V O L U M E 2 4 䡠 N U M B E R 1 䡠 J A N U A R Y 1 2 0 0 6
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`From the Genitourinary Oncology
`Service, Division of Solid Tumor Oncol-
`ogy, Departments of Medicine and
`Radiology, Memorial Sloan-Kettering
`Cancer Center, New York, NY; Massa-
`chusetts General Hospital; Dana-Farber
`Cancer Institute, Boston, MA; Univer-
`sity of Michigan, Ann Arbor, MI; Fox
`Chase Cancer Center, Philadelphia, PA;
`University of Wisconsin, Madison, WI;
`University of California Los Angeles,
`Los Angeles; Pfizer Inc, La Jolla; and
`University of California San Francisco,
`San Francisco, CA.
`
`Submitted April 5, 2005; accepted
`May 31, 2005.
`
`Supported by Pfizer Inc, La Jolla, CA.
`
`Presented in part at the 40th Annual
`Meeting of the American Society of
`Clinical Oncology, June 5-8, 2004,
`New Orleans, LA.
`
`D.J.G. and B.I.R. contributed equally to
`the study.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Address reprint requests to Robert
`Motzer, MD, Memorial Sloan-Kettering
`Cancer Center, 1275 York Ave, New
`York, NY 10021; e-mail: motzerr@
`mskcc.org.
`
`© 2006 by American Society of Clinical
`Oncology
`
`0732-183X/06/2401-16/$20.00
`
`DOI: 10.1200/JCO.2005.02.2574
`
`Activity of SU11248, a Multitargeted Inhibitor of Vascular
`Endothelial Growth Factor Receptor and Platelet-Derived
`Growth Factor Receptor, in Patients With Metastatic Renal
`Cell Carcinoma
`Robert J. Motzer, M. Dror Michaelson, Bruce G. Redman, Gary R. Hudes, George Wilding, Robert A. Figlin,
`Michelle S. Ginsberg, Sindy T. Kim, Charles M. Baum, Samuel E. DePrimo, Jim Z. Li, Carlo L. Bello,
`Charles P. Theuer, Daniel J. George, and Brian I. Rini
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`Renal cell carcinoma (RCC) is characterized by loss of von Hippel Lindau tumor suppressor gene
`activity, resulting in high expression of pro-angiogenic growth factors: vascular endothelial growth
`factor (VEGF) and platelet-derived growth factor (PDGF). SU11248 (sunitinib malate), a small
`molecule inhibitor with high binding affinity for VEGF and PDGF receptors, was tested for clinical
`activity in patients with metastatic RCC.
`Patients and Methods
`Patients with metastatic RCC and progression on first-line cytokine therapy were enrolled onto a
`multicenter phase II trial. SU11248 monotherapy was administered in repeated 6-week cycles of
`daily oral therapy for 4 weeks, followed by 2 weeks off. Overall response rate was the primary end
`point, and time to progression and safety were secondary end points.
`Results
`Twenty-five (40%) of 63 patients treated with SU11248 achieved partial responses; 17 additional
`patients (27%) demonstrated stable disease lasting ⱖ 3 months. Median time to progression in
`the 63 patients was 8.7 months. Dosing was generally tolerated with manageable toxicities.
`Conclusion
`SU11248, a multitargeted receptor tyrosine kinase inhibitor of VEGF and PDGF receptors, demon-
`strates antitumor activity in metastatic RCC as second-line therapy, a setting where no effective
`systemic therapy is presently recognized. The genetics of RCC and these promising clinical results
`support the hypothesis that VEGF and PDGF receptor-mediated signaling is an effective therapeutic
`target in RCC.
