PFIZER INC.
These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. PROPRIETARY DRUG NAME®/GENERIC DRUG NAME:  INLYTA®/Axitinib (AG-013736) PROTOCOL NO.:  A4061032 PROTOCOL TITLE:  Axitinib (AG-013736) as second line therapy for metastatic renal cell cancer: Axis trial Study Center(s): There were 175 sites in 22 countries that enrolled patients.  Of these, there were 5 sites in Australia, 2 sites in Austria, 4 sites each in Brazil, and Poland, 6 sites each in Canada, and Republic of Korea, 7 sites each in China, Germany, and Russian Federation, 10 sites each in France, and United Kingdom, 2 sites in Greece, 5 sites in India, 1 site each in Ireland, and Singapore, 13 sites in Italy, 18 sites in Japan, 3 sites each in Slovakia, and Sweden, 8 sites in Spain, 4 sites in Taiwan, 48 sites in United States, an additional 19 sites were shipped study drug (including 4 sites in The Netherlands), but did not enroll any patients. Study Initiation Date and Primary Completion and Final Completion Dates: Study Initiation Date = 15 September 2008 Primary Completion Date = 31 August 2010 Final Completion Date = 25 February 2016 Phase of Development: Phase 3 Study Objectives: The primary objective of this study was to: • Compare the Progression Free Survival (PFS) of patients with metastatic renal cell carcinoma (mRCC) receiving AG-013736 (Axitinib) vs Sorafenib following failure of prior systemic first-line regimen containing one or more of the following: sunitinib, bevacizumab + IFN-α, temsirolimus or cytokine(s). The secondary objectives were to: ● Compare the Overall Survival (OS) of patients in each arm; • Compare the Objective Response Rate (ORR) of patients in each arm; ● Evaluate the safety and tolerability of AG-013736 (Axitinib); ● Estimate the Duration of Response (DR) of patients in each arm; Protocol A4061032 – Final 2 – 25 April 2017 • Compare the kidney specific symptoms, and health status of patients in each arm as measured by the FACT-Advanced Kidney Cancer Symptom Index (FKSI), and EuroQol-5D (EQ-5D).
METHODS
Study Design:
This was a 2-arm, randomized, open-label, multicenter, Phase 3 study of Axitinib vs Sorafenib in patients with mRCC following failure of 1 prior systemic first-line regimen containing 1 or more of the following: sunitinib, bevacizumab + IFN-α, temsirolimus, or cytokine(s).  Six-hundred fifty patients were planned to be randomized in a 1:1 ratio to receive either Axitinib, at a starting dose of 5 mg twice daily (BID), or Sorafenib, at a dose of 400 mg BID.  The patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) and by prior therapy (i.e., sunitinib-containing regimens vs bevacizumab-containing regimens vs temsirolimus-containing regimens vs cytokine- containing regimens).  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.  A schedule of activities is provided in Table 1. 3bdbc6a1\Approved\Approved On: 04-May-2017 09

Table 1
Schedule of Activities
* Cycle length was 4 weeks. ** Unnecessary to be repeated before the first dose if screening assessment was performed within 7 days before the first dose. Abbreviations:  BP = blood pressure, C = Cycle, D = Day, RECIST = Response Evaluation Criteria in Solid Tumors, Wks = weeks a Before any procedures performed solely for this study. b Including information on prior systemic first-line regimen, which was required to contain 1 or more of the following: sunitinib, bevacizumab + IFN α, temsirolimus, or cytokine(s) as first-line treatment for metastatic renal cell carcinoma; and type of documentation showing disease progression according to RECIST criteria (Version 1.0). c Collected from screening to the follow-up period. d Examination of major body systems (including neurological examination).  Abnormalities from subsequent history and physical examinations were recorded as adverse events. c Height did not need to be collected after the first measurement. f BP was to be measured with the patient in the seated position after the patient had been sitting quietly for 5 minutes.
