORR by third-party independent review was 31% for sunitinib versus 6% for IFN-α (P = 0.000001). The median PFS by third-party independent review was 11 months versus 5 months in favor of sunitinib-treated patients (P = 0.00001). Toxicities related to sunitinib were similar to the ones observed in previous second-line Phase II trials. However, when compared with IFN-α, more hypertension, dermatitis, and stomatitis were observed in sunitinib-treated patients. This trial has demonstrated that sunitinib is superior to IFN-α in untreated advanced RCC patients, making sunitinib one of several frontline treatment options for advanced RCC patients.
The antitumor activity of continuous daily dosing of sunitinib in patients with advanced RCC has been evaluated.57 A total of 107 cytokine-refractory metastatic RCC received continuous oral sunitinib at 37.5 mg daily. The preliminary data suggest that more than 80% of patients have tumor shrinkage, and 10% of patients have had a confirmed partial response. Therapy was well tolerated with neither dose reduction nor treatment delay required in the majority of patients. This dose and schedule appears to have a comparable safety profile to the current recommended regimen of 50 mg/day administered on a 4/2 schedule.
Sunitinib was also recently evaluated in patients who have failed prior bevacizumab-based therapy. A multi-institutional Phase II trial enrolled 61 bevacizumab-refractory patients. Sunitinib was administered in a standard fashion at 50 mg daily by mouth for 4 weeks followed by a 2-week rest period. Response assessment was performed every 12 weeks. An ORR of 16% was demonstrated with 61% of patients achieving stable disease. Of those, 56% of patients had tumor shrinkage. The most common Grade 3 toxicities included fatigue, hypertension, dermatitis/hand-foot syndrome (HFS), and diarrhea (31%, 15%, 5%, and 5%, respectively).58 Although the precise mechanisms of response to sunitinib in bevacizumab-refractory RCC have not been elucidated, this clinical activity supports the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance and provides support for continued targeting of the VEGF-VEGFR signaling pathway.
Sorafenib (Nexavar) is an orally bioavailable biaryl urea Raf kinase inhibitor with demonstrated inhibition in Ras-dependent human tumor xenograft models.59 Activated Ras promotes cell proliferation through the Raf/MEK/ERK pathway by binding to and activating Raf kinase. Sorafenib has also demonstrated direct inhibition of VEGFR-2, VEGFR-3, and PDGFR-β.60 Xenograft models treated with daily sorafenib demonstrated significant inhibition of tumor angiogenesis, as measured by anti-CD31 immunostaining.
A Phase II randomized discontinuation study with sorafenib has been reported in refractory solid tumors, including 202 patients with metastatic RCC.61 All patients received oral sorafenib, 400 mg twice a day, and patients with stable disease after 12 weeks of treatment were randomized (double-blind) to either continue the drug or receive placebo. The primary endpoint of the study was PFS. Patients with >25% tumor shrinkage, by the sum of the bidimensional measurement, at 12 weeks continued open-label sorafenib. The vast majority of patients were low or intermediate risk, using the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic factors.45 During the run-in phase of the study, 73 patients had tumor shrinkage of >25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo (n = 33). At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = 0.0077). Median PFS from randomization was significantly longer with sorafenib (24 weeks) than placebo (6 weeks; P = 0.0087). Median overall PFS was 29 weeks for the entire RCC population (n = 202). Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity.
A subsequent Phase III randomized trial of sorafenib versus placebo in previously treated (cytokine-refractory) metastatic RCC was conducted.51 Seven (2%) patients receiving the drug had an objective response, defined by RECIST criteria. Stable disease was observed in 78% of patients receiving sorafenib, compared with 55% of those in the placebo arm. Overall, 74% of sorafenib-treated patients had some degree of tumor shrinkage. The median PFS for the patients receiving sorafenib was 24 weeks, compared with 12 weeks for the placebo group (P = 0.000001). PFS across all subgroups of patients receiving sorafenib appeared to be superior to placebo, including a subset of patients who had not received prior cytokine therapy. Based on these results, the study was modified to allow crossover from placebo to sorafenib. Additional analyses, including overall survival, were recently presented in abstract form.62 After 6 months from cross-over (placebo to sorafenib), the median overall survival was 19.3 months for sorafenib-treated patients versus 15.9 months for patients receiving placebo. Although the P value was 0.015 favoring sorafenib, the study's predetermined boundary for significance was P = 0.0094. Further follow up will be required to determine if sorafenib has a significant survival impact in patients with cytokine-refractory metastatic RCC.