`
`J Clin Oncol 24:16-24. © 2006 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Renal cell carcinoma (RCC) accounts for more than
`30,000 new cases of cancer and more than 12,000
`deaths in the United States annually.1 Patients with
`RCC metastases have a poor prognosis, with few
`other solid tumor cell types showing such uniform
`resistance to cytotoxic chemotherapy agents.2
`Over decades of drug testing, only interleukin-2
`(IL-2) has demonstrated enough clinical activity to
`warrant a US Food and Drug Administration indi-
`cation for treatment of metastatic RCC.1,2 In pivotal
`trials, high-dose intravenous IL-2 administered in
`an intensive care unit setting demonstrated a 14%
`partial or complete response rate.3 Other cytokine
`regimens, including lower doses of subcutaneously
`
`administered interferon alfa (IFN-␣), have demon-
`strated the same or lower response rates, but with
`better tolerance.4,5 These two strategies represent the
`near sum of options available to patients with met-
`astatic RCC, and no proven treatments exist for pa-
`tients whose disease has progressed despite cytokine
`therapy. Overall median survival after progression
`after cytokine therapy is only 12 months, and the
`median survival is approximately 7 months in pa-
`tients with an unfavorable clinical feature, such as
`anemia or decreased performance status.6
`There are several recognized subtypes of RCC,
`but more than 80% of all tumors demonstrate clear-
`cell carcinoma histology. Cytogenetic studies have
`demonstrated frequent and early loss of heterozy-
`gosity in chromosome 3p 25-26 in 90% or more of
`
`16
`
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`Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
`
`AVENTIS EXHIBIT 2075
`Mylan v. Aventis, IPR2016-00712
`
`

`
`SU11248 for Metastatic Renal Cell Carcinoma
`
`spontaneous clear cell carcinomas.7,8 The high frequency of clear
`cell RCC in patients with von Hippel Lindau (VHL) syndrome led
`investigators to identify the VHL gene in this setting.9 Subsequent
`sequencing analyses have demonstrated additional VHL mutations
`in the remaining allele in 50% to 60% of clear cell carcinomas.10
`Further second-hit silencing by hypermethylation and other epi-
`genetic mechanisms likely account for even higher rates of bi-
`allelic gene loss.11 Restoration of VHL function in VHL (⫺/⫺)
`RCC cell lines suppresses their ability to form tumors in nude mice
`xenograft models, supporting the hypothesis that VHL is a renal
`cancer tumor suppressor gene, which when inactivated leads to
`disease progression.12
`Elucidation of VHL protein function in cells has identified targets
`for therapy in this highly resistant malignancy.13 The VHL gene prod-
`uct normally forms stable complexes with elongin B, elongin C, cullin
`2, and Rbx1 that regulate the protein degradation of hypoxia inducible
`factor-alpha (HIF-␣).14 When VHL protein function is absent, HIF-␣
`is allowed to accumulate and bind with constitutively present HIF-
`␤,13 forming a transcriptional factor complex resulting in unregulated
`expression of hypoxia-inducible genes, including vascular endothelial
`growth factor (VEGF) and platelet-derived growth factor (PDGF).
`These growth factors are secreted and bind to specific tyrosine kinase
`receptors on the surface of endothelial cells and vascular pericytes,
`respectively, resulting in cell migration, proliferation, and survival.
`Phenotypically, these growth factors promote tumor angiogenesis that
`may contribute to the hypervascular histology of RCC.1 Conse-
`quently, inhibition of VEGF and PDGF signaling pathways may re-
`verse in part the physiologic consequences of losing VHL protein
`function and may inhibit tumor growth.
`SU11248 (sunitinib malate) is a highly potent, selective inhib-
`itor of certain protein tyrosine kinases, including VEGF-R types 1
`to 3, PDGF-R-␣, and PDGF-R-␤.15-19 Preclinical data suggest that
`SU11248 has antitumor activity that may result from both inhibi-
`tion of angiogenesis and direct antiproliferative effects on certain
`tumor cell types.15-19 A phase I clinical study of SU11248 demon-
`strated evidence of antitumor activity in several patients with met-
`astatic RCC, supporting the working hypothesis that RCC represented
`an ideal proof-of-concept tumor type for further study of this dual
`VEGF and PDGF receptor inhibitor.20 The recommended dose for
`phase II trials was defined in phase I trials as 50 mg orally once daily for
`4 weeks, followed by 2 weeks off, in repeated 6-week cycles.20,21 Using
`this schedule, a multicenter, phase II clinical trial was conducted to
`assess the clinical efficacy and safety of SU11248 in patients with
`cytokine-refractory metastatic RCC.