* Cycle length was 4 weeks. ** Unnecessary to be repeated before the first dose if screening assessment was performed within 7 days before the first dose. Abbreviations:  BP = blood pressure, C = Cycle, CO, = carbon dioxide, D = Day, ECOG = Eastern Cooperative Oncology Group, Hgb = hemoglobin, INR = International Normalized Ratio, mm Hg = millimeters of mercury, SGOT = serum glutamic oxaloacetic transaminase, SGPT = serum glutamic pyruvic transaminase, T 3 = tri-iodothyronine, T4 = thyroxine, TSH = thyroid stimulating hormone, WBC = white blood cell, Wks = weeks § All patients (in both study arms) were provided a BP monitoring device.  Patients were to measure their BP at least twice daily before taking each dose of medication, and was recorded in a patient diary.  Patients were instructed by the study staff to contact their physician immediately for guidance if their systolic BP rose above BP 150 mm Hg, diastolic BP rose above 100 mm Hg, or if they developed symptoms perceived to be related to elevated BP (e.g., headache, visual disturbance). h Hemoglobin, white blood cell count, neutrophil count, lymphocyte count, and platelet count. ' Blood urea nitrogen, creatinine, sodium, potassium, chloride, calcium, bicarbonate or carbon dioxide, alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase (or SGPT), aspartate aminotransferase (or SGOT), total protein, albumin, total bilirubin, glucose, phosphate, lipase, and amylase.  INR was to be performed to monitor patients taking concomitant warfarin with Sorafenib and when clinically indicated.  Bicarbonate and venous carbon dioxide were optional for sites in Japan. ³ Thyroid function tests (free T 3 , free T 4 , and TSH) were to be performed for all randomized patients (in both study arms) at baseline (C1, D1 predose or within 7 days b C1, D1).  Subsequently, TSH was done at C1, D15; C2, D1; C3, D1; and C4, D1; and then every 8 weeks starting from C6, D1.  Free T 3 and free T 4 was to be performed when clinically indicated.  Hypothyroidism was to be treated per standard medical practice to maintain euthyroid state. k Protein, glucose, and blood.  If protein ≥2+ by semiquantitative method (e.g., urine dipstick), protein was to be quantified by 24-hour urine collection.  Dose adjustment have been required (adjustment of the dose once patient was on-study; this did not depend on baseline proteinuria).
* Cycle length was 4 weeks. Abbreviations:  C = Cycle, CR = complete response, CT = computed tomography, D = Day, ECG = electrocardiogram, MRI = magnetic resonance imaging, PR = partial response, QTc = corrected QT interval, RECIST = Response Evaluation Criteria in Solid Tumors, Wks = weeks †ECGs: 3 consecutive 12-lead ECGs were to be performed approximately 2 minutes apart to determine the mean QTc interval.  The triplicate ECGs were performed at C1, DI predose (baseline), approximately 1 to 2 hours following a dose of Axitinib on CI, DIS at T any (for the first 50 patients randomized to Axitinib only).  For all remaini patients (including the control arm), a single ECG measurement was to be collected at CI, D1 predose.  If the mean QTc interval was prolonged (>500 msec), then the ECGs were to be re-read by a cardiologist or other qualified person at the site for confirmation.  Additional ECGs could have been performed as clinically indicated. m Prestudy objective evidence of disease progression per RECIST was confirmed by the Principal Investigator and documented in the patient's medical record.  Baseline screening) tumor assessments required CT/MRI (no chest x-ray) of the chest, abdomen, and pelvis and a bone scan at the minimum.  The baseline CT/MRI and baseline bone scan were submitted to the imaging core laboratory for retrospective review.  If the interval between any of the baseline tumor assessments and randomization became >28 days, the expired baseline tumor imaging was repeated.  For all patients, CT/MRI (covering the same anatomy as the baseline scans, except brain) was required every 6 weeks ×2 then every 8 weeks by calendar.  If baseline bone scan showed metastatic lesions, bone imaging was required every 6 weeks ×2 then every 8 weeks by calendar to coincide with the time of the CT/MRI, otherwise, repeat bone scan only if clinically indicated.  Response (CR/PR) required confirmation with CT/MRI and a bone scan at least 4 weeks after the response was first noted.  Since the progression-free survival, as determined by the independent review committee, was the primary endpoint of this study, these tumor assessments were performed by calendar as scheduled until progression of disease by RECIST or death, regardless of whether the patient was receiving study medication or not until permanent discontinuation of study treatment.  All radiographic images and bone scans for tumor assessments were submitted for the independent review committee. °CT or MRI of brain was required at baseline and the images were sent to the independent review committee for retrospective confirmation.  Patients with any evidence of brain metastasis were excluded from the study.  Subsequent CT or MRI of brain was not required, but could have been performed if clinically indicated.
