`
`Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`NDA 21-938
`NDA 21-968
`
`
`
`Laurie M. Strawn, Ph.D.
`Associate Director, Worldwide Regulatory Strategy
`
`Pfizer, Inc.
`10777 Science Center Drive
`San Diego, CA 92121
`
`Attention:
`
`
`
`Dear Dr. Strawn:
`
`Please refer to your new drug applications (NDAs) dated August 10, 2005, received, August 11, 2005,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for SUTENT® (sunitinib
`malate) Capsules, 12.5 mg, 25 mg, and 50 mg.
`
`
`We acknowledge receipt of your submissions dated August 31, September 15 (2), 23, and 30 (2),
`October 6 (2), 11, 14 (2), 20, 24 (2), 26 (2), and 28 (2), November 11 (2), 14, 16, 23, and 28,
`December 5, 6, 16, 19, 20 (2), and 21, 2005, and January 5, 10, and 12 (2), 2006. We completed our
`review of these applications, as amended.
`
`These new drug applications provide for the use of SUTENT® (sunitinib malate) Capsules for
`the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib
`mesylate and for the treatment of advanced renal cell carcinoma. Approval for advanced renal cell
`carcinoma is based on partial response rates and duration of responses. There are no randomized trials
`of SUTENT demonstrating clinical benefit such as increased survival or improvement in disease-
`related symptoms in renal cell carcinoma.
`
`NDA 21-938 for the treatment of gastrointestinal stromal tumor after disease progression on or
`intolerance to imatinib mesylate is approved, effective on the date of this letter, for use as
`recommended in the agreed-upon labeling text.
`
`NDA 21-968 for the treatment of advanced renal cell carcinoma is approved under the provisions of
`accelerated approval regulations (21 CFR 314.510), effective on the date of this letter, for use as
`recommended in the agreed-upon labeling text. Marketing of this drug product and related activities
`must adhere to the substance and procedures of the referenced accelerated approval regulations.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert
`and immediate container labels). Marketing the product with FPL that is not identical to the approved
`labeling text may render the product misbranded and an unapproved new drug.
`
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 001
`
`

`

`NDA 21-938 and 21-968
`Page 2
`
`
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
`of the copies on heavy-weight paper or similar material. For administrative purposes, designate these
`submissions “FPL for approved NDA 21-938” and “FPL for approved NDA 21-968.” Approval of
`these submissions by FDA is not required before the labeling is used.
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled studies to verify and describe clinical benefit. We remind you of your
`post marketing study commitments specified in your submission dated January 25, 2006, for
`NDA 21-968 for the treatment of advanced renal cell carcinoma. These commitments, along with any
`completion dates agreed upon, are listed below.
`
`1. Provide the response rate and duration of response data from the first interim efficacy analysis of
`study titled “A Phase 3, Randomized Study of SU011248 versus Interferon-α as First-Line
`Systemic Therapy for Patients with Metastatic Renal Cell Carcinoma”. Also, submit the
`comparative safety data that are available at the time of data cutoff for the interim analysis. This
`will include an interim study report as well as raw and derived datasets.
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`submitted 06/2004
`08/2004
`by 03/2006
`
`
`2. Submit efficacy data obtained at the final analysis, including progression-free survival, overall
`survival, response rate and duration of response; as well as updated safety data for study titled “A
`Phase 3, Randomized Study of SU011248 versus Interferon-α as First-Line Systemic Therapy for
`Patients with Metastatic Renal Cell Carcinoma”. This submission will include the final study
`report as well as raw and derived data sets.
`
`
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`submitted 06/2004
`08/2004
`by 07/2006
`
`
`3. Submit raw and derived datasets containing the core imaging facility assessments used to derive
`the updated response rate and median duration of response on study titled “A Pivotal Study of
`SU011248 in the Treatment of Patients with Cytokine-Refractory Metastatic Renal Cell
`Carcinoma”.
`
`
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`submitted 11/2003
`02/2004
`by 03/2006
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 002
`
`

