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

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

Frequency of symptomatic toxicities in Phase III renal cell carcinoma trial (black bar. 48% of the patients initially assigned to placebo crossed over to sorafenib soon after the PFS analysis. This cutpoint was chosen based on the equal distribution of patients above and below this value. this trial established clinical activity in most patients. The antiangiogenic activity of sorafenib in vivo has been investigated in the context of the large phase 2 trial of sorafenib. in the context of sorafenib therapy. in part.3% decline. www.8 months. the objective response rate does not adequately summarize the effect of sorafenib on the natural history of metastatic RCC. identification of a serum marker of pharmacodynamic effect would be preferable.5 versus 2. Taken together with the patients with tumor regression (median PFS. 3. we did baseline dynamic contrast-enhanced magnetic resonance imaging and a followup assessment after several weeks of therapy. patients must at least undergo imaging studies beyond those required for clinical staging. as it is seen even among people without cancer. This is. patients (n = 65) were randomized to continue sorafenib or cross over to placebo. 749s Clin Cancer Res 2007. In addition.aacrjournals. 0.13(2 Suppl) January 15. Progression-free survival Kaplan-Meier analysis in Phase III renal cell carcinoma trial. ref. The investigator-assessed objective response rate was 10% by Response Evaluation Criteria in Solid Tumors criteria. and interpreting the results requires a significant amount of expertise. each of these variables was treated as continuous. Among a cohort of 20 patients treated with sorafenib.01) but not with the amount of tumor regression by computed tomography (P = 0. As hypothesized. 95% confidence interval. P = 0. 2. This will undoubtedly limit the statistical power to detect a survival advantage for sorafenib. The comparison of progression-free survival (PFS) in this cohort was the primary end point of the study. elevated K tr at baseline was significantly correlated with time-to-progression (P = 0. both adverse prognostic signs in RCC. We have observed that serum VEGF levels increase during the initial weeks of therapy with sorafenib.1-74. P < 0.Sorafenib in RCC Fig. the first interim analysis for PFS was revealed to the investigators. this small pilot study will require validation in a larger trial. Previous studies in patients with other tumor types have correlated elevated K tr with high microvessel density and serum VEGF levels. it is possible that K tr is detecting this type of effect and that changes in tumor size are somewhat independent. Unexpectedly. In the setting of VEGF inhibition. Of course. Given that some tumors develop macroscopic evidence of necrosis.02). Clearly. those who had a doubling or more in serum VEGF had a more Fig. Of note. Although this study was designed to compare overall survival. 60. 46. This seems to be a class phenomenon for the VEGF-targeted agents in this disease. Therefore.0005 was required to yield a definitive benefit. We conducted a pilot study using dynamic contrast-enhanced magnetic resonance imaging as a method of detecting changes in tumor vascular permeability (K tr. An interim analysis for overall survival revealed a nonsignificant trend toward improved survival (hazard ratio.72.00001) for sorafenib was nearly identical to that observed in the phase 2 trial (Fig. due to the related observation that many metastatic RCC lesions develop radiographically evident necrosis while on sorafenib therapy.0087) confirmed that disease stabilization was attributable to sorafenib. and the trial was terminated prematurely with placebo-treated patients crossed over to sorafenib (22). reduction in K tr significantly correlated with prolonged time-toprogression (P = 0.018). Gadolinium diffuses across tumor vasculature more readily than normal vessels. 2007 . The median PFS (5. grey bar. gadolinium diffusion into tumors is reduced. This can be quantified by comparing the area under the time-enhancement curves before and during treatment. any CTC grade. Nine hundred three patients with clear cell RCC refractory to one prior therapy were enrolled. 24 versus 6 weeks. 4. Among 17 patients with varied RCC histologic subtypes. 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. P < 0. This is not a tumorrelated phenomenon but rather a systemic response to VEGF blockade. The significant difference in PFS (median. 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. This will happen in the context in the E2804 (to be discussed later). Correlative studies.6%). 23).22). K tr was significantly lower after sorafenib treatment (median. P = 0. this marker of otherwise poor prognosis seems to identify those most likely to receive clinical benefit. This technique takes advantage of the influence of VEGF on vascular permeability and has been validated in preclinical models. 40 weeks). 3). relatively large tumors are needed (>3 cm in some cases) to obtain robust measurements of K tr. Although dynamic contrast-enhanced magnetic resonance imaging can assess metastatic tumors in a variety of metastatic sites. Although these patients continue to be followed up for overall survival. grade 3).

