`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`202324Orig1s000
`
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES-TEAM LEADER’S MEMO
`
`NDA/BLA Serial
`Number:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`Review Priority:
`
`Biometrics Division:
`Primary Reviewer:
`Secondary Reviewer:
`Concurring reviewer:
`Medical Division:
`Clinical Team:
`
`Project Manager:
`
`
`
`
`202-324 / S-000
`
`
`
`Inlyta® (axitinib)
`Treatment of patients with advanced renal cell carcinoma.
`Pfizer, Inc.
`Submitted: April 14, 2011
`PDUFA: February 14, 2012
`Review Completed: January 11, 2012
`Standard
`
`Division of Biometrics V (HFD-711)
`Somesh Chattopadhyay, Ph.D.
`Shenghui Tang, Ph.D., Team Leader
`Rajeshwari Sridhara, Ph.D., Director
`Division of Oncology Products 1 (HFD-150)
`Amy McKee, M.D., Medical Reviewer
`John R. Johnson, M.D., Medical Team Leader
`Ms. Lisa Skarupa
`
`
`Reference ID: 3070441
`
`

`

`In the past six years, the treatment options for patients with advanced RCC have
`increased from IFN-α and IL-2 to six new agents with two different modes of actions:
`vascular endothelial growth factor receptor (VEGF-R) inhibitors sorafenib, sunitinib, and
`pazopanib and VEGF antibody bevacizumab; and mammalian target of rapamycin
`(mTOR) inhibitors temsirolimus and everolimus. All of the approvals for advanced RCC
`since 2005 have been given the broad indication of advanced RCC, except everolimus,
`which received a second-line indication. Most of the trials to support these broad
`indications were conducted in treatment-naïve patients; however, the pivotal trials for
`both sorafenib and pazopanib had mixed populations of treatment-naïve patients, patients
`who had received cytokine regimens, or patients who had received other regimens such
`as traditional chemotherapies or hormonal agents.
`
`The applicant has submitted results from one multicenter, phase III, randomized, open-
`label, clinical trial (Study A4061032) comparing axitinib, a new molecular entity (NME),
`to sorafenib in patients with metastatic renal cell carcinoma (RCC) following failure of
`one prior systemic first line regimen containing one or more of the following: sunitinib,
`bevacizumab + IFN-α, temsirolimus, or cytokine(s). Study A4061032 randomized 723
`patients in a 1:1 ratio to receive either axitinib at a starting dose of 5 mg twice daily or
`sorafenib 400 mg twice daily. The randomization was stratified by ECOG performance
`status and prior therapy. The primary endpoint was progression-free survival (PFS) based
`on the radiologic assessment by an independent review committee (IRC). The secondary
`endpoints included investigator-assessed PFS, overall survival (OS), objective response
`rate (ORR) as assessed by IRC, and duration of response. The axitinib arm showed
`statistically significant improvement over sorafenib in PFS as assessed by IRC in all
`randomized patients. The median PFS was 6.7 months in the axitinib arm and 4.7 months
`in the sorafenib arm with a hazard ratio (HR) of 0.67 (95% CI: 0.55-0.81). The difference
`in median PFS for patients previously treated with cytokines was 5.6 months (HR: 0.47;
`95% CI 0.32-0.68), whereas the difference in patients previously treated with sunitinib
`was 1.4 months (HR: 0.74; 95% CI: 0.58-0.96). The study did not show difference in OS
`between axitinib and sorafenib arms (HR: 0.97; 95% CI: 0.80-1.17). For further details
`regarding the designs, data analyses, and results of Study A4061032, please refer to the
`statistical review by Dr. Somesh Chattopadhyay (January 11, 2012).
`
`The application was discussed at the Oncologic Drug Advisory Committee meeting on
`December 7, 2011. The committee voted unanimously in favor of axitinib to the question
`whether the benefit-risk ratio of axitinib is favorable.
`
`This team leader concurs with the recommendations and conclusions of the statistical
`reviewer (Dr. Somesh Chattopadhyay) of this application. The statistical results from
`Study A4061032 provide adequate evidence to support the PFS claim proposed in the
`NDA.
`
`
`Reference ID: 3070441
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHENGHUI TANG
`01/11/2012
`
`RAJESHWARI SRIDHARA
`01/11/2012
`
`Reference ID: 3070441
`
`