`
`PATIENTS AND METHODS
`
`Patients
`Sixty-three patients were enrolled onto the study between January and
`July 2003. Eligibility criteria included informed consent, histologic confirma-
`tion of RCC, measurable disease with evidence of metastases, failure of one
`cytokine (IFN-␣, IL-2) -based therapy because of disease progression or un-
`acceptable toxicity, Eastern Cooperative Oncology Group performance status
`of 0 or 1, normal serum amylase and lipase, a normal adrenocorticotropic
`hormone stimulation test, and adequate hematologic, hepatic, renal, and car-
`diac function. The latter was determined as a normal left ventricular ejection
`fraction by echocardiogram or multigated acquisition (MUGA) scan. Patients
`were excluded for the presence of brain metastases or ongoing cardiac dys-
`
`rhythmia, prolongation of QTc interval, or any significant cardiac event within
`the previous 12 months.
`The study was approved by the institutional review board at each of the
`seven participating centers and was performed in accordance with the Decla-
`ration of Helsinki and Good Clinical Practice Guidelines.
`
`Study Design and Treatment
`The starting dose of SU11248 was 50 mg per day administered in re-
`peated 6-week cycles of daily therapy for 4 weeks, followed by 2 weeks off.
`SU11248 was self-administered orally once daily without regard to meals.
`Intrapatient dose escalation by 12.5 mg/d (up to 75 mg/d) was permitted in the
`absence of treatment-related toxicity. Dose reduction for toxicity was allowed
`to 37.5 mg/d and then to 25 mg/d, according to a nomogram for grade 3 to
`4 severity.
`
`Evaluation
`Baseline evaluations included medical history and physical examina-
`tion; computed tomography scan of the chest, abdomen, and pelvis; bone
`scan (in patients with known bone metastases); assessment of Eastern
`Cooperative Oncology Group performance status; CBC; biochemical pro-
`file (including serum amylase and lipase); cardiac function (12-lead ECG
`and either an echocardiogram or MUGA scan); and adrenocorticotropic
`hormone stimulation test. The rigorous evaluations of cardiac, adrenal,
`and pancreatic function were incorporated in the study as safety assess-
`ments based on preclinical data.
`
`Assessment of Efficacy, Safety, and Quality of Life
`Objective clinical response was assessed by Response Evaluation Criteria
`in Solid Tumors (RECIST) using computed tomography or magnetic reso-
`nance imaging scan and bone scan (if bone metastases were present at base-
`line) after cycles 1, 2, and 4, and every two cycles thereafter until the end of
`treatment. CBC, cardiac enzymes, and biochemical profiles were obtained
`throughout the study. Cardiac function was assessed by ECG and echocardio-
`gram or MUGA scan on day 28 of each treatment cycle. Quality of life was
`assessed using the Functional Assessment of Chronic Illness Therapy–Fatigue
`scale (FACIT-Fatigue) and the EuroQoL EQ-5D instrument (EQ-5D). Pa-
`tients completed the FACIT-Fatigue questionnaire before receiving SU11248
`on day 1 (as the baseline assessment) and weekly for cycles 1 through 4 and the
`EQ-5D on days 1 and 28 of each cycle.
`SU11248 treatment was continued until disease progression, unaccept-
`able toxicity, or withdrawal of consent. Individual patients continued
`SU11248 treatment after progression if the investigator felt that the patient
`continued to derive clinical benefit. However, for purposes of analysis, the
`patient was considered to have met the study end point of disease progression.
`Response was assessed by investigators according to RECIST criteria and
`severity of adverse events according to the National Cancer Institute Com-
`mon Toxicity Criteria version 2.0.
`
`Assessment of SU11248 Levels and Biomarkers
`Plasma concentrations of SU11248 and its active metabolite, SU12662,
`were determined on days 1 and 28 of cycles 1 to 4. Plasma concentrations of
`SU11248 and SU12662 were determined predose by a liquid chromatography/
`mass spectrometry method at BASi (West Lafayette, IN), with a lower limit of
`detection of 0.1 ng/mL for SU11248 and SU12662.
