Sorafenib and Sunitinib in Renal Cell Carcinoma Mark N

CCR Drug Updates

Sorafenib and Sunitinib in Renal Cell Carcinoma Mark N. Stein1and Keith T. Flaherty2

The Food and Drug Administration has recently approved endothelial cells and NIH 3T3–VEGFR-2 cells stimulated with sorafenib and sunitinib, two oral multitargeted tyrosine kinase VEGF.Similarly, sorafenib inhibited VEGFR-2 autophosphor- inhibitors, for the treatment of advanced renal cell carcinoma ylation in human umbilical vein endothelial cells, and NIH (RCC).Because of the central role of vascular endothelial 3T3–VEGFR-2 cells and PDGFR-autophosphorylation in pri- growth factor (VEGF) in this disease and the activity of mary human aortic smooth muscle cells at a concentration of VEGF-targeted agents, RCC serves as a unique arena for the <100 nmol/L (4, 8). evaluation of antiangiogenic agents.In clear cell RCC, mutation In human xenograft models, treatment with sorafenib at or deletion of the von Hippel-Lindau gene is the defining 30 to 60 mg/kg resulted in growth stasis in HT-29, Colo-205, somatic genetic event (1).This results in unopposed activity of and DLD-1 colon cancer cell lines, as well as the A549 lung the hypoxia-inducible factor signaling complex that regulates cancer cell line, all of which have mutations in KRAS or BRAF. the transcription of a number of proangiogenic growth factors, However, in the Colo-205 and A549 tumors, ERK-1/2 of which VEGF is the best studied.Supporting the essential role phosphorylation was not reduced by sorafenib.Inhibition of of VEGF in the malignant phenotype in RCC, a monoclonal vascularization in RENCA murine renal adenocarcinoma, Colo- antibody targeted to VEGF exerts its greatest single-agent activity 205, and MDA-MB-231 xenografts occurred even in the absence in this disease (2).Sorafenib and sunitinib antagonize VEGF of RAF inhibition in the tumor itself (9).Taken together, these receptor (VEGFR) tyrosine kinases as well as numerous other preclinical studies suggest that tumor growth inhibition by signaling molecules.The role of these agents as VEGFR sorafenib is mediated by inhibition of the mitogen-activated inhibitors in RCC is well established; however, their unique protein kinase pathway in some settings, whereas in others, spectra of activity deserve additional consideration. tumor growth inhibition is mediated predominantly by inhibiting angiogenesis via VEGF and PDGF inhibition. Sorafenib Clinical trials. Four phase I trials of sorafenib, using different schedules, have been reported (10).Treatment cycles Preclinical data. Sorafenib, a biaryl urea, is a small molecule lasted 14 days (7 days on/7 days off; ref.11), 28 days (21 days tyrosine kinase inhibitor selected in screening experiments on/7 days off; ref.12), and 35 days (28 days on/7 days off; against c-Raf (c-Raf IC = 6 nmol/L), resulting in diminished 50 ref.13).In the fourth and largest phase I trial by Strumberg MEK-1 and ERK-1 phosphorylation (3, 4).Biochemical assays et al., patients received a starting dose of 50 mg on day 1 of a showed the inhibition of multiple tyrosine kinases with a low weekly treatment cycle (14).After an initial period of dose nanomolar IC , including B-Raf (22 nmol/L), V599E B-Raf 50 escalation according to a once weekly single-dosing schedule, (38 nmol/L), VEGFR-1 (26 nmol/L), VEGFR-2 (90 nmol/L), dose escalation shifted to twice daily (b.i.d.) drug administra- VEGFR-3 (20 nmol/L), platelet-derived growth factor receptor h tion.Sixty-nine patients were enrolled in this study, 22 on a (PDGFR; 57 nmol/L), FLT-3 (33 nmol/L), and c-KIT (58 nmol/L; noncontinuous dosing schedule and 47 with continuous b.i.d. refs.4–6).Crystallization of sorafenib with wild-type B-Raf dosing.Patients on the noncontinuous dosing schedule did not and the oncogenic V599E B-Raf showed that the pyridyl ring experience any dose-limiting toxicities.Dose-limiting, grade 3 of sorafenib directly interacts with three amino acids within diarrhea and fatigue occurred in three of six patients treated the ATP adenine binding pocket and that the urea moiety with 800 mg b.i.d. At 600 mg b.i.d., 4 of 14 patients (29%) forms several hydrogen bonds with the enzyme (7). experienced at least one first cycle dose-limiting skin toxicity; In vitro, sorafenib interrupts ERK phosphorylation in therefore, 400 mg b.i.d. of sorafenib was determined to be the multiple cell lines including cells with mutations in either maximum tolerated dose and the recommended phase II dose. K-Ras or V599E B-Raf, as well as human umbilical vein Given that the rate of grade 3 toxicity was <33%, and skin toxicities could diminish with continued dosing, it is unclear whether 600 mg twice daily was truly intolerable. 