`

`NDA 21-938 and 21-968
`Page 3
`
`
`
`
`
`4. Submit follow-up left ventricular ejection fraction (LVEF) data for patients 16, 46, and 81 on the
`study titled “A Pivotal Study of SU011248 in the Treatment of Patients with Cytokine-Refractory
`Metastatic Renal Cell Carcinoma”. Case narratives should be submitted and should include
`additional cardiac evaluations that were performed and treatments that were administered for
`congestive heart failure. Additionally, submit LVEF data and clinical narratives for any patient
`who, after the data cutoff for the initial NDA submission, had a documented LVEF of ≤ 40%
`and/or signs and symptoms of cardiac failure.
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`submitted 11/2003
`02/2004
`by 05/2006
`
`
`5. Submit comparative LVEF and cardiac safety data for patients enrolled on the adjuvant renal cell
`carcinoma trial, E2805 titled “A Randomized, Double-Blind Phase III Trial of Adjuvant Sunitinib
`versus Sorafenib versus Placebo in Patients with Resected Renal Cell Carcinoma”. The protocol
`will be revised to include a plan acceptable to the FDA for ejection fraction monitoring at baseline
`and follow-up.
`
`
`
`
`Initial Protocol Submission:
`Revised Protocol Submission:
`Study Start:
`
`
`
`Final Report Submission:
`
`
`submitted 11/2005
`by 05/2006
`by 03/2006
`by 06/2011
`
`
`Submit final study reports to NDA 21-968 as a supplemental application. For administrative purposes,
`all submissions relating to these postmarketing study commitments must be clearly designated
`"Subpart H Postmarketing Study Commitments.”
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We are
`waiving the pediatric study requirement for these applications.
`
`In addition, we note your following postmarketing study commitments for both NDAs, specified in
`your submission dated January 25, 2006, that are not a condition of the accelerated approval for
`NDA 21-968. These commitments are listed below:
`
`6. Provide an analysis of the relationship between exposure and efficacy outcomes from the study
`titled “A Phase 3, Randomized Study of SU011248 versus Interferon-α as First-Line Systemic
`Therapy for Patients with Metastatic Renal Cell Carcinoma”.
`
`
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`submitted 06/2004
`08/2004
`by 07/2006
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 003
`
`

`

`NDA 21-938 and 21-968
`Page 4
`
`
`
`7. Submit the completed report and datasets for study titled “A Phase 1 Study to Evaluate the Effect
`of SU011248 on QTc Interval in Subjects with Advanced Solid Tumors”.
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`8. Submit the completed report and datasets for study titled “A Phase 1 Study to Evaluate the
`Pharmacokinetics of SU011248 in Subjects with Impaired Hepatic Function”.
`
`submitted 07/2004
`08/2004
`by 03/2006
`
`
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`submitted 08/2005
`09/2005
`by 05/2006
`
`
`9. Submit completed final study report for study titled “A Phase III, Randomized, Double-Blind,
`Placebo-Controlled Study of SU011248 in the Treatment of Patients with Imatinib Mesylate
`(Gleevec®, Glivec®)-Resistant or Intolerant Malignant Gastrointestinal Stromal Tumor”.
`
`
`
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to both NDAs. In addition, under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to both NDAs. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last annual
`report, and, for clinical studies, number of patients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`“Postmarketing Study Commitment Protocol”, “Postmarketing Study Commitment Final
`Report”, or “Postmarketing Study Commitment Correspondence.”
`
`For NDA 21-938 for the treatment of gastrointestinal stromal tumor after disease progression on or
`intolerance to imatinib mesylate, submit three copies of the introductory materials that you propose to
`use for this product. Submit all proposed materials in draft or mock-up form, not final print.
`
`As required by 21 CFR 314.550, for NDA 21-968 for the treatment of advanced renal cell carcinoma,
`submit all promotional materials at least 30 days before the intended time of initial distribution of
`labeling or initial publication of the advertisement. Send one copy to the Division of Drug Oncology
`Products and two copies of all promotional materials and the package insert directly to:
`
`
`Protocol Submission:
`Study Start:
`
`
`Final Report Submission:
`
`submitted 11/2003
`12/2003
`by 12/2006
`
`Food and Drug Administration
`
`
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`Food and Drug Administration
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 004
`
`

`

`NDA 21-938 and 21-968
`Page 5
`
`We have not completed validation of the regulatory methods. However, we expect your continued
`cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with the reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event
`reports that are received directly by the FDA. New molecular entities and important new biologics
`qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for
`this product. To participate in the program, please see the enrollment instructions and program
`description details at www.fda.gov/medwatch/report/mmp.htm.
`
`If you have any questions, call Christy Cottrell, Consumer Safety Officer, at (301) 796-1347.
`
`
`Enclosure
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, M.D.
`Director
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`
`
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 005
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Richard Pazdur
`1/26/2006 01:41:37 PM
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 006
`
`