`

`
`
`
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Science
`Office of Biostatistics
`
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
`
`NDA/BLA Serial
`Number:
`Drug Name:
`Indication(s):
`Applicant:
`Date(s):
`
`Review Priority:
`
`Biometrics Division:
`Statistical Reviewer:
`Concurring Reviewers:
`
`Medical Division:
`Clinical Team:
`
`202-324 / S-000
`
`Inlyta® (axitinib)
`
`Treatment of patients with advanced renal cell carcinoma.
`
`Pfizer, Inc.
`
`Submitted: April 14, 2011
`PDUFA: February 14, 2012
`Review Completed: January 9, 2012
`Standard
`
`
`
`
`
`Division of Biometrics V (HFD-711)
`
`Somesh Chattopadhyay, Ph.D.
`
`Shenghui Tang, Ph.D., Team Leader
`
`Rajeshwari Sridhara, Ph.D., Director
`
`Division of Oncology Products 1 (HFD-150)
`
`Amy McKee, M.D., Medical Reviewer
`John R. Johnson, M.D., Medical Team Leader
`Ms. Lisa Skarupa
`
`Project Manager:
`
`
`Keywords: Intent-to-treat, interim analysis, Kaplan-Meier product limit, logrank test,
`multiple endpoints, proportional hazards, randomization, stratification, subgroup analysis,
`survival analysis.
`
`
`
`
`
`
`Reference ID: 3070220
`
`

`

`Table of Contents
`LIST OF TABLES.......................................................................................................................................................3
`LIST OF FIGURES.....................................................................................................................................................4
`1. EXECUTIVE SUMMARY .................................................................................................................................5
`2.
`INTRODUCTION ...............................................................................................................................................6
`2.1. OVERVIEW......................................................................................................................................................6
`2.1.1. Background............................................................................................................................................6
`2.1.2.
`Regulatory History.................................................................................................................................6
`2.1.3.
`Specific Studies Reviewed.....................................................................................................................7
`2.2. DATA SOURCES ..............................................................................................................................................7
`3. STATISTICAL EVALUATION ........................................................................................................................8
`3.1. DATA AND ANALYSIS QUALITY .....................................................................................................................8
`3.2. EVALUATION OF EFFICACY ............................................................................................................................8
`3.2.1.
`Study Objectives....................................................................................................................................8
`3.2.1.1.
`Primary Objective .............................................................................................................................................. 8
`3.2.1.2.
`Secondary Objectives......................................................................................................................................... 8
`3.2.2.
`Study Design..........................................................................................................................................9
`3.2.3.
`Schedule of Assessments .......................................................................................................................9
`3.2.4.
`Efficacy Endpoints...............................................................................................................................10
`3.2.5.
`Sample Size Considerations.................................................................................................................12
`3.2.6.
`Interim Analyses..................................................................................................................................14
`3.2.7.
`Efficacy Analysis Methods..................................................................................................................15
`3.2.7.1. Analysis Populations........................................................................................................................................ 15
`3.2.7.2. Analysis of Primary Endpoint.......................................................................................................................... 16
`3.2.7.3. Analysis of Secondary Endpoints..................................................................................................................... 16
`3.2.7.4.
`Patient Reported Outcome Analyses................................................................................................................ 17
`3.2.8.
`Sponsor’s Results and FDA Statistical Reviewer’s Findings/Comments ............................................17
`3.2.8.1.
`Patient Disposition ........................................................................................................................................... 18
`3.2.8.2. Baseline Characteristics ................................................................................................................................... 19
`3.2.8.3.
`Primary Efficacy Analysis ............................................................................................................................... 20
`3.2.8.4.
`Secondary Efficacy Analyses........................................................................................................................... 22
`3.2.8.5.
`Sensitivity Analyses of PFS ............................................................................................................................. 26
`3.3. EVALUATION OF SAFETY..............................................................................................................................28
`4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS .............................................................................29
`4.1. GENDER, RACE, AGE AND GEOGRAPHIC REGION .........................................................................................29
`4.2. OTHER SPECIAL/SUBGROUP POPULATIONS ..................................................................................................30
`5. SUMMARY AND CONCLUSIONS ................................................................................................................33
`5.1.
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE .......................................................................................33
`5.2. CONCLUSIONS AND RECOMMENDATIONS .....................................................................................................34
`CHECK LIST ............................................................................................................................................................37
`
`
`
`Reference ID: 3070220
`
`2
`
`

