Sorafenib in Renal Cell Carcinoma

Keith T. Flaherty


Sorafenib is an orally available inhibitor of vascular endothelial growth factor receptors, plateletderived growth factor receptor-h, and RAF kinases. A dose of 400 mg twice daily administered continuously was selected for phase 2 testing, although 600 mg twice daily formally met criteria for a maximum tolerated dose. It is well tolerated compared with cytokine therapy. Antitumor activity was shown clearly in the context of a randomized discontinuation phase 2 trial. In this setting, even disease stabilization was established as a treatment-related phenomenon. A phase 3 trial with sorafenib confirmed a benefit of therapy across the vast majority of patients treated with sorafenib as opposed to placebo. Limited investigations into the mechanism of action of sorafenib in renal cell carcinoma support vascular endothelial growth factor receptor antagonism as the primary mediator of effect. The toxicity profile of sorafenib allows for its use in combination regimens.The focus of efforts to improve on the efficacy of sorafenib is on use with IFN, bevacizumab, or temsirolimus. Preliminary evidence with this approach is promising and will be the subject of the next generation of randomized trials in renal cell carcinoma.

Recently approved by the Food and Drug Administration, sorafenib (Bayer Pharmaceuticals, West Haven, CT) is an agent with established single-agent efficacy in metastatic renal cell carcinoma (RCC). It is among 17 inhibitors of vascular endothelial growth factor (VEGF) receptor (VEGFR) 2 (VEGFR2 or KDR) in clinical testing. However, the spectrum of kinase inhibition offered by sorafenib differentiates it from other agents and deserves consideration (Table 1). The unique clinical development path of sorafenib has uncovered some properties of the agent that may contribute to further advances in RCC treatment. In this review, we consider the important preclinical, clinical, and translational data that support the efficacy of sorafenib and the avenues for further clinical investigation.
Sorafenib was initially identified as a potent inhibitor of c-RAF. When hypertension was observed in the context of phase 2 trials, sorafenib was hypothesized to be a VEGFR inhibitor. Biochemical assays established that it is a potent inhibitor of VEGFR2 and VEGFR3. Both of these transmembrane receptors are implicated in tumor pathophysiology (Fig. 1). VEGFR2, previously referred to as KDR, is one of two high-affinity receptors for VEGF-A (VEGF165; ref. 1). Transgenic mice lacking VEGFR2 do not survive embryogenesis and have impaired

Author’s Affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania Received 8/17/06; revised 11/7/06; accepted 11/10/06. Presented at the Second Cambridge Conference on Innovations and Challenges in Renal Cancer, March 24-25, 2006, Cambridge, Massachusetts. Requests for reprints: Keith T. Flaherty, Abramson Cancer Center, University of Pennsylvania, 51North 39th Street, MAB 103, Philadelphia, PA 19104. Phone: 215662-8624. E-mail: ktflaherty@ F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-06-2063

blood vessel formation (2). Selective disruption of the VEGF-A/ VEGFR2 interaction is associated with tumor growth inhibition in human tumor xenografts in mice (3). The importance of VEGFR1 in VEGF-A – mediated angiogenesis is less clear because abrogation of the kinase activity of VEGFR1 does not affect vessel formation in transgenic mice (4). VEGFR3 has been identified as a high-affinity receptor for VEGF-C and VEGF-D, which mediate lymphangiogenesis (5). Tumor metastasis via lymphatics can be inhibited by interference with the VEGF-C VEGFR3 interaction (6). Thus, activity against VEGFR2 and VEGFR3 in a disease that is VEGF driven, such as RCC, is an attractive feature of sorafenib. Platelet-derived growth factor (PDGF) receptor-h has been the focus of several recent preclinical investigations and seems to be a valid target for angiogenesis inhibition. In addition to VEGF, hypoxia also induces secretion of PDGF (7). PDGF and PDGF receptor expressions are up-regulated in microvessel endothelial cells compared with mature vessels (8). Signaling through the PDGF receptor pathway in pericytes is essential for their recruitment (9, 10). In turn, the recruitment of pericytes is essential to the maturation and stabilization of immature blood vessels (11). Microvessels that are endowed with pericytes are no longer dependent on VEGF for their survival (12). Similar to the role of VEGF as a survival factor for immature endothelial tubes, under hypoxic conditions, pericytes are dependent on PDGF for survival (13). Inhibition of PDGF, in the absence of VEGF inhibition, inhibits blood vessel formation and tumor growth in human tumor xenografts (14). In an animal model of pancreatic islet cell tumors, the dual inhibition of VEGF and PDGF seems to be markedly more effective at blocking angiogenesis than blockade of either alone (15). Several lines of evidence suggest that inhibition of RAF signaling inhibits angiogenesis. In cells that overexpress the VEGF receptor, flk-1/KDR, VEGF signaling through the RAF –mitogenactivated protein kinase/extracellular signal-regulated kinase kinase – mitogen-activated protein kinase pathway is necessary for proliferation (16). In endothelial cells, VEGF-induced