1 Authors’ Affiliations: Department of Medicine, University of Medicine and Substantial accumulation in plasma concentrations were Dentistry of New Jersey-Robert Wood Johnson Medical School, The Cancer t Institute of New Jersey, New Brunswick, New Jersey and 2Abramson Cancer observed following multiple b.i.d. administrations. Mean 1/2 Center, University of Pennsylvania, Philadelphia, Pennsylvania ranged from 24 to 38 h. Cmax and area under the curve values Received 12/13/06; revised 4/12/07; accepted 4/27/07. were highly variable following single doses of sorafenib from Note: Supplementary data for this article are available at Clinical Cancer Research 100 to 400 mg, and multiple doses from 400 to 800 mg.Intake Online (http://clincancerres.aacrjournals.org/). Conflicts of interest: K. Flaherty is on the advisory boards of Bayer, Onyx, of food before dosing had a minimal effect on pharmacokinetic and Pfizer. variables.Phorbol myristate acetate stimulated lymphocytes Requests for reprints: Mark N. Stein, Department of Medicine, University of taken before treatment on day 0, day 2, day 7, and weekly Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School,The thereafter for at least 6 weeks showed partial inhibition ERK Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903. Phone: 732-235-9892; Fax: 732-235-8681; E-mail: [email protected]. phosphorylation at 200 mg b.i.d. continuous dosing and F 2007 American Association for Cancer Research. almost complete inhibition of ERK phosphorylation at 400 mg doi:10.1158/1078-0432.CCR-06-2844 b.i.d. on day 21 of a continuous dosing schedule.

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In a pooled analysis of the sorafenib phase I results, 179 to Response Evaluation Criteria in Solid Tumors (RECIST) patients were evaluated for safety and efficacy (10).Across all standards was 10% versus 2% in favor of sorafenib (2% versus dose levels and schedules, 12% of patients experienced 0% with central review), with 76% versus 25% of patients stabilization of previously progressive disease for at least having some reduction in the burden of disease.The median 6 months, and 6% were stabilized for at least 1 year.Analysis PFS, according to independent review, was 5.5 months for of the subset of patients treated close to the recommended sorafenib versus 2.8 months for placebo (P < 0.001) and phase II dose (300-600 mg b.i.d.) suggested that patients benefit was present in all subgroups based on age (>65 years, experiencing grade 2 skin toxicity/diarrhea had a longer time Motzer score, prior interleukin 2, location of metastases and to progression compared with patients who did not experience time from diagnosis, >1.5 years for diagnosis). Although the toxicity.However, it is unclear if these toxicities reflect an primary end point of this trial was intended to be overall increase in drug exposure to BAY-43-9006 or unique suscepti- survival, the magnitude of benefit in PFS prompted an bility to the drug due to polymorphisms in sorafenib targets. alteration in the conduct of the study, with placebo-treated Based on preclinical models and phase I data showing that patients being offered cross-over treatments to sorafenib.Based the primary benefit of sorafenib was disease stabilization, a on a planned interim analysis at 220 deaths, that there was an phase II study was conducted using a novel randomized estimated 39% improvement in survival for patients receiving discontinuation design in which all patients received study drug sorafenib versus those receiving placebo (P = 0.02; hazard ratio, (sorafenib, 400 mg b.i.d.) for an initial run-in period, followed 0.72). However, the median overall survival for sorafenib was by random assignment of patients with disease stabilization to not reached at the time of this analysis and the threshold for either the study drug or placebo (15).The trial was initially statistical significance of the interim analysis of survival was not designed to focus on patients with colorectal cancer, while achieved.The final survival analysis will be conducted when allowing patients with other tumor types to enroll.When 540 events have occurred, but will undoubtedly be influenced responses were observed in patients with RCC, but not by the cross-over effect. colorectal cancer, recruitment was directed to that population. A total of 502 patients were enrolled, with 202 patients having Sunitinib advanced RCC.All patients had Eastern Cooperative Oncology Group performance status 0 or 1, 75% had clear cell RCC and Preclinical data. Sunitinib is a selective inhibitor of the class 7% (15 patients) had papillary RCC, 89% had prior nephrec- III and V receptor tyrosine kinases, including the PDGFRs, tomy, and 76% had previous interleukin 2 or IFN.In patients c-KIT, FLT-3, and the VEGFRs.In biochemical assays, sunitinib with RCC, investigator assessment of response (by WHO exhibited competitive inhibition against VEGFR-2 and criteria) after the 12-week run-in determined that 36% of PDGFRh, with a Ki of 9 and 8 nmol/L, respectively (17, 18). patients had tumor shrinkage by >25%, 34% had stable disease, In cellular inhibition assays, sunitinib inhibited VEGF- and 25% had progression at or before week 12.Of note, 4% dependent VEGFR-2 phosphorylation and PDGF-dependent of patients had an independently confirmed partial response at PDGFRh phosphorylation with IC50 values of 10 nmol/L for week 12 (11% by investigator assessment).Of the 15 patients both receptor tyrosine kinases (17).In addition, sunitinib with papillary RCC, there were 2 partial responses and inhibited VEGF and basic fibroblast growth factor–induced 3 patients with tumor shrinkage of 25% to 49%.At week proliferation of human umbilical vein endothelial cells. 