`

`
`LIST OF TABLES
`
`
`Table 1: Reasons for Censoring of IRC-assessed PFS ................................................................................................13
`Table 2: Demographic Characteristics: Gender, Race and Age at Randomization in FAS .........................................20
`Table 3: Baseline Characteristics (Stratification Factors)............................................................................................20
`Table 4: Analysis of PFS Based on Independent Review in FAS ...............................................................................21
`Table 5: Analysis of PFS Based on Investigator’s Assessment in FAS ......................................................................22
`Table 6: Analysis of OS in FAS (Interim Analysis, August 31, 2010 Cut-off)...........................................................24
`Table 7: Analysis of OS in FAS (Final Analysis, November 1, 2011 Cut-off) ...........................................................25
`Table 8: Sensitivity Analysis of PFS Using Scheduled Assessment Time Based on Independent Review in FAS ....26
`Table 9: Sensitivity Analysis of PFS Treating the Discontinuation Due to Deteriorating Heath Status as Events
`Based on Independent Review in FAS ........................................................................................................................27
`Table 10: Sensitivity Analysis of PFS Treating Censoring Due to Discontinuation without Progression, Missed
`Tumor Assessments and the Start of Subsequent Anticancer Therapy as Events........................................................27
`Table 11: Sensitivity Analysis of PFS based on IRC Assessment but Treating the Discontinuation due to
`Investigator-assessed Progression with no Subsequent Scans as Events.....................................................................27
`Table 12: Sensitivity Analysis of PFS based on IRC Assessment in Safety Analysis Set...........................................28
`Table 13: Sensitivity Analysis of PFS Using Earlier of IRC-assessed and Investigator-assessed time Scheduled
`Assessment Time Based on Independent Review in FAS ...........................................................................................28
`Table 14: Exploratory Analysis of PFS by Gender .....................................................................................................29
`Table 15: Exploratory Analysis of PFS by Race .........................................................................................................29
`Table 16: Exploratory Analysis of PFS by Age Group ...............................................................................................30
`Table 17: Exploratory Analysis of PFS by Geographic Region ..................................................................................30
`Table 18: Exploratory Analysis of PFS by Baseline ECOG Performance Status........................................................31
`Table 19: Exploratory Analysis of PFS by Prior Therapy...........................................................................................31
`Table 20: Exploratory Analysis of PFS by Prior Therapy and Region........................................................................31
`
`
`
`
`Reference ID: 3070220
`
`3
`
`

`

`
`LIST OF FIGURES
`
`Figure 1: Patient Disposition .......................................................................................................................................18
`Figure 2: Kaplan-Meier Plot of PFS in FAS Based on Independent Review ..............................................................21
`Figure 3: Kaplan-Meier Plot of PFS Based on Investigator’s Assessment in FAS .....................................................23
`Figure 4: Kaplan-Meier Plot of OS in FAS (Interim Analysis, August 31, 2010 Cut-off)..........................................24
`Figure 5: Kaplan-Meier Plot of OS in FAS (Final Analysis, November 1, 2011 Cut-off) ..........................................25
`
`
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`Reference ID: 3070220
`
`4
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`