Clin Cancer Res 2007;13(2 Suppl) January 15, 2007

PKC.Table 1. Eligibility was not restricted based on histologic subtype or number of prior therapies. investigating distinct schedules of administration: three with interrupted dosing and one with continuous administration (20). where BRAF harbors activating mutations and might serve a more definitive test of sorafenib RAF-inhibitory properties. such as melanoma. meeting criteria for a conventional objective response. Phase 2 and 3 trials. Sorafenib targets in tumor cells. Sorafenib was evaluated in four phase 1 trials. direct tumor cytotoxicity may be a component of the clinical efficacy observed in RCC. and hand-foot syndrome. EGFR. This leads one to speculate that a unique target of sorafenib. This last group of Fig. 1. epidermal growth factor receptor. (18) have developed a nanoparticle delivery system that specifically targets tumor endothelium. Other targets. might mediate this . 2007 748s www. According to the modified WHO criteria used in the protocol. 4 of 14 at 600 mg twice daily. In vivo.13(2 Suppl) January 15. At doses of 200 mg twice daily and higher. none of the 15 treated at 400 mg twice daily. sorafenib inhibits the proliferation of RCC cell lines. hand-foot syndrome. protein kinase C. and then after 2 months of therapy with 400 mg. The most common moderate or severe toxic effects were rash. it is possible that longterm therapy at 600 mg twice daily is feasible. inhibition of mitogen-stimulated RAF activity was observed in peripheral mononuclear cells. 600. The phase 3 trial comparing sorafenib to placebo in cytokinerefractory RCC provides the best summary of sorafenib-related toxic effects at 400 mg twice daily (Fig. and 3 of 6 at 800 mg twice daily. It is possible to link some of the common sorafenibassociated toxicities with known molecular targets by comparing the toxicities seen with other targeted therapies with overlapping spectrum of activity. Given that it has been the only RAF kinase inhibitor to be evaluated clinically. This trial used modified WHO response criteria to avoid randomizing patients with clinically significant reductions in tumor volume. sunitinib. Nonetheless. Pruritus is exclusively present in the setting of rash. Consideration of other cancers. when other toxicities. The macular-papular rash associated with sorafenib is not commonly observed with bevacizumab (a VEGF antibody). have dissipated. PDGFR-h FLT-3. Sorafenib is one of the few toxicities that emerges relatively late in the course of treatment. Clinical Data Phase 1 and toxicity. This time course makes one wonder if this is less likely a signal transduction effect on intestinal epithelial cells and perhaps more related to chemical irritation from the carriers in the formulation. Although it still difficult to discern which of the targets of sorafenib might be mediating this effect. Delivery of a mutant RAF gene. to tumor endothelium results in inhibition of angiogenesis and tumorassociated endothelial cell apoptosis. such as p38. V599E BRAF p38. These data support the necessity of RAF activity in the VEGF-induced activation of endothelial cells. This is associated with apoptosis of tumor cells and prolonged regression of primary and metastatic tumors. PDGF receptor-h. grade 3 events were infrequent. and pericytes. Most patients had clear cell RCC. 2). are relatively unique to sorafenib and could be implicated in any of the toxicities that are unique to this agent. if not as a starting dose. activation of mitogen-activated protein kinase is inhibited by expression of a truncated form of RAF that binds to Ras but cannot phosphorylate mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase (17). ERK IC50 2 nmol/L 6-10 nmol/L 20-40 nmol/L 28-38 nmol/L 40-80 nmol/L Inactive at 10 mmol/L Abbreviations: PDGFR-h. Coupling of an integrin 3 ligand to the surface of nanoparticles results in selective trafficking of particles to angiogenic blood vessels in tumor-bearing mice. In that study. an experimental system that is independent of angiogenesis. Although it is reasonable to infer that the 600 mg dose level was intolerable based on a 29% dose-limiting toxicity rate. the agent clearly affects the maintenance of tumor vasculature and angiogenesis (19). MEK. Dose-limiting toxicity was observed in 1 of 6 patients treated at 200 mg twice daily. VEGFR3 WT BRAF. PKC. incapable of binding ATP. most patients experience a decline in toxic effects after the first 4 to 6 weeks of treatment. such as RAF. Hood et al. 36% had tumor regressions of at least 25% and 32% had regression or progression of <25%. Nonetheless. diarrhea.aacrjournals. is beyond the scope of this review. Therefore. such as rash. diarrhea. mitogenactivated protein kinase/extracellular signal-regulated kinase kinase. Hypertension is class effect of essentially all VEGF-targeted therapies and is discussed in detail below. 11% of patients had 50% regression by WHO criteria. Clin Cancer Res 2007. The clinical development of sorafenib is notable for the large randomized discontinuation phase 2 trial. in which activity in RCC was first observed (21). it is difficult to determine the relative contribution of each sorafenib target to the antitumor activity. and 800 mg. ERK. endothelial cells. extracellular signal-regulated kinase. Considering all grades of toxic effects. the three toxic effects that were clearly treatment related were rash. It should be noted that in vitro. and fatigue. Of the 202 RCC patients enrolled. and the median number of prior therapies was 2. Spectrum of sorafenib in isolated kinase assays Kinase assays c-RAF mVEGFR2. 400 mg twice daily was selected for further development. Pharmacokinetic data support the selection of this dose because exposure did not increase significantly between cohorts treated with 400. and other small-molecule inhibitors of VEGFR and PDGF receptor. it is difficult to verify this point. MEK. c-KIT EGFR.