`Plasma samples were collected on days 1 and 28 of each cycle for assess-
`ment of soluble proteins that may be correlates of angiogenic activity and/or
`pharmacodynamic inhibition of VEGF receptor-mediated signaling.20-22
`Each cycle consisted of 4 weeks of treatment followed by 2 weeks off. Solu-
`ble proteins were analyzed with enzyme-linked immunosorbent assay (ELISA)
`kits (R&D Systems, Minneapolis, MN). The VEGF-A ELISA assay measured
`the VEGF-A165 and VEGF-A121 isoforms. A soluble form of VEGF-R2
`(sVEGF-R2) was quantified with an ELISA that measured the extracellular
`(soluble) domain of VEGF-R2.23 An ELISA assay for placenta growth
`factor (PlGF) was also used (PlGF is a VEGF family member and a specific
`ligand of VEGF-R1).24
`
`www.jco.org
`
`17
`
`Downloaded from jco.ascopubs.org on June 17, 2016. For personal use only. No other uses without permission.
`Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Motzer et al
`
`RECIST were achieved in 25 patients (40%; 95% CI, 28% to 53%;
`Table 1). Best response of stable disease for ⱖ 3 months was observed
`in an additional 17 patients (27%). Twenty-one patients (33%) had
`either progressive or stable disease of less than 3 months duration or
`were not assessable.
`The majority of patients had a reduction in measurable disease.
`Figure 1 shows each patient’s maximum percentage of tumor reduc-
`tion at the time of analysis achieved during treatment with SU11248.
`Percentages were calculated using the summed unidimensional mea-
`surements of target lesions per RECIST.
`Each of the patients with a partial response had evidence of
`progressive disease at the time of study entry. The median time to first
`observation of partial response was 2.3 months. Twenty-four partial
`responders had clear cell histology, and one had a papillary-cell type.
`Responding lesions included sites of local recurrence and lymphatic,
`hepatic, pulmonary, bone, and adrenal metastases, examples of which
`are shown in patients who achieved partial responses (Fig 2). These
`images highlight responses in multiple metastatic sites, as well as in the
`large primary tumor in patient 1 (Figs 2A, 2B, and 2C), multiple
`hepatic, lung, and pleural metastases in patient 2 (Figs 2D and 2E), and
`a large retroperitoneal lymphadenopathy and hepatic metastases in
`patient 3 (Figs 2F and 2G). Also noted in images of patient 3 (Fig 2F),
`there is decreased attenuation of the retroperitoneal masses consistent
`with tumor necrosis and response.
`Tumor images suggested treatment with SU11248 resulted not
`only in regression in tumor size, but also in qualitative changes in
`contrast uptake that accompanied or preceded tumor regressions.
`This observation raises the possibility that changes in tumor perfusion
`may be a pharmacodynamic marker of SU11248 effect. Figure 3 dem-
`onstrates an example in which lack of contrast enhancement and
`marked central low attenuation within the hepatic masses after initial
`treatment led to an apparent increase in tumor size, reflecting interval
`response with tumor necrosis. Soft tissue and pulmonary lesions con-
`comitantly regressed, and subsequent scans revealed regression of
`hepatic metastases and an overall partial response after three cycles.
`Of 25 patients who achieved a partial response, 15 patients expe-
`rienced disease progression, two patients discontinued treatment due
`to adverse events, and eight patients remain on therapy and are pro-
`gression free at 21⫹ to 24⫹ months from the start of therapy at the
`time of analysis. Median time to progression for the 63 patients was
`
`Statistical Evaluations
`The primary end point was objective tumor response rate (complete
`response or partial response, as defined by RECIST). Sample size was deter-
`mined using Simon’s Minimax two-stage design.25 Sixty-three treated patients
`were required for evaluation of the hypothesis that the objective tumor
`response rate was ⱖ 15%, with an alpha level of 5% and 85% power. Time-to-
`event variables were estimated using the Kaplan-Meier method.26
`
`RESULTS
`
`Patient Characteristics
`Sixty-three patients were treated with SU11248 (Table 1). The
`median age was 60 years, and 55 patients (87%) had clear cell histol-
`ogy. Only four patients (6%) had achieved a complete or partial
`response to the prior cytokine therapy.