`

`
`1. EXECUTIVE SUMMARY
`
`The applicant has submitted results from one multicenter, phase III, randomized, open-label,
`clinical trial (Study A4061032) comparing axitinib, a new molecular entity (NME), to sorafenib
`in patients with metastatic renal cell carcinoma (RCC) following failure of one prior systemic
`first line regimen containing one or more of the following: sunitinib, bevacizumab + IFN-α,
`temsirolimus, or cytokine(s). The axitinib arm showed statistically significant improvement over
`sorafenib in progression-free survival (PFS) as assessed by independent radiology committee in
`all randomized patients. However, the axitinib arm did not show statistically significant
`improvement with respect to overall survival (OS). The application was discussed at the
`Oncologic Drug Advisory Committee meeting on December 7, 2011. The committee voted
`unanimously in favor of axitinib to the question whether the benefit-risk ratio of axitinib is
`favorable. The statistical results provide adequate evidence to support the PFS claim proposed in
`the NDA.
`
`This application is based on one Phase III trial (Study A4061032) and three uncontrolled single-
`arm Phase II studies (A4061012, A4061035 and A4061023). This review is primarily based on
`the Phase III study. In Study A4061032 patients were randomized in a 1:1 ratio to receive
`axitinib at a starting dose of 5 mg twice daily orally with food or sorafenib at a starting dose of
`400 mg twice daily orally without food. The randomization was stratified by ECOG
`performance status (0 vs. 1) and by prior therapy (sunitinib-containing regimens vs.
`bevacizumab-containing regimens vs. temsirolimus-containing regimens vs. cytokine-containing
`regimens). The study was initiated on September 15, 2008. The data cut-off date was August 31,
`2010. A total of 723 patients were randomized, 361 to axitinib and 362 to sorafenib. Patients
`were enrolled at 175 centers in 22 countries. The primary efficacy endpoint was progression-free
`survival (PFS) as assessed by the independent radiology committee (IRC) review. The secondary
`efficacy endpoints were investigator-assessed PFS, overall survival (OS), objective response rate
`(ORR) as assessed by IRC review and duration of response.
`
`The axitinib arm showed statistically significant improvement over sorafenib with respect to PFS
`as assessed by the IRC in the full analysis set (FAS) [hazard ratio=0.667, 95% confidence
`interval: (0.546, 0.814), log-rank test stratified by ECOG performance status and prior therapy,
`one-sided p-value<0.0001]. The median PFS and its 95% confidence interval in axitinib and
`sorafenib arms were 6.7 months [95% CI: (6.3 months, 8.4 months)] and 4.7 months [95% CI:
`(4.6 months, 5.6 months)], respectively. Analysis of the primary endpoint PFS as assessed by
`IRC is shown in Table 4 and the Kaplan Meier plot is shown in Figure 2. The study did not show
`a difference in OS between axitinib and sorafenib arms in the FAS [hazard ratio=0.969, 95%
`confidence interval: (0.800, 1.174), stratified log-rank test, one-sided p-value=0.3744]. Analysis
`of OS is shown in Table 7 and the Kaplan Meier plot of OS is presented in Figure 5. No
`adjustment to the level of significance was made for multiple secondary endpoints. Therefore p-
`values are not interpretable for the secondary endpoints. The objective response rate was 19.4%
`in the axitinib arm and 9.4% in the sorafenib arm based on the responses assessed by the IRC.
`
`
`
`
`
`Reference ID: 3070220
`
`5
`
`