patients must at least undergo imaging studies beyond those required for clinical staging.aacrjournals. P < 0. We conducted a pilot study using dynamic contrast-enhanced magnetic resonance imaging as a method of detecting changes in tumor vascular permeability (K tr.72. in the context of sorafenib therapy. We have observed that serum VEGF levels increase during the initial weeks of therapy with sorafenib. As hypothesized. due to the related observation that many metastatic RCC lesions develop radiographically evident necrosis while on sorafenib therapy. This cutpoint was chosen based on the equal distribution of patients above and below this value. This seems to be a class phenomenon for the VEGF-targeted agents in this disease. this trial established clinical activity in most patients. patients (n = 65) were randomized to continue sorafenib or cross over to placebo. The phase 3 trial of sorafenib in RCC used a more conventional one-to-one randomization at the time of study entry to sorafenib versus placebo.01) but not with the amount of tumor regression by computed tomography (P = 0. Among 17 patients with varied RCC histologic subtypes. P = 0. Progression-free survival Kaplan-Meier analysis in Phase III renal cell carcinoma trial. and the trial was terminated prematurely with placebo-treated patients crossed over to sorafenib (22). 2. Although dynamic contrast-enhanced magnetic resonance imaging can assess metastatic tumors in a variety of metastatic sites. Therefore. reduction in K tr significantly correlated with prolonged time-toprogression (P = 0. Clearly. 0. Although these patients continue to be followed up for overall survival. The significant difference in PFS (median. The median PFS (5.02). The investigator-assessed objective response rate was 10% by Response Evaluation Criteria in Solid Tumors criteria. P = 0. ref. 95% confidence interval.Sorafenib in RCC Fig. The Kaplan-Meier PFS for patients with baseline K tr > 3 mL/mL/min and baseline K tr < 3 mL/mL/min is shown in Fig. elevated K tr at baseline was significantly correlated with time-to-progression (P = 0. This is not a tumorrelated phenomenon but rather a systemic response to VEGF blockade. Of course. as it is seen even among people without cancer. 60. Correlative studies. in part. 46.6%). the objective response rate does not adequately summarize the effect of sorafenib on the natural history of metastatic RCC. Although this study was designed to compare overall survival. This will happen in the context in the E2804 (to be discussed later).018). P < 0.00001) for sorafenib was nearly identical to that observed in the phase 2 trial (Fig. This is. The comparison of progression-free survival (PFS) in this cohort was the primary end point of the study. Thus. This can be quantified by comparing the area under the time-enhancement curves before and during treatment. An interim analysis for overall survival revealed a nonsignificant trend toward improved survival (hazard ratio. relatively large tumors are needed (>3 cm in some cases) to obtain robust measurements of K tr. Gadolinium diffuses across tumor vasculature more readily than normal vessels. www. This technique takes advantage of the influence of VEGF on vascular permeability and has been validated in preclinical models. This will undoubtedly limit the statistical power to detect a survival advantage for sorafenib. and interpreting the results requires a significant amount of expertise. the first interim analysis for PFS was revealed to the investigators. Given that some tumors develop macroscopic evidence of necrosis. Frequency of symptomatic toxicities in Phase III renal cell carcinoma trial (black bar. 24 versus 6 weeks. both adverse prognostic signs in RCC. we did baseline dynamic contrast-enhanced magnetic resonance imaging and a followup assessment after several weeks of therapy. 48% of the patients initially assigned to placebo crossed over to sorafenib soon after the PFS analysis. each of these variables was treated as continuous. gadolinium diffusion into tumors is reduced. grey bar. In addition. 40 weeks). Previous studies in patients with other tumor types have correlated elevated K tr with high microvessel density and serum VEGF levels. Taken together with the patients with tumor regression (median 749s Clin Cancer Res 2007. Unexpectedly. this small pilot study will require validation in a larger trial. 3.5 versus 2.8 months.0087) confirmed that disease stabilization was attributable to sorafenib. Of note. it is possible that K tr is detecting this type of effect and that changes in tumor size are somewhat independent. grade 3). 23). In the setting of VEGF inhibition.0005 was required to yield a definitive benefit. Nine hundred three patients with clear cell RCC refractory to one prior therapy were enrolled.22). identification of a serum marker of pharmacodynamic effect would be preferable. Among a cohort of 20 patients treated with sorafenib. this marker of otherwise poor prognosis seems to identify those most likely to receive clinical benefit.13(2 Suppl) January 15. The antiangiogenic activity of sorafenib in vivo has been investigated in the context of the large phase 2 trial of sorafenib. those who had a doubling or more in serum VEGF had a more Fig. 4. any CTC grade.3% decline. 3). 2007 . K tr was significantly lower after sorafenib treatment (median.