12, patients were randomly assigned to receive sorafenib In human xenograft models, sunitinib induced regression in (32 patients) or placebo (33 patients).The primary end point HT-29 and Colo-205 tumors.(17).Complete and durable of the study, the percentage of randomly assigned patients who regression occurred in six out of eight mice bearing large A431 remained progression-free at 12 weeks following random (epidermoid) tumors.Additionally, in some models, such as assignment (24 weeks after study entry), was 50% of patients luciferase-expressing PC-3 prostate tumor transplants, treat- receiving sorafenib versus 18% of patients receiving placebo ment with sunitinib caused decreased fluorescence and growth (P = 0.0077). The median progression-free survival (PFS) after stasis, but no reduction in tumor size.In SF763T glioma randomization was 24 weeks with sorafenib versus 6 weeks tumors, sunitinib treatment resulted in an f40% reduction in with placebo (P = 0.0087; hazard ratio, 0.29). microvessel density.Oral administration of sunitinib to mice The clinical benefit of sorafenib in advanced RCC has been bearing Colo-205 tumors that do not express PDGFRh lead to confirmed in a multicenter, double-blind, randomized phase decreased phosphorylation of this receptor, indicating that III trial of sorafenib versus placebo in 903 cytokine-refractory decreased phosphorylation was occurring in pericytes, and patients (16).Common treatment-related adverse events, of stromal tissue.Thus, sunitinib demonstrates the ability to any grade, occurring more frequently in patients treated reduce tumor cell viability and inhibit angiogenesis, even when with sorafenib compared with placebo, included diarrhea tumors do not express receptor tyrosine kinases in the spectrum (43% versus 13%), rash (40% versus 16%), fatigue (37% of activity of sunitinib.In animal experiments designed to versus 28%), hand-foot syndrome (30% versus 7%), and determine the target plasma concentration of sunitinib, the hypertension (17% versus 2%).Frequent grade 3/4 toxicities minimum plasma concentration required to inhibit receptor included hand-foot reaction (6% versus 0%), hypophosphate- phosphorylation was concluded to be 100 ng/mL.Furthermore, mia (13% versus 3%), and elevated lipase (12% versus 7%). this concentration had to be maintained for at least 12 h on a Three percent of patients in both arms discontinued therapy daily dosing regimen for efficacy to be maintained. due to an adverse event.In the sorafenib and control arms, dose Clinical trials. In the phase I trial of sunitinib in patients interruption due to an adverse event occurred in 21% and 6% with advanced solid tumors, the recommended phase II dose of patients, and doses were reduced in 13% and 3% of patients, was 50 mg daily for 4 weeks, followed by 2 weeks off treatment respectively.The investigator-assessed response rate according in 6-week cycles (19).In this study, body surface area dosing

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Sorafenib and Sunitinib in RCC was initially used, however, pharmacokinetic analyses revealed hypertension (8% versus 1%), hand-foot syndrome (5% versus that normalizing for body surface area did not reduce the 0%), neutropenia (12% versus 7%), thrombocytopenia (8% variability in exposure and flat dosing was subsequently versus 0%), and elevated amylase (5% versus 3%).In the employed.Dose-limiting toxicities of fatigue, hypertension, sunitinib and IFN arms, dose interruption due to an adverse and skin toxicity were observed at doses z75 mg/d, but event occurred in 38% and 32% of patients, and doses were generally resolved completely during the 2-week treatment reduced in 32% and 21% of patients, respectively.However, break.Sunitinib had a long t1/2, ranging from 41 to 86 h.The patients in the sunitinib group reported a significantly better Cmax occurred 5 h after administration and accumulation of quality of life than did patients in the IFN-a group using sunitinib over time was observed.Doses of 50 mg per day led validated questionnaires. to plasma trough concentrations generally ranging from 50 to In addition to the toxicities reported above, evaluation of 100 ng/mL, whereas patients experiencing dose-limiting tox- safety data from trials of sunitinib in gastrointestinal stromal icities had plasma trough concentrations of >100 ng/mL.Serum tumor and RCC suggests an association between treatment with VEGF concentrations tended to increase during the 28-day sunitinib and the development of treatment-related hypothy- treatment, whereas