`

`
`
`
`
`SUTENT® (SUNITINIB MALATE) CAPSULES
`
`DESCRIPTION
`
`Page 1 of 20
`
`SUTENT®, an oral multi-kinase inhibitor targeting several receptor tyrosine kinases (RTK), is
`the malate salt of sunitinib. Sunitinib malate is described chemically as Butanedioic acid,
`hydroxy-, (2S)-, compound with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-
`3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (1:1). The molecular
`formula is C22H27FN4O2 • C4H6O5 and the molecular weight is 532.6 Daltons. The chemical
`structure of sunitinib malate is:
`O
`
`CH3
`
`N C
`
`H3
`
`OH
`
`CO2H
`
`NH
`
`CH3
`
`NH
`
`O
`
`CH3
`
`.
`
`NH
`
`F
`
`HO2C
`
`H
`
`
`Sunitinib malate is a yellow to orange powder with a pKa of 8.95. The solubility of sunitinib
`malate in aqueous media over the range pH 1.2 to pH 6.8 is in excess of 25 mg/mL. The log of
`the distribution coefficient (octanol/water) at pH 7 is 5.2.
`
`SUTENT (sunitinib malate) capsules are supplied as printed hard shell capsules containing
`sunitinib malate equivalent to 12.5 mg, 25 mg or 50 mg of sunitinib together with mannitol,
`croscarmellose sodium, povidone (K-25) and magnesium stearate as inactive ingredients.
`
`The orange gelatin capsule shells contain titanium dioxide, and red iron oxide. The caramel
`gelatin capsule shells also contain yellow iron oxide and black iron oxide. The printing ink
`contains shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide.
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`
`Sunitinib malate is a small molecule that inhibits multiple RTKs, some of which are implicated
`in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was
`evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified
`as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular
`endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor
`(KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R),
`and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 007
`
`

`

`
`
`
`
`Page 2 of 20
`
`activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition
`of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits
`similar potency compared to sunitinib in biochemical and cellular assays.
`
`Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor
`xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor
`regression and/or inhibited metastases in some experimental models of cancer. Sunitinib
`demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs
`(PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor
`angiogenesis in vivo.
`
`Pharmacokinetics
`
`The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy
`volunteers and in 266 patients with solid tumors.
`
`Absorption, Distribution, Metabolism, and Elimination
`
`Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12
`hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib.
`Sunitinib may be taken with or without food.
`
`Binding of sunitinib and its primary metabolite to human plasma protein in vitro was 95% and
`90%, respectively, with no concentration dependence in the range of 100 – 4000 ng/mL. The
`apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25 - 100
`mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionately
`with dose.
`
`Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its
`primary active metabolite, which is further metabolized by CYP3A4. The primary active
`metabolite comprises 23 to 37% of the total exposure. Elimination is primarily via feces. In a
`human mass balance study of [14C] sunitinib, 61% of the dose was eliminated in feces, with renal
`elimination accounting for 16% of the administered dose. Sunitinib and its primary active
`metabolite were the major drug-related compounds identified in plasma, urine, and feces,
`representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively. Minor
`metabolites were identified in urine and feces but generally not found in plasma. Total oral
`clearance (CL/F) ranged from 34 to 62 L/hr with an inter-patient variability of 40%.
`
`Following administration of a single oral dose in healthy volunteers, the terminal half-lives of
`sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours,
`respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the
`primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its
`primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma
`concentrations of sunitinib and its active metabolite ranged from 62.9 – 101 ng/mL. No
`significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were
`observed with repeated daily administration or with repeated cycles in the dosing regimens
`tested.
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 008
`
`