For that reason. 2007 750s www. This is a class effect observed not only with VEGFR inhibitors but also with the VEGF monoclonal antibody. epidermal growth factor. Based on its toxicity profile and target spectrum. Mammalian target of rapamycin. favorable outcome than those with little or no change in VEGF (Fig. we suspect that sorafenib is inhibiting nitric oxide production in endothelial cells. 5. In that study. A thorough analysis of the relation between changes in blood pressure and outcome has not been reported. Angiogenesis is mediated by other factors in addition to VEGF and PDGF. This threshold was selected based on nearly even numbers of patients above and below this value. basic fibroblast growth factor. In particular. As the number of targeted agents with relevance to RCC increases. regulates the expression of hypoxia-inducible factor 1-a (28). 5). Clin Cancer Res 2007. CA) has been shown previously to deplete serum VEGF to undetectable levels at doses of 3 mg/kg and higher (27). The combination of sorafenib and temsirolimus is being evaluated in a phase 1 trial. We observed a consistent elevation in blood pressure for the entire cohort (Fig. Figlin: Is it possible that the vascular endothelial growth factor (VEGF) receptor antagonists are working best on the hypoxic environment of VEGF-dependent tumors and are not working well on the VHL-dependent tumor in the outer rim? Fig. it is hypothesized that targeting multiple angiogenic growth factors will yield even greater benefits in RCC. The armamentarium of targeted agents against these factors is limited. Open Discussion Dr. Greater increases in VEGF levels in the setting of VEGFR blockade may simply relate to higher drug exposure. the development of new areas of tumor necrosis within tumors. the number of potential combination regimens multiplies. the target of temsirolimus. One combination of particular interest is simultaneous blockade of VEGFRs with depletion of secreted VEGF. The combination of sorafenib and bevacizumab is in the midst of phase 1 evaluation. In an effort to evaluate the currently available agents as doublets in parallel. Bevacizumab (Genentech. The currently available evidence suggests that VEGFR antagonism is being achieved. There are several potential explanations for this relationship. including sorafenib. This will be the focus of investigations in the next generation of clinical trials. This is supported by the rapid normalization of blood pressure following interruption of sorafenib. 4.aacrjournals. triggering more VEGF production. However. 6). The rationale behind this approach is founded on the observation that serum VEGF levels increase following administration of VEGFR inhibitors.13(2 Suppl) January 15. it remains possible that increased VEGF production eventually mediates resistance to therapy. South San Francisco. we conducted an investigation of the mechanism of sorafenib-induced hypertension in patients with metastatic RCC (24). may be evidence of greater degrees of tumor hypoxia. In addition. which is manifested on computed tomography scans. Conclusions Sorafenib has established efficacy in RCC and is well tolerated. An even more convenient biomarker of sorafenib effect might be treatment-related hypertension. which has been shown previously to be VEGF mediated (25). Sorafenib is sufficiently tolerable to be combined with other agents. transforming growth factors a and h. temsirolimus may complement the effects of sorafenib at the level of the endothelial cell.Fig. Although we could not measure it directly. The spectrum of kinases inhibited by sorafenib goes far beyond VEGFRs and is unique compared with other agents in this class. Assessment of vascular permeability (Ktr) by DCE-MRI correlated with PFS or sorafenib (N = 17). sorafenib is well suited to inclusion in combination regimens. In addition to bevacizumab. we are initiating a randomized phase 2 trial in the cooperative groups (E2804). Wyeth Pharmaceuticals. The contribution of these various targets to the activity of sorafenib in RCC is not known. PA) is another agent that seems to affect angiogenesis at a point that is different from sorafenib. Sorafenib in combination . A more thorough evaluation of the blood pressure as a potential marker of VEGF inhibition is warranted. temsirolimus (CCI-779. Collegeville. By down-regulating hypoxia-inducible factor 1-a in the tumor cell. and interleukin 8 have all been implicated in tumor angiogenesis (26). Changes in serum VEGF while on sorafenib correlate with PFS. sorafenib will be combined with bevacizumab and temsirolimus. which is up-regulated by the loss of the von Hippel Lindau gene in RCC. Although we have observed that increases in VEGF correlate with clinical benefit. We found no significant relationship between previously described mediators of blood pressure and magnitude of increase.