Overall, sorafenib is well tolerated, and side effects are manageable. Most patients in the studies discussed above developed Grade 1 or 2 toxicities that included hypertension, fatigue, gastrointestinal, dermatologic, and neurologic symptoms. Only 8% of patients in the Phase II and 9% of patients in the Phase III study receiving sorafenib discontinued therapy due to an adverse event. The FDA granted approval of this agent in December 2005 for the treatment of patients with advanced RCC. An ongoing randomized Phase II trial evaluating sorafenib versus IFN-α in untreated metastatic RCC patients will further define the role of sorafenib in untreated metastatic RCC patients.63
Two trials have evaluated the addition of sorafenib to IFN-α therapy in untreated mRCC patients.64,65 Gollob et al64 evaluated 31 untreated mRCC patients. Treatment consisted of 8-week cycles of sorafenib 400 mg by mouth twice daily plus 10 MU of IFN-α SC 3 times a week. Among the 24 patients evaluable for response, the ORR by RECIST criteria was 42% (38% partial response, 4% complete response). An additional 46% had stable disease for at least 1 cycle, including 8% with >20% tumor shrinkage. Toxicities were mostly Grade 1/2: fatigue (78%), anorexia (74%), rash (70%; 11% Grade 3), diarrhea (67%), weight loss (63%), hypophosphatemia (59%; 33% Grade 3), nausea (56%), neutropenia (48%; 19% Grade 3), alopecia (44%), and oral mucositis (26%).
A SWOG trial also evaluated 58 previously untreated metastatic RCC patients. Sorafenib and IFN-α therapy were given at doses and schedule similar to the first trial. Overall response rate was 19%. Toxicities affecting >50% of subjects were similar to those previously reported. These trials demonstrate the feasibility of combination therapy with sorafenib and cytokines. Further investigation will be required to demonstrate clinical benefit of this combination over monotherapy.
MAMMALIAN TARGET OF RAPAMYCIN (MTOR) INHIBITORS
Temsirolimus (CCI-779) is an inhibitor of mammalian target of rapamycin (mTOR), a molecule implicated in multiple tumor-promoting intracellular signaling pathways, including hypoxia-inducible factor (HIF) transcription (Figure 2).66,67 A Phase II trial in patients with treatment-refractory, metastatic RCC randomized 111 patients to one of multiple dose levels (25 mg, 75 mg, or 250 mg IV weekly).68 The ORR was 7%, with additional patients demonstrating minor responses. Given the high number of dose reductions and treatment discontinuations at the higher dose levels, the investigators advocated the 25 mg IV weekly dose for future CCI-779 studies. Retrospective assignment of risk criteria to patients in this study identified a poor-prognosis group (n = 49). Temsirolimus-treated patients in this poor-prognosis group had a median overall survival of 8.2 months compared with 4.9 months for first-line IFN-α-treated patients (historical controls, n = 437).53 Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) may be more common in poor-risk patients and may account for this finding because mutation of this tumor suppressor gene would activate mTOR and potentially increase the relevance of mTOR-targeted therapy in this subgroup.69 A subsequent randomized Phase III trial was conducted in patients with poor-risk metastatic RCC as defined by existing prognostic schema.52 Patients with metastatic RCC and no prior systemic therapy were enrolled in this open-label study if they had at least 3 of 6 adverse risk factors, including Karnofsky performance status <80%, time to metastatic disease <1 year, hemoglobin < lower limit of normal, LDH >1.5× upper limit of normal, corrected serum calcium >10 mg/dL, and >1 metastatic disease site.53,70 Patients were equally randomized to receive IFN-α up to 18 MU SC 3 times a week, temsirolimus 25 mg IV once a week, or temsirolimus 15 mg IV once a week plus IFN-α 6 MU SC 3 times a week. The primary endpoint was overall survival, and the study compared each of the temsirolimus-containing arms to the IFN-α arm. Preliminary results demonstrated that patients treated with temsirolimus had a statistically longer survival than those treated with IFN-α alone (10.9 months versus 7.3 months, P = 0.0069). Overall survival of patients treated with IFN-α and temsirolimus plus IFN-α was not statistically different (7.3 months versus 8.4 months, P = 0.6912). Similarly, the ORR for each treatment arm was 7% IFN-α, 9% temsirolimus, and 11% for the combination arm. The lack of survival benefit in the combination arm could be the result of a lower dose of temsirolimus coupled with an increased number of patients unable to receive temsirolimus secondary to IFN-α-related toxicities. Further investigation of this agent is planned in patients with fewer adverse risk features and in combination with VEGF-targeting therapies.