`

`
`
`
`
`Page 3 of 20
`
`The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient
`populations tested, including patients with gastrointestinal stromal tumor (GIST) and metastatic
`renal cell carcinoma (MRCC) (see CLINICAL STUDIES).
`
`Special Populations
`
`Population pharmacokinetic analyses of demographic data indicate that there are no clinically
`relevant effects of age, body weight, creatinine clearance, race, gender or ECOG score on the
`pharmacokinetics of SUTENT or the active metabolite.
`
`The pharmacokinetics of sunitinib have not been evaluated in pediatric patients.
`
`Hepatic Insufficiency
`
`No clinical studies were conducted in patients with impaired hepatic function. Studies that were
`conducted excluded patients with ALT or AST > 2.5 x ULN or, if due to underlying disease,
`> 5.0 x ULN.
`
`Renal Insufficiency
`
`No clinical studies were conducted in patients with impaired renal function. Studies that were
`conducted excluded patients with serum creatinine > 2.0 x ULN. Population pharmacokinetic
`analyses have shown that sunitinib pharmacokinetics were unaltered in patients with calculated
`creatinine clearances in the range of 42 –347 mL/min.
`
`Drug-Drug Interactions
`
`In vitro studies indicate that sunitinib does not induce or inhibit major CYP enzymes.
`
`In Vitro Studies of CYP Inhibition and Induction: The in vitro studies in human liver
`microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6,
`CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that
`sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug
`interactions with drugs that may be metabolized by these enzymes.
`
`CYP3A4 Inhibitors: Concurrent administration of sunitinib malate with the strong CYP3A4
`inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary
`active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of sunitinib malate
`in healthy volunteers. A dose reduction for SUTENT should be considered when it must be co-
`administered with strong CYP3A4 inhibitors (see DOSAGE AND ADMINISTRATION).
`
`CYP3A4 Inducers: Concurrent administration of SUTENT with the strong CYP3A4 inducer,
`rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active
`metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy
`volunteers. A dose increase for SUTENT should be considered when it must be co-administered
`with CYP3A4 inducers (see DOSAGE AND ADMINISTRATION).
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 009
`
`

`

`
`
`
`
`CLINICAL STUDIES
`
`Page 4 of 20
`
`The clinical safety and efficacy of SUTENT have been studied in patients with gastrointestinal
`stromal tumor (GIST) after progression on or intolerance to imatinib mesylate, and in patients
`with metastatic renal cell carcinoma (MRCC) after failure of cytokine-based therapy.
`
`Gastrointestinal Stromal Tumor (GIST)
`
`Study A
`
`Study A was a two-arm, international, randomized, double-blind, placebo-controlled trial of
`SUTENT in patients with GIST who had disease progression during prior imatinib mesylate
`(imatinib) treatment or who were intolerant of imatinib. The primary objective was to compare
`time-to-tumor progression (TTP) in patients receiving SUTENT plus best supportive care versus
`patients receiving placebo plus best supportive care. Secondary objectives included progression-
`free survival (PFS), objective response rate (ORR), and overall survival (OS). Patients were
`randomized (2:1) to receive either 50 mg SUTENT or placebo orally, once daily, on a schedule
`of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) until disease progression or
`withdrawal from the study for another reason. Treatment was unblinded at the time of disease
`progression. Patients randomized to placebo were then offered crossover to open-label
`SUTENT, and patients randomized to SUTENT were permitted to continue treatment per
`investigator judgment.
`
`The intent-to-treat (ITT) population included 312 patients. Two-hundred seven patients were
`randomized to the SUTENT arm, and 105 patients were randomized to the placebo arm.
`Baseline age, gender, race and ECOG performance status were comparable between the placebo
`and SUTENT groups. Prior exposure to imatinib was similar between the two study arms.
`Demographics and patient characteristics are shown in Table 1.
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 0010
`
`

`

`Table 1. Baseline Demographics in Study A
`
`SUTENT (N=207)
`Gender [N (%)]
`
` Male
`132 (64)
` Female
`75 (36)
`Self-identified Race [N (%)]
`
` White
`183 (88)
` Asian
`10 (5)
` Black
`8 (4)
` Not reported
`6 (3)
`Age Group [N (%)]
`
` < 65 years
`143 (69)
` ≥ 65 years
`64 (31)
`Performance Status [N (%)]
`
` 0
`92 (44)
` 1
`113 (55)
` 2
`2 (1)
`Prior Treatment [N (%)]
`
` Surgery (other than biopsy)
`194 (94)
` Radiotherapy
`16 (8)
`Imatinib outcome [N (%)]
`
` Intolerance
`9 (4)
` Progression within 6 months
`36 (17)
` Progression beyond 6 months
`162 (78)
`
`Page 5 of 20
`
`Placebo (N=105)
`
`64 (61)
`41 (39)
`
`92 (88)
`5 (5)
`4 (4)
`4 (4)
`
`76 (72)
`29 (28)
`
`48 (46)
`55 (52)
`2 (2)
`
`98 (93)
`16 (15)
`
`4 (4)
`17 (16)
`84 (80)
`
`
`
` A
`
` planned interim efficacy and safety analysis was performed after 149 TTP events had
`occurred. There was a statistically significant advantage for SUTENT over placebo in the
`primary endpoint of TTP, as well as in the secondary endpoint of progression-free survival. Data
`were not mature enough to determine the overall survival benefit. Efficacy results are
`summarized in Table 2.
`
`Table 2. GIST Efficacy Results (interim analysis)
`
`Efficacy Parameter
`
`HR
`(95% CI)
`0.33
`(0.23, 0.47)
`0.33
`(0.24, 0.47)
`
`
`Study A
`Placebo
`P-value (log-
`(N = 105)
`rank test)
`6.4
`<0.0001*
`(4.4, 10.0)
`6.0
`(4.4, 9.9)
`0
`
`<0.0001*
`
`0.006c
`
`
`SUTENT
`(N = 207)
`Time to Tumor Progressiona [median,
`27.3
`(16.0, 32.1)
`weeks (95% CI)]
`Progression Free Survivalb [median,
`24.1
`(11.1, 28.3)
`weeks (95% CI)]
`6.8
`Objective Response Rate (PR) [%, (95%
`(3.7, 11.1)
`CI)]
`CI=Confidence interval, HR=Hazard ratio, PR=Partial response
`* A comparison is considered statistically significant if the p-value is < 0.0042 (O’Brien Fleming stopping boundary)
`a Time from randomization to progression; deaths prior to documented progression were censored at time of last radiographic
`evaluation
`b Time from randomization to progression or death due to any cause
`c Pearson chi-square test
`
`
`Breckenridge Exhibit 1103
`SUTENT Approval
`Page 0011
`
`