`Efficacy
`All 63 patients received the study drug and were included in the
`analysis of efficacy end points. Partial responses determined by
`
`Table 1. Patient Characteristics and Best Responses to SU11248 Treatment
`Characteristic
`No.
`%
`
`Total
`Sex
`Male
`Female
`Age, years
`Median
`Range
`ECOG performance status
`0
`1
`Prior nephrectomy
`Yes
`No
`Prior systemic treatment
`Interferon-alphaⴱ
`IL-2ⴱ
`Interferon-alpha ⫹ IL-2ⴱ
`Radiation therapy
`Histology
`Clear cell
`Papillary
`Sarcomatoid variant (not otherwise specified)
`Unspecified
`Site of metastatic disease
`Lung
`Liver
`Bone
`No. of metastatic sites
`1
`ⱖ 2
`MSKCC risk factors for second-line therapy6
`0
`ⱖ 1
`Best response to SU11248 treatment
`Partial response
`Stable disease for ⱖ 3 months
`Progressive disease, stable disease for ⬍ 3
`months or not assessable
`
`63
`
`43
`20
`
`60
`24-87
`
`34
`29
`
`58
`5
`
`35
`19
`9
`25
`
`55
`4
`1
`3
`
`52
`10
`32
`
`8
`55
`
`34
`29
`
`25
`17
`21
`
`100
`
`68
`32
`
`—
`—
`
`54
`46
`
`92
`8
`
`56
`30
`14
`40
`
`87
`6
`2
`5
`
`81
`16
`51
`
`13
`87
`
`54
`46
`
`40
`27
`33
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; IL-2, interleukin-2;
`MSKCC, Memorial Sloan-Kettering Cancer Center.
`ⴱMay have included additional agents other than cytokines.
`
`Fig 1. Maximal percentage of tumor reduction for target lesions by Response
`Evaluation Criteria in Solid Tumors (RECIST).
`
`18
`
`JOURNAL OF CLINICAL ONCOLOGY
`Downloaded from jco.ascopubs.org on June 17, 2016. For personal use only. No other uses without permission.
`Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
`
`

`
`SU11248 for Metastatic Renal Cell Carcinoma
`
`Fig 2. Computed tomography scan im-
`ages of responding lesions from three pa-
`tients who achieved partial
`responses:
`(A,B,C) responses in patient with multiple
`metastatic sites from a large primary renal
`tumor after treatment; (D,E) responses in
`patient 2 with multiple hepatic, lung, and
`pleural metastases; (F,G) responses in pa-
`tient 3 with large retroperitoneal lymphade-
`nopathy and hepatic metastases.
`
`cluded lymphopenia without infection (32%) and elevated serum
`lipase (21%) without clinical signs or symptoms of pancreatitis. No
`patient developed adrenal insufficiency associated with SU11248
`treatment. Four patients were removed from the study per proto-
`col for a decline in cardiac ejection fraction; three patients were
`without clinical signs and symptoms, and the fourth patient was
`noted to have dyspnea.
`Dose reductions were performed in 22 patients (35%) from 50 to
`37.5 mg/d, and the dose for two of these patients was further reduced
`to 25 mg/d. Common reasons for dose reductions included asymp-
`tomatic hyperlipasemia or hyperamylasemia (11 patients, per proto-
`col) and fatigue (five patients). The dose was escalated in five patients
`from 50 to 62.5 mg/d and in one patient to 75 mg/d, with no evidence
`of improved response.
`
`Quality of Life
`Assessable baseline EQ-5D questionnaires were received from 60
`patients. Questionnaires were consistently returned from ongoing
`patients, with compliance rates at or above 95% at each assessment on
`days 1 and 28 of cycles 1 through 4. Mean and median baseline health
`state visual analog scale scores (77.1 and 80.0, respectively, of a possible
`100) indicated that the study population’s quality of life before
`SU11248 treatment was similar to that of an age-matched US general
`population.27 Mean and median health state visual analog scale scores
`were similar to the baseline scores through 24 weeks of treatment (data
`not shown).