et al. Itin A. Flaherty: Yes. Karkkainen MJ. Overholser JP. Flaherty: With SU11248. Mechanism of sorafenib-induced hypertension in patients with metastatic RCC. et al. 13. Rohovsky SA. Angiogenesis during human extraembryonic development involves the spatiotemporal control of PDGF ligand and receptor gene expression. from you and others. et al. Keshet E. Science 1992. Flaherty: One potential explanation is that the dependence of the rim on tumor vasculature to deliver nutrients and oxygen is different than the core. and over time. 7. Everyone believed 5 years ago that angiogenesis happened only in wound healing and after a myocardial infarction in adults. Dr. et al.13(2 Suppl) January 15. Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Brekken RA. Wouldn’t this lead to rebound growth of RCC when VEGF receptor inhibitors are stopped abruptly? Dr. Gertsenstein M. Karkkainen MJ. 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The rash may be a RAF-driven phenomenon because it is different from the epidermal growth factor receptor rash. tumor cells in the rim probably aren’t dependent on tumor vasculature entirely for delivery of blood and nutrients. Design of GFB-111. With these agents. Curr Eye Res 2001 . 12. Figlin: How does that explain how these drugs work in this disease? Dr. Kodama T.23:93 ^ 7. Stastny VA. Flaherty: The rash didn’t correlate with progression-free survival. Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation.376:66 ^ 70. Flaherty: Exactly. for example. These inhibitors are probably only working on a subset of the tumor vasculature. Dr. et al. et al. we have all seen data. Flaherty: We’ve never compared bevacizumab and this drug in a rigorous way. and perhaps compartments that are more complex with both VEGF-dependent components as well as components dependent on other growth factors. but that is not the case. 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