An additional study that evaluated the activity of RAD-001 (Everolimus), an oral serine-threonine kinase inhibitor of mTOR, as second-line therapy in advanced RCC has been reported.71 Twenty-five previously treated mRCC patients received oral RAD-001 at a dose of 10 mg daily without an interruption (28-day cycle), with dose modifications for toxicity. The ORR observed was 33% (7 of 22 patients). Eleven patients have stable disease ≥3 months, with a median duration of 7 months of therapy (range ≥1 to ≥9). Treatment-related adverse events included mucositis, skin rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, anemia, and elevated liver function tests. These studies demonstrate the importance of mTOR as a therapeutic target in RCC and suggest a potential benefit of these agents in a broader RCC population.
ADDITIONAL TESTED AGENTS IN ADVANCED RCC
Several other novel agents that have shown activity in advanced RCC include the immunomodulatory agent lenalidomide (Revlimid),72,73 the α-5β1 integrin antibody volociximab (M200),74 the reversible inhibitor of EGFR/ErbB2 tyrosine kinases lapatinib (Tykerb),75 and GW786034 (Pazopanib), a multitarget tyrosine kinase inhibitor that inhibits VEGFR-1, -2, -3, PDGFR-α, PDGFR-β, and c-kit.76 Another promising agent in advanced RCC is AG013736 (Axitinib), an orally bioavailable small-molecule tyrosine kinase inhibitor of VEGFR-2 and PDGFR-β. A Phase II single-arm, multicenter trial of AG013736 in cytokine-refractory RCC patients (n = 52) demonstrated an overall response rate of 40%.77 Stable disease was observed in 21 (40%) of patients with 20 of the patients experiencing tumor shrinkage <30%. Median TTP has not been reached with a median of 12 to 18 months of follow up for most patients. Similar to other small-molecule tyrosine kinase inhibitors, most toxicity was Grade 1 or 2 and included gastrointestinal, dermatologic, fatigue, hypertension, and proteinuria. An additional study evaluating the activity of this agent in sorafenib-refractory metastatic RCC patients is underway.
FUTURE OF ANTIANGIOGENIC THERAPY IN RCC
Better understanding of the molecular pathogenesis of RCC has resulted in the identification of VEGF-directed approaches with clear antitumor activity. Albeit difficult to directly compare results from Phase II trials using antiangiogenic agents in RCC, ORRs vary significantly from 2% to 40%. More interesting, however, is the significant proportion of patients who have tumor shrinkage not meeting RECIST criteria for objective response, approximately 70% to 75% with each VEGF-targeted agent. Although it appears that these patients may have a clinical benefit from such a response, the effect of magnitude of tumor shrinkage on PFS or overall survival is not clear. Further investigation of the relationship among magnitude and duration of objective response with TTP and overall survival is warranted. Additionally, the simultaneous emergence of several active agents in RCC leads to important questions regarding agent selection, risk-benefit ratio of combinations versus monotherapy, and their timing and utility in refractory settings. All these questions need to be addressed in prospective clinical trials.
It is also clear that non-VEGF therapeutic targets in advanced RCC need further evaluation, as was clearly demonstrated by the temsirolimus Phase III trial. Redundancy within molecular pathways implicated in tumor cell growth, coupled with the ability for crosstalk between the components of these pathways, suggests that single-target inhibition of VEGF and its pathway may be insufficient to induce durable antitumor effects in all patients. Thus, there is a pressing need to design clinical trials to allow simultaneous inhibition of relevant pathways involved in the pathogenesis of RCC. Such trials should exploit VEGF-targeted agents that have already shown clear antitumor activity with other novel compounds capable of inhibiting other molecularly relevant pathways implicated in RCC. Several clinical trials following this molecular rationale are underway and will help to define the role of multitargeted therapy in RCC.
Although VEGF-targeted therapy has clearly revolutionized the treatment of advanced RCC, we still fall short from achieving complete and durable responses in the majority of patients. Therefore, a multidisciplinary approach is required when treating advanced RCC patients. No single therapy should be considered as standard of care in this challenging group of patients. Instead patients should be counseled about the features of their disease (eg, histology, prior therapy, similarity to trial populations) and the impact on prognosis and outcome. Individualizing therapy based on these features, followed by a concise discussion about the utility of surgery, risk-benefit profile of each novel therapeutic agent, and the timing of initiation of systemic therapy, should be the first step before selecting therapy. Finally, further work and more collaboration between clinicians and scientists is required to broaden our understanding of this disease and continue with the success and progress we have observed over the past few years in the management of patients' advanced RCC.