`

`
`
`
`
`Figure 1. Kaplan-Meier Curve of TTP in Study A (Intent-to-Treat Population)
`
`Page 6 of 20
`
`SUTENT (N=207)
` Median 27.3 Weeks
`Placebo (N=105)
` Median 6.4 Weeks
`Hazard Ratio = 0.33
`95% CI (0.23, 0.47)
`p < 0.0001
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Time to Tumor Progression Probability (%)
`
`0
`
`6
`
`12
`
`18
`
`30
`24
`Time (Weeks)
`
`36
`
`42
`
`48
`
`54
`
`
`
`Study B
`
`Study B was an open-label, multi-center, single-arm, dose-escalation study conducted in patients
`with GIST following progression on or intolerance to imatinib. Following identification of the
`recommended Phase 2 regimen (50 mg once daily on Schedule 4/2), 55 patients in this study
`received the 50 mg dose of SUTENT on treatment Schedule 4/2. Partial responses were
`observed in 5 of 55 patients [9.1% PR rate, 95% CI (3.0, 20.0)].
`
`Metastatic Renal Cell Carcinoma (MRCC)
`
`The use of single agent SUTENT in the treatment of cytokine-refractory MRCC was investigated
`in two single-arm, multi-center studies. All patients enrolled into these studies experienced
`failure of prior cytokine-based therapy. In Study 1, failure of prior cytokine therapy was based
`on radiographic evidence of disease progression defined by RECIST or World Health
`Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy
`treatment (interferon-α, interleukin-2, or interferon-α plus interleukin-2; patients who were
`treated with interferon-α alone must have received treatment for at least 28 days). In Study 2,
`failure of prior cytokine therapy was defined as disease progression or unacceptable
`treatment-related toxicity. The primary endpoint for both studies was ORR. Duration of
`response (DR) was also evaluated.
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`One hundred six patients were enrolled into Study 1, and 63 patients were enrolled into Study 2.
`Patients received 50 mg SUTENT on Schedule 4/2. Therapy was continued until the patients
`met withdrawal criteria or had progressive disease. The baseline age, gender, race and ECOG
`performance statuses of the patients were comparable between Studies 1 and 2. Approximately
`86-94% of patients in the two studies were white. Men comprised 65% of the pooled SUTENT
`population. The median age was 57 years and ranged from 24 to 87 years in the studies. All
`patients had an ECOG performance status <2 at the screening visit.
`
`The baseline malignancy and prior treatment history of the patients were comparable between
`Studies 1 and 2. Across the two studies, 95% of the pooled population of patients had at least
`some component of clear-cell histology. All patients in Study 1 were required to have a
`histological clear-cell component. Most patients enrolled in the studies (97% of the pooled
`population) had undergone nephrectomy; prior nephrectomy was required for patients enrolled in
`Study 1. All patients had received one previous cytokine regimen. Metastatic disease present at
`the time of study entry included lung metastases in 81% of patients. Liver metastases were more
`common in Study 1 (27% vs. 16% in Study 2) and bone metastases were more common in Study
`2 (51% vs. 25% in Study 1); 52% of patients in the pooled population had at least 3 metastatic
`sites. Patients with known brain metastases or leptomeningeal disease were excluded from both
`studies.
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`Results of Studies 1 and 2
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`The ORR and DR data from Studies 1 and 2 are provided in Table 3.
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`Table 3. MRCC Efficacy Results
`Efficacy Parameter
`
`Study 1
`(N = 106)
`25.51 (17.5, 34.9)
`27.1(24.4, *)
`
`Study 2
`(N = 63)
`36.52 (24.7, 49.6)
`54 (34.3, 70.1)
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`Objective Response Rate (PR) [%, (95% CI)]
`Duration of Response [median, weeks (95% CI)]
`CI=Confidence interval, PR=Partial response
`1 Assessed by blinded core radiology laboratory
`2 Assessed by investigators
`* Data not mature enough to determine upper confidence limit
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`There were 27 PRs in Study 1 as assessed by a core radiology laboratory for an ORR of 25.5%
`(95% CI 17.5, 34.9). There were 23 PRs in Study 2 as assessed by the investigators for an ORR