mean sVEGFR-2 levels decreased.Of note, roidism, potentially explaining some cases of sunitinib-induced sunitinib was the first VEGF-targeted therapy to be developed fatigue.In patients with gastrointestinal stromal tumor and with intermittent drug exposure. normal thyroid-stimulating hormone at baseline, development Based on partial responses seen in patients with RCC in the of abnormal serum thyroid-stimulating hormone concentra- phase I trial, a multicenter phase II study of sunitinib in tions whereas being treated with sunitinib was documented in 63 patients and a second ‘‘confirmatory’’ phase II study in 26 of 42 patients (62%; ref.23).Furthermore, the risk of 106 patients was undertaken in patients who progressed on one developing hypothyroidism seemed to correlate with the previous cytokine therapy (20, 21).In both studies, sunitinib duration of exposure to sunitinib.Although 4 out of 22 was given 50 mg daily in the ‘‘4 weeks on/2 weeks off’’ schedule. (18%) patients taking sunitinib for 36 weeks developed The second trial was limited to patients with clear cell RCC. hypothyroidism, 9 out of 10 (90%) patients treated for more Tumor responses assessed using RECIST standards were similar than 96 weeks with sunitinib developed increased levels of in the two trials (40% and 43% partial response rate by thyroid-stimulating hormone.The mean time to development investigator assessment, 34% by independent review of trial of hypothyroidism was 50 weeks.In patients with RCC treated 2 results), with one complete response in the second trial.In with sunitinib, who underwent thyroid function testing, 56 out pooled results from 168 patients, the partial response rate was of 66 (85%) of patients had one or more thyroid function test 42%, the stable disease rate (z3 months) was 24%, and 34% abnormalities, which developed after a median of two cycles of patients progressed or had stable disease for <3 months. (24).Whether these findings result from sunitinib inducing Median PFS in the combined analysis was 8.2 months (95% antithyroid immunity, impairing thyroid vascularization, or confidence intervals, 7.8-10.4). Median PFS in patients with interfering with the normal physiologic function of VEGF in a complete response or partial response was 14.8 months, and thyroid homeostasis, and the extent to which these findings are in patients with stable disease of 3 months or longer, it was unique to sunitinib versus sorafenib, remains to be clarified. 7.9 months. The median trough sunitinib concentration in this Decreased cardiac ejection fraction has also been observed in trial was 84.3 ng/mL, with no accumulation of drug across patients treated with sunitinib.As noted above, in the phase III dosing cycles.In study 1, VEGF-A and placental growth factor trial of sunitinib versus IFN, a decrease in LVEF to below the (PIGF) levels increased from days 1 to 28, whereas sVEGFR-2 lower limit of normal were seen in 10% of patients receiving levels decreased.A decrease in left ventricular ejection fraction sunitinib and in 3% of patients receiving IFN.In the (LVEF) was noted in 8 out of 106 patients (4.7%) in the gastrointestinal stromal tumor–randomized trial of sunitinib second phase II RCC study.In the first study, 35% of patients versus placebo, identical rates of decreased LVEF were seen in had their dose reduced while on treatment for asymptomatic the treatment and control groups (25).In both trials, a grade 3 hyperlipasemia, hyperamylasemia, or significant fatigue. decrease in LVEF to <40% was rare, occurring in f2% of Recently, interim results were reported for a randomized phase patients.In most cases, decreased LVEF either recovered III trial of sunitinib (50 mg/d for 4 out of 6 weeks versus IFN; spontaneously or with dose reduction of sunitinib and/or titrated up to 9 million units thrice a week) in patients with cardiac medications such as antihypertensive or diuretic previously untreated, metastatic, clear cell RCC (22).Three medications (26).Ongoing studies such as the Eastern hundred and seventy-five patients were randomized to each arm. Cooperative Oncology Group trial of adjuvant sunitinib, The primary end point of the study, median PFS, was 11 months sorafenib, or placebo in high-risk RCC, will prospectively for sunitinib (10–12) versus 5 months for IFN (hazard ratio, evaluate the incidence of LVEF decline in these two receptor 0.42; P < 0.001; refs. 4–6) as assessed by independent central tyrosine kinase inhibitors. review.Median overall survival was not reached for either arm at the time of the analysis.The investigator-assessed response rate How are Sunitinib and Sorafenib Different? was 37% with sunitinib and 9% with IFN (31% versus 6% with central review).Common treatment-related adverse events of Although the recent and contemporaneous approval of two any grade (for sunitinib compared with IFN) were fatigue (51% multitargeted tyrosine kinase inhibitors that both seem to alter versus 51%), diarrhea (53% versus 12%), nausea (44% versus the natural history of RCC (improved PFS with first line 33%), stomatitis (25% versus 2%), hypertension (24% versus sunitinib and after cytokine therapy for sorafenib) tempts one 1%), hand-foot syndrome (20% versus 1%), and ejection to lump these two drugs together, this approach may obscure fraction decline (10% versus 3%).Frequent grade 3/4 toxicities the differences that determine how best to use these drugs in included fatigue (7% versus 12%), diarrhea (5% versus 0%), the control (if not yet the cure) of metastatic RCC and other