`Valid baseline questionnaires for the FACIT-Fatigue scale
`were received from 62 patients. Questionnaires were consistently
`returned from ongoing patients, with compliance rates at or
`greater than 90% for each weekly assessment from cycle 1 through
`
`8.7 months (95% CI, 5.5 to 10.7; Fig 4A) and median survival was 16.4
`months (95% CI, 10.8 to NA [not yet attained]; Fig 4B).
`Treatment Administration and Adverse Events
`Median duration of treatment was 9 months (range, ⬍ 1 to 24⫹
`months). The most common adverse event was fatigue, which was
`categorized as grade 3 severity in seven patients (11%; Table 2). The
`most frequently occurring grade 3 to 4 laboratory abnormalities in-
`
`Fig 3. Tumor responses of hepatic metastases: Computed tomography scan
`images through the liver of a patient after one cycle of treatment with SU11248.
`Before treatment, several hepatic metastases are apparent. After the first cycle
`of treatment, the lesions demonstrate lack of enhancement and marked low
`attenuation consistent with tumor necrosis.
`
`www.jco.org
`
`19
`
`Downloaded from jco.ascopubs.org on June 17, 2016. For personal use only. No other uses without permission.
`Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Motzer et al
`
`Fig 4. Kaplan-Meier plots of (A) time to tumor progression (TTP) and (B) overall survival. NA, not yet attained.
`
`the end of cycle 4 dosing. Mean and median baseline scores for the
`study population were 40.4 and 44, respectively, which is similar to
`the scores (40.0 and 42, respectively) of a nonanemic cancer population
`but lower than the scores (43.6 and 47, respectively) of a general
`United States population.28 Median and mean fatigue scores were
`similar to the baseline scores through 24 weeks of treatment, although
`the fatigue level seemed to increase during the treatment period and to
`return to baseline during the 2 weeks off, suggesting a mild and
`reversible treatment effect on fatigue (Fig 5).
`
`Assessment of Plasma SU11248 Levels
`and Biomarkers
`Patients achieved and maintained steady-state trough plasma
`concentrations (Cmin) of SU11248 and its active metabolite through-
`out the dosing periods for multiple cycles. Median Cmin (SU11248 and
`SU12662 combined) in all patients was 84.3 ng/mL, which is within
`the range of 50 to 100 ng/mL shown to inhibit target receptor tyrosine
`kinases in preclinical models.19 Accumulation of study drug or its
`active metabolite was not observed across dosing cycles.
`
`Table 2. Selected Treatment-Related Adverse Events of Interest and Laboratory Abnormalities by Grade Occurring in at Least 5% of Patients (n ⫽ 63)
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Total
`
`Adverse Event
`
`Treatment-related adverse events
`Fatigue
`Diarrhea
`Nausea
`Dyspepsia
`Stomatitis
`Vomiting
`Constipation
`Ejection fraction declineⴱ
`Anorexia
`Dermatitis
`Hypertension
`Laboratory abnormalities
`Lymphopenia
`Neutropenia
`Anemia
`Hyperlipasemia
`Thrombocytopenia
`Creatinine
`Creatine kinase
`Hyperamylasemia
`Hepatic transaminase
`Total bilirubin
`
`No. of
`Patients
`
`17
`13
`10
`10
`11
`6
`8
`6
`4
`4
`2
`
`25
`20
`17
`2
`11
`9
`7
`1
`3
`3
`
`ⴱOn two or more assessments of cardiac function.
`
`%
`
`27
`21
`16
`16
`17
`10
`13
`9
`6
`6
`3
`
`40
`32
`27
`3
`18
`14
`11
`2
`5
`5
`
`No. of
`Patients
`
`7
`2
`2
`0
`1
`2
`0
`1
`0
`1
`1
`
`20
`7
`5
`12
`0
`0
`1
`5
`2
`0
`
`%
`
`11
`3
`3
`0
`2
`3
`0
`2
`0
`2
`2
`
`32
`11
`8
`19
`0
`0
`2
`8
`3
`0
`
`No. of
`Patients
`
`%
`
`No. of
`Patients
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`0
`1
`1
`1
`0
`0
`1
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`0
`2
`2
`2
`0
`0
`2
`0
`0
`0
`
`24
`15
`12
`10
`12
`8
`8
`7
`4
`5
`3
`
`45
`28
`23
`15
`11
`9
`9
`6
`5
`3
`
`%
`
`38
`24
`19
`16
`19
`13
`13
`11
`6
`8
`5
`
`72
`45
`37
`24
`18
`14
`15
`10
`8
`5
`
`20
`
`JOURNAL OF CLINICAL ONCOLOGY
`Downloaded from jco.ascopubs.org on June 17, 2016. For personal use only. No other uses without permission.
`Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
`
`

`
`SU11248 for Metastatic Renal Cell Carcinoma
`
`Fig 5. Median Functional Assessment of
`Chronic Illness Therapy (FACIT) –fatigue
`score: assessment of degree of fatigue: a
`lower score indicates a higher level of
`fatigue (range, 0 to 52). (*), Cella et al.28
`
`As putative biomarkers of VEGF-R inhibition, plasma VEGF-A,
`sVEGF-R2, and PlGF levels were serially measured in patients on
`study. In the majority of cases, both VEGF-A and PlGF levels increased
`and sVEGF-R2 levels decreased by the end of each dosing cycle (day
`28); after the 2 weeks off, the levels of all three biomarkers returned to
`near baseline levels (Fig 6). The differences between days 1 and 28
`levels for all biomarkers were highly significant in all cycles through
`cycle 8 (P ⱕ .002). In the PlGF assay, sample readings below the lowest
`level of quantitation (26.2 pg/mL) were omitted from the plot.
`
`DISCUSSION
`
`Over the past decade, the discovery of genetic alterations in the VHL
`gene that occur in the vast majority of clear cell RCC tumors, together
`with elucidation of the biochemical consequences of these changes,
`has led to the identification of rational therapeutic targets. Loss of the
`VHL gene product results in dysregulation and aberrant activation of
`HIF complex and overexpression of VEGF, PDGF, and other growth
`factor signals important to tissue perfusion and hypoxic survival.
`Inhibition of these downstream growth factor signals may in part
`mitigate the physiologic consequences of HIF activation in clear cell
`RCC. Based on this hypothesis, SU11248, a multitargeted inhibitor of
`VEGF and PDGF receptors, was tested in patients with cytokine-
`resistant, metastatic RCC.
`The concept of therapeutically targeting vasculature of solid tu-
`mors has been clinically established.29 Bevacizumab, a VEGF-A–neu-
`tralizing monoclonal antibody, has demonstrated activity against
`RCC.30 A randomized phase II trial of bevacizumab versus placebo
`showed that high-dose bevacizumab therapy produced a 10% partial
`response rate and prolonged time to progression by 2.3 to 4.8 months
`compared with placebo.30 Although these results are of modest clinical
`benefit, the study established proof-of-principle for VEGF-targeted
`therapy in metastatic RCC. In colorectal cancer, bevacizumab
`combined with cytotoxic chemotherapy resulted in more robust
`improvements in objective response rate, progression-free sur-
`vival, and overall survival.31
`
`Historically, RCC is one of the most uniformly resistant solid
`tumors in oncology. Cytokines are the only drugs that have been
`shown to induce tumor regressions in some patients.1 However, be-
`cause most patients do not respond, RCC is considered a priority
`malignancy for development and study of novel therapies.32 This
`multicenter, phase II study demonstrated a high percentage of
`partial responses (25 [40%] of 63 patients). Regressions were seen
`in many patients without a RECIST-defined partial response,
`which suggests a departure from the natural history of this disease. Cur-
`rently, SU11248 as a treatment of metastatic RCC is being further inves-
`tigated in a confirmatory single-arm trial in second-line therapy and in a
`randomized, phase III trial in first-line therapy compared with IFN-␣.