A more thorough evaluation of the blood pressure as a potential marker of VEGF inhibition is warranted. 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. Although we could not measure it directly. The contribution of these various targets to the activity of sorafenib in RCC is not known. favorable outcome than those with little or no change in VEGF (Fig. The combination of sorafenib and bevacizumab is in the midst of phase 1 evaluation. 5). The armamentarium of targeted agents against these factors is limited.aacrjournals. CA) has been shown previously to deplete serum VEGF to undetectable levels at doses of 3 mg/kg and higher (27). However. Sorafenib is sufficiently tolerable to be combined with other agents. This is supported by the rapid normalization of blood pressure following interruption of sorafenib. Open Discussion Dr. A thorough analysis of the relation between changes in blood pressure and outcome has not been reported. Sorafenib in combination regimens. South San Francisco. In an effort to evaluate the currently available agents as doublets in parallel. epidermal growth factor. we suspect that sorafenib is inhibiting nitric oxide production in endothelial cells. . 4.13(2 Suppl) January 15. Assessment of vascular permeability (Ktr) by DCE-MRI correlated with PFS or sorafenib (N = 17). which has been shown previously to be VEGF mediated (25). Although we have observed that increases in VEGF correlate with clinical benefit. 2007 750s www. sorafenib will be combined with bevacizumab and temsirolimus. Mammalian target of rapamycin. We found no significant relationship between previously described mediators of blood pressure and magnitude of increase. including sorafenib. One combination of particular interest is simultaneous blockade of VEGFRs with depletion of secreted VEGF. This will be the focus of investigations in the next generation of clinical trials. sorafenib is well suited to inclusion in combination regimens. and interleukin 8 have all been implicated in tumor angiogenesis (26). This threshold was selected based on nearly even numbers of patients above and below this value. 5. PA) is another agent that seems to affect angiogenesis at a point that is different from sorafenib. Angiogenesis is mediated by other factors in addition to VEGF and PDGF. Bevacizumab (Genentech. Based on its toxicity profile and target spectrum. The combination of sorafenib and temsirolimus is being evaluated in a phase 1 trial. As the number of targeted agents with relevance to RCC increases. In particular. the development of new areas of tumor necrosis within tumors. we conducted an investigation of the mechanism of sorafenib-induced hypertension in patients with metastatic RCC (24). 6). which is manifested on computed tomography scans. Wyeth Pharmaceuticals. An even more convenient biomarker of sorafenib effect might be treatment-related hypertension. temsirolimus may complement the effects of sorafenib at the level of the endothelial cell. Greater increases in VEGF levels in the setting of VEGFR blockade may simply relate to higher drug exposure. Clin Cancer Res 2007. it remains possible that increased VEGF production eventually mediates resistance to therapy. We observed a consistent elevation in blood pressure for the entire cohort (Fig. it is hypothesized that targeting multiple angiogenic growth factors will yield even greater benefits in RCC. Changes in serum VEGF while on sorafenib correlate with PFS. By down-regulating hypoxia-inducible factor 1-a in the tumor cell. There are several potential explanations for this relationship. For that reason. which is up-regulated by the loss of the von Hippel Lindau gene in RCC. regulates the expression of hypoxia-inducible factor 1-a (28). may be evidence of greater degrees of tumor hypoxia. The currently available evidence suggests that VEGFR antagonism is being achieved. In addition to bevacizumab. we are initiating a randomized phase 2 trial in the cooperative groups (E2804). The spectrum of kinases inhibited by sorafenib goes far beyond VEGFRs and is unique compared with other agents in this class. In addition. triggering more VEGF production.Fig. In that study. basic fibroblast growth factor. Conclusions Sorafenib has established efficacy in RCC and is well tolerated. This is a class effect observed not only with VEGFR inhibitors but also with the VEGF monoclonal antibody. the target of temsirolimus. The rationale behind this approach is founded on the observation that serum VEGF levels increase following administration of VEGFR inhibitors. temsirolimus (CCI-779. transforming growth factors a and h. the number of potential combination regimens multiplies.