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Fig. 1. A kinase dendrogram of a panel of uniform binding assays for 113 different proteins kinases. Red circles, kinases represented in the assay panel (circle sizes are proportional to binding affinities). In this assay, sunitinib bound 73 kinases in addition toVEGFR-2, whereas sorafenib bound 40 additional kinases.These differences may result in different spectrums of activity and/or toxicity. Using this standard assay to compare sunitinib and sorafenib, the dissociation constants for VEGFR-2 and PDGF were 0.23 versus 93 nmol/L and 0.21versus 41nmol/L, respectively, implying a significant difference in in vitro potency [see Fabian et al. (27); SupplementaryTable S4]. Kinase families: TK, nonreceptor tyrosine kinases; RTK, receptor tyrosine kinases; TKL, tyrosine kinase-like kinases; CK, casein kinase family; PKA, protein kinase A family; CAMK, calcium/calmodulin-dependent kinases; CDK, cyclin-dependent kinases; MAPK, mitogen-activated protein kinases; CLK, CDK-like kinases.The kinase dendrogram was adapted from Fabian et al. (27) after Manning et al. (45), and is reproduced with permission from Nature Biotechnology, Science, and Cell SignalingTechnology, Inc.3

cancers.These drugs clearly have different molecular profiles. The importance of RAF-MEK-ERK signaling in tumor The differences, depicted graphically in the form of a angiogenesis has been shown in a variety of experimental dendrogram (Fig.1) have recently been quantified in a systems (36–38) and dominant-negative Raf targeted to the reproducible manner using an in vitro assay in which the test neovasculature of tumors induced endothelial apoptosis and compounds and immobilized kinase ligands compete for inhibited tumor growth (39).Recently, sorafenib, was shown to binding to kinase domains, expressed as fusions to the T7 cause a significant reduction in endothelial cell p-ERK bacteriophage (27).Bound bacteriophage is then quantified expression in K1735 murine melanomas (in which VEGF is with quantitative PCR.In this assay, sunitinib bound 73 kinases not the mediator of angiogenesis), as well as RENCA renal in addition to VEGFR-2, whereas sorafenib bound 40 addi- tumors and Colo-205 cancers.Sorafenib-treated blood vessels tional kinases.The clinical importance of inhibiting ‘‘off also had decreased endothelial cell proliferation as measured by target’’ kinases such as JAK1, KIT, and the calcium/calmodulin- Ki-67, and increased endothelial cell apoptosis, as measured by dependent protein kinases is not yet known, yet these differences terminal nucleotidyl transferase–mediated nick end labeling may result in different spectrums of activity and/or toxicity.Of staining (40).As the authors note, however, down-modulation note, using this standard assay to compare sunitinib and of p-ERK would be expected if VEGFR-2, Raf, or both were sorafenib, the dissociation constants for VEGFR-2 and PDGF targeted by sorafenib in endothelial cells. were 0.23 versus 93 nmol/L and 0.21 versus 41 nmol/L, At this point, it remains unclear how resistance to sunitinib respectively, implying a significant difference in in vitro potency. or sorafenib develops.One can speculate that if sorafenib As previously noted, sorafenib, unlike sunitinib, is a potent targets endothelial cell Raf directly rather than through VEGFR- inhibitor of Raf kinase, the downstream target of Ras in the 2 inhibition, it is possible that sorafenib may be able to mitogen-activated protein kinase.Raf has been identified as a overcome resistance to VEGFR-2 inhibition occurring through mediator of cellular proliferation, differentiation, adhesion, up-regulation of VEGF, or other angiogenic factors signaling migration, metastasis, and survival pathways (28, 29).In RCC, through the Raf pathway.This is currently a critical question as activated, phosphorylated Raf-1 was identified in 6 of 11 (55%) there is no data to guide to sequential use of these therapies. tumors (30), although no activating BRAF mutations were Clinically, there are differences between these two medica- identified in a series of RCCs (31).Furthermore, Ras, the tions, in variables such as toxicity (lower grade 3 toxicity rate upstream target of Raf has only been identified as oncogenic in with sorafenib and fewer dose modifications in the phase III 10% of RCCs (32), suggesting that Raf in RCC is predominantly trial), response rate (higher objective response rate