`Responses to SU11248 as second-line therapy were achieved in
`patients after cytokine failure. Patients in this setting are generally
`managed by supportive care (including radiation therapy) or treat-
`ment in clinical trials of experimental agents. After disease progression
`with an initial treatment with IFN-␣ or IL-2, second-line treatment
`with the alternative cytokine is associated with response rates in fewer
`than 5% of patients treated.33 Further, in a series of 251 patients
`treated in 29 clinical trials of various new agents given as second-line
`therapy for metastatic RCC, only 4% of patients achieved a partial
`response.6 The observed median time to progression in this study (8.7
`months) compares favorably with the median times of 2.4 months for
`treatment in second-line therapy at Memorial Sloan-Kettering Cancer
`Center (New York, NY)6 and 2.5 months for treatment with placebo
`after cytokine failure in a phase II trial.30
`Direct or surrogate measures of VEGF- and PDGF-receptor in-
`hibition are difficult in clinical settings. As a potential biomarker
`correlate of tissue hypoxia or biochemical inhibition of VEGF activity,
`serial plasma VEGF-A, PlGF, and sVEGF-R2 levels were measured in
`patients in this study. There were increases of VEGF-A and PlGF and
`decreases of sVEGF-R2 after SU11248 exposure during each cycle of
`treatment. VEGF levels are known to increase in response to hypoxia
`and pharmacologic angiogenesis inhibition.34-37 The mechanism be-
`hind the consistent decrease in sVEGF-R2 levels observed in the
`SU11248 clinical studies is not entirely understood at present, as
`
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`21
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`Copyright © 2006 American Society of Clinical Oncology. All rights reserved.
`
`

`
`Motzer et al
`
`biochemical characterization of the naturally occurring sVEGF-R2
`protein has only recently begun.23 However, the results from the phase
`I trials20-21 and this phase II study clearly indicate that sVEGF-R2 levels
`change in response to SU11248 treatment, perhaps reflective of a
`feedback regulatory loop.
`The clinical effectiveness of small-molecule receptor tyrosine ki-
`nase inhibitors to date has largely been predicated on the inhibition of
`a dominant mutated signaling pathway, such as BCR-ABL rearrange-
`ments in chronic myelogenous leukemia, KIT mutations in gastroin-
`testinal stromal tumors, and epidermal growth factor mutations in
`lung cancer.38-41 In contrast, the drug targets for SU11248 in RCC are
`thought to be nonmutated proteins present largely on endothelial cells
`and pericytes. To date, there is little clinical evidence of direct mito-
`genic or antiapoptotic activity for either VEGF or PDGF receptor
`signaling on RCC cells. These findings support the hypothesis that loss
`of tumor-suppressor gene function can be clinically mitigated in part
`by inhibition of downstream targets, and that such an approach can
`have clinically relevant antitumor effects. Alternatively, an off-target
`effect of SU11248 may account for its clinical activity; however, the
`consistent qualitative changes in contrast uptake seen in tumors, cou-
`pled with the frequent and reproducible changes in plasma VEGF-A,
`sVEGF-R2, and PlGF levels, and prior results of bevacizumab in this
`disease setting, all support the hypothesis that SU11248 inhibits VEGF
`signaling in vivo.
`Why might SU11248 result in such a high frequency of tumor
`regressions in RCC tumors? One possibility is that inhibition of VEGF
`and PDGF receptors targets two compartments of tumor vasculature,
`endothelial cells, and pericytes. Preclinical studies support this ratio-
`nale, demonstrating additional antitumor efficacy with the combina-
`tion of VEGF- and PDGF-receptor inhibition over VEGF-receptor
`inhibition alone.42 Moreover, a preliminary report of another agent
`with a similar profile of VEGF-R and PDGF-R inhibitory properties is
`also reporting antitumor activity against RCC.43
`In summary, SU11248, a multitargeted receptor tyrosine ki-
`nase inhibitor of VEGF and PDGF receptors, demonstrates robust
`antitumor activity in metastatic RCC as second-line therapy, a
`setting where no effective systemic therapy is presently recognized.
`The genetics of RCC and these promising clinical results support the
`hypothesis that nonmutated VEGF and PDGF receptor-mediated signal-
`ing is an effective therapeutic target in RCC and a promising new treat-
`ment strategy.
`
`Fig 6. Vascular endothelial growth factor (VEGF) -A, sVEGF-R2, and placenta
`growth factor (PlGF) levels during treatment with SU11248: (A) VEGF-A, (B)
`sVEGF-R2, and (C) PlGF levels in plasma measured on days 1 and 28 of each
`cycle. The number of cases available for each time point is listed in parentheses
`below each time point. Black bars denote mean values for each cycle.
`
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