`

`2. INTRODUCTION
`
`
`2.1. Overview
`
`
`Renal cell carcinoma (RCC) is the third leading urologic cancer. About thirty percent of patients
`with RCC have metastatic disease at the time of diagnosis, and a significant proportion of
`patients with localized disease treated with curative nephrectomy relapse subsequently with
`metastatic disease. The most frequent locations of metastases are the lungs, mediastinum, bone,
`liver, and brain. Metastatic RCC is currently incurable with a low 5-year survival rate and is
`frequently associated with a quality-of-life burden, based on physical, psychological, and social
`criteria.
`
`Clear cell RCC, which represents 75% to 85% of the RCC population, frequently displays allelic
`loss on chromosome 3p, accompanied by mutational inactivation of the von Hippel- Lindau
`(VHL) tumor suppressor gene. VHL-associated RCC are known for their vascularity, and these
`tumors produce high levels of VEGF. In addition, recent studies suggest that in sporadic clear
`cell RCC, increased expression of VEGF is closely correlated with neovascularization, which is
`a prerequisite of tumor growth and metastasis. RCC tumors over express the receptors for these
`peptides. These ligands and receptors may be involved in the autocrine stimulation of tumor cell
`growth, or in the paracrine stimulation of neovascular or stromal fibroblast growth that supports
`tumor expansion. For these reasons, the angiogenic pathway is a logical target of potential
`therapies for advanced RCC.
`
`
`2.1.1. Background
`
`Angiogenesis, the formation and growth of new blood vessels, is a fundamental step in the
`transition of tumors from a dormant to a malignant state. The angiogenic process is initiated by
`various factors including vascular endothelial growth factor (VEGF), a cell-specific glycoprotein
`that plays a role in endothelial cell proliferation, survival, and migration by binding to tyrosine
`kinase receptors. These receptors are implicated in pathologic angiogenesis, tumor growth, and
`metastatic progression of cancer. The inhibition of angiogenesis through effects on VEGF has
`been a major target in the development of cancer therapies. Axitinib, a substituted indazole
`derivative, is an oral, potent, and selective tyrosine kinase inhibitor (TKI) of vascular endothelial
`growth factor receptor (VEGFR) 1, 2, and 3.
`
`
`2.1.2. Regulatory History
`
`Axitinib is a new molecular entity (NME). This application is based on a single randomized
`Phase III and three single arm Phase II trials. The trials were conducted under IND 63,662. The
`study protocol for the Phase III trial A4061032 was submitted for a Special Protocol Assessment
`(SPA) on December 18, 2007. FDA sent a non-agreement letter on January 31, 2008. The
`sponsor resubmitted the SPA on March 14, 2008 making modification to the protocol according
`to FDA’s recommendations. FDA sent an agreement letter on April 17, 2008. The Pre-NDA
`
`
`6
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`Reference ID: 3070220
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`

`

`meeting was scheduled to be held on February 28, 2011. The sponsor cancelled the meeting after
`receiving FDA responses to their questions.
`
`
`2.1.3. Specific Studies Reviewed
`
`This application is based on one Phase III trial (Study A4061032) and three uncontrolled Phase
`II studies (A4061012, A4061035 and A4061023). Studies A4061012 and A4061035 were single-
`arm, single-agent Phase II trials in patients with cytokine-refractory advanced RCC. Study
`A4061023 was a single-arm, single-agent Phase II trial in patients with sorafenib-refractory
`advanced RCC.
`
`This review is primarily based on the Phase III study. Study A4061032 was a multicenter,
`international, randomized, controlled, Phase III study to evaluate the efficacy of axitinib
`compared to sorafenib in patients with metastatic RCC following failure of one prior systemic
`first line regimen containing one or more of the following: sunitinib, bevacizumab + IFN-α,
`temsirolimus, or cytokine(s). Patients were randomized in a 1:1 ratio to receive axitinib at a
`starting dose of 5 mg twice daily orally with food or sorafenib at a starting dose of 400 mg twice
`daily orally without food. The randomization was stratified by ECOG performance status (0 vs.
`1) and by prior therapy (sunitinib-containing regimens vs. bevacizumab-containing regimens vs.
`temsirolimus-containing regimens vs. cytokine-containing regimens). The study was initiated on
`September 15, 2008. The data cut-off date was August 31, 2010.
`
` A
`
` total of 723 patients were randomized, 361 to axitinib and 362 to sorafenib. Of the randomized
`patients, 523 were men and 200 were women, 547 were White, and the median age was 61 years
`(age range: 20 to 82 years). Randomized patients were enrolled at 175 centers in 22 countries.
`There were 169 patients from US.
`
`
`
`2.2. Data Sources
`
`
`Data used for this review are from the electronic submissions dated April 14, 2011, June 9, 2011
`and December 14, 2011. The paths are
`\\Cdsesub1\EVSPROD\NDA202324\0000\m5\datasets\a4061032,
`\\Cdsesub1\EVSPROD\NDA202324\0004\m5\datasets\a4061032 and
`\\Cdsesub1\EVSPROD\NDA202324\0022\m5\datasets\a4061032, respectively.
`
`
`
`Reference ID: 3070220
`
`7
`
`