with activated by increased levels of ligands for growth factor sunitinib, which may be important for patients with bulky and symptomatic disease), and schedule (interrupted dosing for receptor tyrosine kinases such as transforming growth factor-a sunitinib versus continuous for sorafenib).On this last point, the (29).Unfortunately, whereas model systems clearly suggest first preliminary report on sunitinib administered continuously an important role for transforming growth factor-a and its suggests that the response rate was significantly lower than that receptor EGFR in the pathogenesis of RCC (33, 34), the clinical observed with the more thoroughly studied 4 days on/2 days off importance of inhibiting the EGFR pathway has been called schedule.De Mulder and colleagues conducted a multicenter into question by a recent trial in which the EGFR inhibitor phase II trial among 104 patients with metastatic RCC in which erlotinib combined with the VEGF inhibitor bevacizumab did patients continuously received 37.5 mg of sunitinib daily (41). not add to the efficacy of bevacizumab alone (35).Therefore, it remains unclear if Ras pathway inhibition has a direct antitumor effect in RCC. 3 http://www.cellsignal.com/

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The preliminary objective response rate was less than half the rate Temsirolimus, a specific inhibitor of the mammalian target reported in the phase II and phase III trials with 50 mg on the of rapamycin, seems to have a potentially unique mechanism 4 days on/2 days off schedule.It is not clear whether progression- of action.There is evidence that mammalian target of free survival or overall survival would be negatively affected rapamycin inhibition is directly toxic to RCCs (42).Further- by continuous dosing, and even the apparently inferior response more, hypoxia-inducible factor 1a expression is regulated by rate would require validation in future trials.Nonetheless, the phosphoinositide-3-kinase pathway and is inhibited by this intriguing result suggests that intermittent dosing may mammalian target of rapamycin inhibition (43, 44).Thus, maximize response rate.This is certainly counterintuitive for either bevacizumab or temsirolimus are rationally targeted agents that are predominantly antiangiogenic and mandates agents to be combined with sorafenib and sunitinib.Phase I more thorough exploration of this issue. trials investigating each combination are under way.A To date, neither sorafenib nor sunitinib have been extensively randomized phase II trial (E2804) is planned to compare to evaluated with patients with papillary or chromophobe RCC.In the following combinations: sorafenib with bevacizumab, the phase II trials of sunitinib, <5% of patients had non–clear sorafenib with temsirolimus, and bevacizumab with temsir- cell histologies and separate reporting of activity in this subgroup olimus.The purpose of these trials will be to select a has not occurred.In the phase III trials of sunitinib and combination regimen to test against the best available single- sorafenib, patients with non–clear cell histology were specifi- agent therapy in a subsequent phase III trial. cally excluded.In the phase II trial of sorafenib, a cohort of At the present time, the relative benefit of sorafenib and patients with papillary RCC were included, as were a very small sunitinib for patients with metastatic RCC has not been compared number of patients with chromophobe RCC.As summarized directly.There is a striking similarity in the reported percentage of above, activity was clearly observed in the papillary RCC subset, patients who experienced some degree of tumor regression in the albeit in a small number of patients.Dedicated phase II trials in context of phase II and phase III trials (roughly 75%).An Eastern papillary RCC are currently being conducted for each agent. Cooperative Oncology Group phase III trial, with patients The nearly simultaneous emergence of sorafenib, sunitinib, randomized to sunitinib versus sorafenib versus placebo in the bevacizumab, and temsirolimus as therapies with established adjuvant setting is ongoing, and may point to the relative clinical benefit in RCC has set the stage for expedient clinical efficacy of these two agents in the future.At the current investigations of targeted therapy combinations.Bevacizumab, time, however, fundamental questions remain unanswered a monoclonal antibody that binds and depletes secreted VEGF, regarding the mechanisms of action of these two drugs and their intervenes at a different point in VEGF signaling than optimal utilization in the clinic.Clinical trials designed to answer sorafenib and sunitinib.It may be a particularly rational molecular questions using neo-adjuvant therapy, serial biopsies, therapy to combine with sorafenib or sunitinib given that the or novel techniques such as evaluation of circulating tumor increase in serum VEGF induced both of those agents. cells may help to define therapy of RCC in the years to come.