`of 36.5% (95% CI 24.7-49.6). The majority (>90%) of objective disease responses were
`observed during the first four cycles; the latest reported response was observed in cycle 10. DR
`data from Study 1 is premature as only 4 of 27 patients (15%) responding to treatment had
`experienced disease progression. At the time of the data cutoff, Study 1 was ongoing with 44 of
`106 patients (41.5%) continuing treatment, and 11 of the 63 patients (17.5%) enrolled on Study 2
`continued to receive SUTENT on continuation protocols.
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`INDICATIONS AND USAGE
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`SUTENT is indicated for the treatment of gastrointestinal stromal tumor after disease
`progression on or intolerance to imatinib mesylate.
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`SUTENT is indicated for the treatment of advanced renal cell carcinoma. Approval for
`advanced renal cell carcinoma is based on partial response rates and duration of responses.
`There are no randomized trials of SUTENT demonstrating clinical benefit such as increased
`survival or improvement in disease-related symptoms in renal cell carcinoma.
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`CONTRAINDICATIONS
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`Use of SUTENT is contraindicated in patients with hypersensitivity to sunitinib malate or to any
`other component of SUTENT.
`
`WARNINGS
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`Pregnancy Category D
`
`Sunitinib was evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/day) and rabbits (0.5, 1, 5, 20
`mg/kg/day) for effects on the embryo. Significant increases in the incidence of embryolethality
`and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5
`times the systemic exposure in patients administered the recommended daily doses [RDD]).
`Significantly increased embryolethality was observed in rabbits at 5 mg/kg/day while
`developmental effects were observed at ≥1 mg/kg/day (approximately 0.3 times the AUC in
`patients administered the RDD of 50 mg/day). Developmental effects consisted of fetal skeletal
`malformations of the ribs and vertebrae in rats. In rabbits, cleft lip was observed at 1 mg/kg/day
`and cleft lip and cleft palate were observed at 5 mg/kg/day (approximately 2.7 times the AUC in
`patients administered the RDD). Neither fetal loss nor malformations were observed in rats
`dosed at ≤ 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD).
`
`As angiogenesis is a critical component of embryonic and fetal development, inhibition of
`angiogenesis following administration of SUTENT should be expected to result in adverse
`effects on pregnancy. There are no adequate and well-controlled studies of SUTENT in pregnant
`women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving
`this drug, the patient should be apprised of the potential hazard to the fetus. Women of
`childbearing potential should be advised to avoid becoming pregnant while receiving treatment
`with SUTENT.
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`PRECAUTIONS
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`Adverse events described in the following sections for MRCC patients are derived from Study 1
`and Study 2. Adverse events discussed for GIST patients are derived from Study A, the
`randomized, placebo-controlled trial.
`
`Left Ventricular Dysfunction
`
`In the two MRCC studies, twenty-five patients (15%) had decreases in left ventricular ejection
`fraction (LVEF) to below the lower limit of normal (LLN). In GIST Study A, 22 patients (11%)
`on SUTENT and 3 patients (3%) on placebo had treatment-emergent LVEF values below the
`LLN. Nine of twenty-two GIST patients on SUTENT with LVEF changes recovered without
`intervention. Five patients had documented LVEF recovery following intervention (dose
`reduction- 1 patient; addition of antihypertensive or diuretic medications- 4 patients). Six
`patients went off study without documented recovery. Additionally, three patients (1%) on
`SUTENT had Grade 3 reductions in left ventricular systolic function to LVEF < 40%; two of
`these patients died without receiving further study drug. No GIST patients on placebo had Grade
`3 decreased LVEF. In GIST Study A, 1 patient