`

`3. STATISTICAL EVALUATION
`
`3.1. Data and Analysis Quality
`
`
`Overall the data and analysis quality of the submission was acceptable for the reviewer to be able
`to perform the statistical review. However there were some problems with the datasets in the
`original and subsequent submissions.
`
`The submission had the following problems.
`• Some variables were missing from the datasets in the original submission.
`•
`In the original submission, parts of the data definition file were unclear including the lack
`of specifications of the key variables for the datasets with multiple records per patient and
`unclear variable labels.
`The applicant corrected the above problems and resubmitted new datasets and data definition
`files to address the above problems.
`
`
`
`3.2. Evaluation of Efficacy
`
`
`The applicant has submitted efficacy results from one Phase III study (Study A4061032) titled
`“Axitinib (AG-013736) as second-line therapy for metastatic renal cell cancer: Axis Trial” and
`three uncontrolled Phase II studies (A4061012, A4061035 and A4061023). Studies A4061012
`and A4061035 were single-arm, single-agent Phase II trials in patients with cytokine-refractory
`advanced RCC. Study A4061023 was a single-arm, single-agent Phase II trial in patients with
`sorafenib-refractory advanced RCC. This review will be primarily based on the Phase III study.
`
`
`3.2.1. Study Objectives
`
`Primary Objective
`
`3.2.1.1.
`
`The primary objective of Study A4061032 was to compare the progression-free survival (PFS) of
`patients with mRCC receiving axitinib versus sorafenib following failure of one prior systemic
`first-line regimen containing one or more of the following: sunitinib, bevacizumab + IFN-α,
`temsirolimus, or cytokine(s).
`
`
`Secondary Objectives
`
`3.2.1.2.
`
`The secondary objectives were to:
`
`
`• Compare the overall survival (OS) of patients between two arms;
`• Compare the objective response rate (ORR) of patients between two arms;
`• Evaluate the safety and tolerability of axitinib;
`• Estimate the duration of response (DR) of patients in each arm; and
`
`
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`Reference ID: 3070220
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`8
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`