References 1. Kim WY, Kaelin WG. Role of VHL gene mutation in and pharmacokinetics of the dual action Raf kinase (2-diethylaminoethyl)amide, a novel tyrosine kinase human cancer. JClin Oncol 2004;22:4991 ^ 5004. and vascular endothelial growth factor receptor inhib- inhibitor targeting vascular endothelial and platelet- 2. Yang JC, Haworth L, Sherry RM, et al. A randomized itor, BAY 43-9006, in patients with advanced, refrac- derived growth factor receptor tyrosine kinase. trial of bevacizumab, an anti-vascular endothelial tory solid tumors. Clin Cancer Res 2005;11:5472 ^ 80. JMed Chem 2003;46:1116^9. growth factor antibody, for metastatic renal cancer. N 12. Awada A, Hendlisz A, Gil T, et al. Phase I safety 19. Faivre S, Delbaldo C,Vera K, et al. Safety, pharmaco- Engl JMed 2003;349:427 ^ 34. and pharmacokinetics of BAY 43-9006 administered kinetic, and antitumor activity of SU11248, a novel oral 3. Lowinger TB, Riedl B, Dumas J, Smith RA. Design for 21 days on/7 days off in patients with advanced, multitarget tyrosine kinase inhibitor, in patients with and discovery of small molecules targeting raf-1 ki- refractory solid tumours. Br JCancer 2005;92: cancer. JClin Oncol 2006;24:25 ^35. nase. Curr Pharm Des 2002;8:2269 ^ 78. 1855 ^ 61. 20. MotzerRJ,RiniBI,BukowskiRM,etal.Sunitinibin 4. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 13. Moore M, Hirte HW, Siu L, et al. Phase I study to patients with metastatic renal cell carcinoma. JAMA exhibits broad spectrum oral antitumor activity and determine the safety and pharmacokinetics of the 2006;295:2516 ^ 24. targets the RAF/MEK/ERK pathway and receptor novel Raf kinase and VEGFR inhibitor BAY 43-9006, 21. MotzerRJ, Michaelson MD,Redman BG, et al.Activ- tyrosine kinases involved in tumor progression and administered for 28 days on/7 days off in patients ity of SU11248, a multitargeted inhibitor of vascular en- angiogenesis. Cancer Res 2004;64:7099 ^ 109. with advanced, refractory solid tumors. Ann Oncol dothelial growth factor receptor and platelet-derived 5.Wilhelm S, Chien DS. BAY 43-9006: preclinical data. 2005;16:1688^94. growthfactorreceptor,inpatientswithmetastaticrenal Curr Pharm Des 2002;8:2255 ^ 7. 14. Strumberg D, Richly H, Hilger RA, et al. Phase I clin- cell carcinoma. JClin Oncol 2006;24:16 ^ 24. 6. Wilhelm S, Carter C, Lynch M, et al. Discovery and ical and pharmacokinetic study of the novel Raf kinase 22. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib development of sorafenib: a multikinase inhibitor for and vascular endothelial growth factor receptor inhib- versus IFN a in metastatic renal-cell carcinoma. N Engl treating cancer. Nat Rev Drug Discov 2006;5:835. itor BAY 43-9006 in patients with advanced refracto- JMed 2007;356:115 ^ 24. 7. WanPT,GarnettMJ,RoeSM,etal.Mechanismof ry solid tumors. JClin Oncol 2005;23:965 ^ 72. 23. Desai J,Yassa L, Marqusee E, et al. Hypothyroidism activation of the RAF-ERK signaling pathway by on- 15. Ratain MJ, EisenT, StadlerWM, et al. Phase IIplace- after sunitinib treatment for patients with gastrointes- cogenic mutations of B-RAF. Cell 2004;116:855 ^67. bo-controlled randomized discontinuation trial of sor- tinal stromal tumors. Ann Intern Med 2006;145: 8. LyonsJF,WilhelmS,HibnerB,BollagG.Discoveryof afenib in patients with metastatic renal cell carcinoma. 660^4. a novel Raf kinase inhibitor. Endocr Relat Cancer JClin Oncol 2006;24:2505 ^ 12. 24. Rini BI,Tamaskar I, Shaheen P, et al. Hypothyroidism 2001;8:219^ 25. 16. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in in patients with metastatic renal cell carcinoma treated 9. ChangYS. BAY 43-9006 (Sorafenib) inhibits ectopic advanced clear-cell renal-cell carcinoma. N Engl J with sunitinib. JNatl Cancer Inst 2007;99:81 ^ 3. and orthotopic growth of a murine model of renal Med 2007;356:125^34. 25. Demetri GD, van Oosterom AT, Garrett CR, et al. adenocarcinoma (Renca) predominantly through inhi- 17. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor Efficacy and safety of sunitinib in patients with ad- bition of tumor angiogenesis. Clin Cancer Res 2005; activity of SU11248, a novel tyrosine kinase inhibitor vanced gastrointestinal stromal tumour after failure of 46:5831. targeting vascular endothelial growth factor and plate- imatinib: a randomised controlled trial. Lancet 2006; 10. Strumberg D, Awada A, Hirte H, et al. Pooled safety let-derived growth factor receptors: determination of 368:1329^ 38. analysis of BAY43 ^ 9006 (sorafenib) monotherapy in a pharmacokinetic/pharmacodynamic relationship. 26. Sunitinib [package insert]. In: NewYork (NY): Pfizer patients with advanced solid tumours: is rash associ- Clin Cancer Res 2003;9:327 ^ 37. Inc.; 2007. ated with treatment outcome? Eur JCancer 2006;42: 18. Sun L, Liang C, Shirazian S, et al. Discovery of 27. Fabian MA, Biggs WH III, Treiber DK, et al. A small 548^56. 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidene- molecule-kinase interaction map for clinical kinase 11. ClarkJW, EderJP, Ryan D, Lathia C, Lenz HJ. Safety methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid inhibitors. Nat Biotechnol 2005;23:329^ 36.