Flaherty: Exactly. Escobedo JA. Flt-1lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Overholser JP. this lack of normal tissue repair causes either ulcerations at pressure points in the mouth or on the hands and feet.103:159 ^ 65. 2. Fong GH. The bigger they get. the more heterogeneous. Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Hirschi KK. Angiogenesis during human extraembryonic development involves the spatiotemporal control of PDGF ligand and receptor gene expression. from you and others. Blaskovich MA.255:989 ^ 91. for example. Carmeliet P. It might be there. 2007 . we have all seen data.376:66 ^ 70.298: 1172 ^ 78. Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. Sosman: But the hand-foot syndrome is seen across the board with all the multitargeted tyrosine kinase inhibitors. Dr. Makinen T. The rash may be a RAF-driven phenomenon because it is different from the epidermal growth factor receptor rash. You have angiogenesis that is part of minor levels of trauma that occur every day. Kuno J. Karkkainen MJ. Design of GFB-111. Egeblad M. With sorafenib. Dr. Benjamin LE. Pfeifer-Ohlsson S. That is why it is harder to make those comments. The fms-like tyrosine kinase. With these agents. Flaherty: The rash didn’t correlate with progression-free survival. Figlin: How does that explain how these drugs work in this disease? Dr.18:5117 ^ 24. RossantJ. Curr Eye Res 2001 . that’s seen with the other drugs as well. Beck LH. 4. De Vries 751s Clin Cancer Res 2007. Cancer Res 2001 . McDermott: You said that you do not believe rebound is happening with this drug. 9. Hemo I. et al. Flaherty: We’ve never compared bevacizumab and this drug in a rigorous way. Keshet E. migration. Gertsenstein M. Nat Cell Biol 2000. Kawamura H. Dr. but I’ve never seen any data that quantify the percentage of. References 1. Hollenbach S. Oku H. I do not believe so. Is that really biologically important in terms of the population of patients? I know there have been anecdotes of patients having minor tumor progression during that 2-week break. and suppression of neointima following vascular injury. 10. Sukhatme: Is it true that the hypertension seen with this drug is actually less than what is seen with. et al. the VEGF levels are clearly up on therapy. Nature 2000. Alitalo K. 125:1591 ^ 8. and over time. Lokker NA. Rohovsky SA. Dr. but after the 2-week break. 11. 6. Kodama T. VEGF-dependent compartments. Dr.Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Itin A.4:E2 ^ 5. Yu JC. KarpanenT. Dr. et al. Dr. Mechanism of sorafenib-induced hypertension in patients with metastatic RCC. 7. Minowa O. Dr. you do not have the normal tissue repair. J Clin Invest 1999. Flaherty: One potential explanation is that the dependence of the rim on tumor vasculature to deliver nutrients and oxygen is different than the core. 113:749 ^ 54. George: There may be different compartments to the vasculature: compartments that are immature. Dr. a platelet-derived growth factor binding www. a receptor for vascular endothelial growth factor. we do not use intermittent dosing. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. Flaherty: Yes. Ueno H. George: These are not homogeneous masses. Lin Q. Role of the Flt-1receptor tyrosine kinase in regulating the assembly of vascular endothelium. such as platelet-derived growth factor. So. 6. what factors do you think are responsible for those side effects? Dr.407:249 ^ 57. Hiratsuka S. Cancer Res 2000. 5. 3. et al.aacrjournals. Rosen: Might the neovessels at the tumor rim and those at the tumor center behave differently—as they may not be at the same stage of maturation—even though they are all driven by the same angiogenic signals from the tumor? Dr. bevacizumab or in any of the early drugs on VEGF trial? Dr. Science 1992. et al. This is a small window of overdrive. To what extent we can add to them and optimize the antiangiogenic effect remains to be seen. Development 1991. they’re down again to baseline. Development 1998. Everyone believed 5 years ago that angiogenesis happened only in wound healing and after a myocardial infarction in adults. The other potential explanation is that the fraction of VEGF-dependent neovessels is differentially present as you move through zones of the tumor. people who have blood pressure elevations over systolic of 150 mm Hg or some other significant threshold. 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Holmgren L. for example.23:93 ^ 7. 14. Atkins: Was there any correlation between rash or hand-foot syndrome and clinical benefit? Of the targets that this drug is hitting. that when you block the VEGF receptor with tyrosine kinase inhibitors serum VEGF levels increase. et al. and perhaps compartments that are more complex with both VEGF-dependent components as well as components dependent on other growth factors. 12. tumor cells in the rim probably aren’t dependent on tumor vasculature entirely for delivery of blood and nutrients. Jain RK. These inhibitors are probably only working on a subset of the tumor vasculature. Circ Res 1999.Sorafenib in RCC Fig. However. 13. Lymphatic endothelium: a new frontier of metastasis research. Nature1995. et al. Brekken RA. Proc Natl Acad Sci U S A 1998. 8.

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