`

`• Compare the kidney-specific symptoms and health status of patients between two arms,
`as measured by the Functional Assessment of Cancer Therapy Kidney Symptom Index
`(FKSI) and European Quality of Life (EuroQol) EQ-5D self-report questionnaire (EQ-
`5D).
`
`
`
`3.2.2. Study Design
`
`This study was a multicenter, international, open-label, randomized, controlled, Phase III study
`to evaluate the efficacy of axitinib compared to sorafenib in patients with metastatic RCC
`following failure of 1 prior systemic first line regimen containing one or more of the following:
`sunitinib, bevacizumab + IFN-α, temsirolimus, or cytokine(s).
`
`Patients were randomized in a 1:1 ratio to receive axitinib at a starting dose of 5 mg twice daily
`orally with food or sorafenib at a starting dose of 400 mg twice daily orally without food (at least
`1 hour before or 2 hours after eating). A centralized registration and randomization system
`(Interactive Voice Response System [IVRS]) was used for randomization. The patients were
`stratified by ECOG performance status (0 vs. 1) and by prior therapy (sunitinib-containing
`regimens vs. bevacizumab-containing regimens vs. temsirolimus-containing regimens vs.
`cytokine-containing regimens).
`
`Study treatment was to continue until disease progression, intolerable adverse drug reactions, or
`withdrawal of consent. Study treatment was required to begin within 7 days of randomization.
`
`Patients who discontinued treatment on this study could receive subsequent therapy based on the
`judgment of the treating physician. Patients were not offered axitinib or sorafenib as a
`subsequent therapy while on-study.
`
`Major inclusion criteria included histologically or cytologically confirmed mRCC with a
`component of clear cell subtype, evidence of unidimensionally measurable disease (i.e., ≥1
`malignant tumor mass that could have been accurately measured in at least 1 dimension ≥ 20 mm
`with conventional computed tomography [CT] scan or magnetic resonance imaging [MRI] scan,
`or ≥ 10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm),
`progressive disease per RECIST 1.0 after 1 prior systemic first-line regimen for mRCC
`containing one or more of sunitinib, bevacizumab + IFN- α, temsirolimus and cytokine(s),
`adequate organ function and ECOG performance status 0 or 1.
`
`
`3.2.3. Schedule of Assessments
`
`Baseline tumor assessments required CT/MRI (no chest x-ray) of the chest, abdomen, and pelvis
`and a bone scan at the minimum within 28 days prior to randomization. CT or MRI of brain was
`required at baseline. Subsequent CT or MRI of the brain could have been performed if clinically
`indicated, as determined by the treating physician. On-study tumor assessments were to be
`performed every 6 weeks for the first 12 weeks, and then every 8 weeks by calendar to determine
`PFS. If a baseline bone scan showed metastatic lesions, the lesions were confirmed with
`
`
`9
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`Reference ID: 3070220
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`

`

`concomitant x-ray, CT, MRI, and bone scans and bone imaging was required at the time points
`matched with the CT/MRI evaluations. All scans were sent to the independent review committee
`(IRC). All patients were evaluated for response according to RECIST (Version 1.0)
`
`Patients removed from axitinib treatment for intolerable toxicity were to be followed with
`regular tumor assessments until disease progression or the start of new treatment, and for
`survival thereafter. Patients removed from sorafenib treatment for intolerable toxicity were to be
`followed for survival.
`
`
`3.2.4. Efficacy Endpoints
`
`Primary endpoints:
`• Progression-free survival (PFS) as assessed by the IRC.
`
`
`Secondary endpoints:
`• Progression-free survival (PFS) as assessed by the investigator.
`• Overall survival (OS)
`• Objective response rate (ORR)
`• Duration of response (DR)
`
`
`Patient reported outcome endpoint:
`• Kidney-specific symptoms as measured by Functional Assessment of Cancer Therapy
`Kidney Symptom Index (FKSI)
`• Health status as measured by European Quality of Life (EuroQol) EQ-5D self-report
`questionnaire (EQ-5D)
`
`
`PFS was defined as the time from randomization to first documentation of objective tumor
`progression or to death due to any cause, whichever occurred first. If tumor progression data
`included more than 1 date, the first date was used. For the purposes of endpoint definitions, the
`term ‘on-study’ includes the period from randomization until 28 days after the last dose of study
`medication.
`
`PFS data were censored on the date of the last tumor assessment (on-study) documenting
`absence of PD for patients
`• Who were alive, on-study, and progression free at the time of the analysis;
`• Who had at least 1, on-study disease assessment and discontinued treatment without
`documented disease progression and without death on-study;
`• For whom documentation of disease progression or death occurred after ≥2 consecutive
`missed tumor assessments; or
`• Who were given antitumor treatment, other than the study treatment, before documented
`disease progression.
`
`
`Patients lacking an evaluation of their disease at baseline had their event time censored on the
`date of randomization. Patients lacking an evaluation of tumor response after randomization also
`
`10
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`Reference ID: 3070220
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`

`

`had their event time censored on the date of randomization unless death occurred prior to the first
`planned assessment (in which case the death was an event).
`
`OS was defined as the time from the date of randomization to the date of death due to any cause.
`For patients st