www.aacrjournals.org 3769 Clin Cancer Res 2007;13(13) July 1, 2007 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. CCR Drug Updates

28. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic inducible factor activates the transforming growth fac- MD, Carter C, Lee WM. Inhibition of tumor endothelial target for therapeutic development against cancer. tor-a/epidermal growth factor receptor growth stimu- ERK activation, angiogenesis, and tumor growth by JClin Oncol 2005;23:6771 ^ 90. latory pathway in VHL(-/-) renal cell carcinoma cells. sorafenib (BAY43-9006). Am JPathol 2006;169: 29. Gollob JA, Wilhelm S, Carter C, Kelley SL. Role of JBiol Chem 2003;278:44966^74. 1875 ^ 85. Raf kinase in cancer: therapeutic potential of targeting 35. Bukowski RM, Kabbinavar F, Figlin RA, et al. Beva- 41. De Mulder PH, Roigas J, Gillessen S, et al. A phase II the Raf/MEK/ERK signal transduction pathway. Semin cizumab with or without erlotinib in metastatic renal study of sunitinib administered in a continuous daily Oncol 2006;33:392 ^ 406. cell carcinoma (RCC). [Meeting Abstracts] JClin regimeninpatients with cytokine-refractorymetastatic 30. Oka H, Chatani Y, Hoshino R, et al. Constitutive ac- Oncol 2006;24:4523. renal cell carcinoma (mRCC). [Meeting Abstracts] tivation of mitogen-activated protein (MAP) kinases 36. Eliceiri BP, Klemke R, Stromblad S, Cheresh DA. JClin Oncol 2006;24:4529. in human renal cell carcinoma. Cancer Res 1995;55: Integrin avh3 requirement for sustained mitogen- 42. Robb VA, Karbowniczek M, Klein-Szanto AJ, 4182 ^ 7. activated protein kinase activity during angiogenesis. Henske EP. Activation of the mTOR signaling pathway 31. Nagy A, Balint I, Kovacs G. Frequent allelic changes JCell Biol 1998;140:1255^ 63. in renal clear cell carcinoma. JUrol 2007;177:346 ^ 52. at chromosome 7q34 but lack of mutation of the 37.Gupta K, Kshirsagar S, LiW, et al.VEGF prevents ap- 43. Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhi- BRAF in papillary renal cell tumors. Int JCancer optosis of human microvascular endothelial cells via bition reverses Akt-dependent prostate intraepithelial 2003;106:980^1. opposing effects on MAPK/ERK and SAPK/JNK sig- neoplasia through regulation of apoptotic and HIF-1- 32. Downward J. Targeting RAS signalling pathways in naling. Exp Cell Res 1999;247:495 ^ 504. dependent pathways. Nat Med 2004;10:594 ^ 601. cancer therapy. Nat Rev Cancer 2003;3:11^ 22. 38. Mukhopadhyay D, Nagy JA, Manseau EJ, Dvorak 44. Pore N, Jiang Z, Shu HK, Bernhard E, Kao GD, Maity 33. de Paulsen N, BrychzyA, Fournier MC, et al. Role of HF. Vascular permeability factor/vascular endothelial A. Akt1 activation can augment hypoxia-inducible transforming growth factor-a in von Hippel-Lindau growth factor-mediated signaling in mouse mesentery factor-1aexpression by increasing protein translation (VHL)(-/-) clear cell renal carcinoma cell proliferation: vascular endothelium. Cancer Res 1998;58:1278 ^ 84. through a mammalian targetof rapamycin-independent a possible mechanism couplingVHL tumor suppressor 39. Hood JD, Bednarski M, Frausto R, et al. Tumor re- pathway.Mol Cancer Res 2006;4:471 ^ 9. inactivation and tumorigenesis. Proc Natl Acad Sci gression by targeted gene delivery to the neovascula- 45. Manning G, Whyte DB, Martinez R, Hunter T, USA2001;98:1387^92. ture. Science 2002;296:2404 ^ 7. Sudarsanam S. The protein kinase complement of the 34. Gunaratnam L, Morley M, Franovic A, et al. Hypoxia 40. Murphy DA, Makonnen S, Lassoued W, Feldman human genome. Science 2002;298:1912^ 34.

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Mark N. Stein and Keith T. Flaherty

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