* Cycle length was 4 weeks. *** If for some reason the sample was not collected at Cycle 1 Day 1, it may have been collected at any time during study. Abbreviations:  AE = adverse event, C = Cycle, D = Day, EQ-SD = EuroQol Group's Self-Reported Health Status Measure, FKSI = Functional Assessment of Cancer Therapy-Kidney Symptom Index, IEC = Independent Ethics Committee, IRB = Institutional Research Board, PK = pharmacokinetics, UGT1A1 = UDP-glucuronosy/transferase 1A1, Wks = weeks ° Patients of childbearing potential were required to have a negative pregnancy test within 3 days before treatment and had to be using appropriate birth control or practici abstinence.  Pregnancy tests could have been repeated as per request of IRB/IECs or if required by local regulations. P Patient number, randomization, and Axitinib bottle number assignments were obtained via centralized randomization.  Required information: site and patient identifiers, demographic information, and stratification variables (including ECOG performance status [0 vs 1] and prior therapy).  Study treatment began within 7 days of randomization. 9 Population PK samples for Axitinib were to be obtained from patients at selected sites on C1, D1; C2, D1; and C3, D1.  For patients who were already past C3, PK samples could have been obtained at any other 1 subsequent clinic visit.  On C1, D1, 1 sample was to be obtained 1 to 2 hours after the first Axitinib dose in clinic.  On other scheduled PK visits, 2 samples were to be collected.  One sample was to be obtained just before (i.e., 15 minutes) the morning Axitinib dose taken in the clinic.  If there scheduling conflicts, then this predose sample could have been obtained up to 2 hours before dosing.  The second sample was to be collected 1 to 2 hours after the morning Axitinib dose.  The exact time of the doses and PK collections was noted. ' One (2 mL) blood sample was to be collected from patients in the Axitinib arm for genotyping of drug metabolizing enzymes and transporters only, including UGT1A1. * AEs were collected from the first day of study treatment throughout the study period until at least 28 days after the last dose of study drug and followed until resolution stabilization.  Serious AEs were monitored and reported from the time the patient provided an informed consent as described in protocol Section 8 of Appendix A1. ' All patients were followed for survival at least every 3 months after discontinuing study treatment until at least 3 years after randomization of the last patient. " FKSI and EQ-5D (patient-reported outcomes) questionnaires were administered on C1, D1 before dosing and before any other clinical assessments, and then every 4 weeks while on-study, at end of study treatment/withdrawal, and at Follow-Up (28 days after last dose). Protocol A4061032 – Final 2 – 25 April 2017
* Cycle length was 4 weeks. *** If, for some reason, the sample was not collected at C1, D1, it could have been collected at any time during the study. Abbreviations:  C = Cycle, D = Day, ECG = electrocardiogram, Wks = weeks Public Disclosure Synopsis
Number of Patients (Planned and Analyzed):
Six-hundred and fifty patients were planned to be randomized 1:1 ratio to receive either Axitinib or Sorafenib.  A total of 723 patients were randomized in the study between 15 September 2008 and 23 July 2010; 361 patients were randomized to Axitinib, of whom 359 patients received treatment, and 362 patients were randomized to Sorafenib, of whom 355 patients received treatment.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Inclusion Criteria: . Histologically or cytologically confirmed mRCC with a component of clear cell subtype . Evidence of unidimensionally measurable disease with conventional computed tomography (CT) scan or magnetic resonance imaging (MRI) scan . Must have failed one prior systemic first-line regimen for mRCC Exclusion Criteria: . Prior treatment for mRCC with more than one systemic first-line therapy . Major surgery less than 4 weeks or radiation less than 2 weeks of starting study drug
Study Treatment:
In this study, patients were randomized at a ratio of 1:1 to receive either Axitinib or Sorafenib.  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.  The starting dose of Axitinib was 5 mg BID taken orally with food. Dose adjustments, including dose increase or dose reduction, were to be based on adverse events (AEs) experienced by the individual patient.  Axitinib was to be taken beginning on Day 1 of the study.  Doses were to be taken approximately 12 hours apart as continuous dosing.  Patients were instructed to take their doses at approximately the same times each day.  Study treatment was to be administered in cycles of 4 weeks in duration.  The starting dose of Sorafenib was 400 mg (2 × 200 mg tablets) BID taken orally without food (at least 1 hour before or 2 hours after eating).  Doses were taken as close to 12 hours apart as possible and at approximately the same times each day. Efficacy Endpoints: Primary Endpoint: Progression-Free Survival (PFS) Secondary Endpoints: Overall Survival (OS) Objective Response Rate (ORR) Duration of Response (DR) Type, incidence, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 3.0), timing, seriousness, and relatedness of AEs, and laboratory abnormalities. Patient Reported Outcomes: Functional Assessment of Cancer Therapy Kidney Symptom Index-15 (FKSI-15) and Euro Quality of Life Questionnaire- 5 Dimension (EQ-5D).
Safety Evaluations:
AEs, clinical laboratory measurements, electrocardiogram (ECG), and vital signs measurements were assessed throughout the study.
Statistical Methods:
Analysis populations used for the study were as follows: 1. The Full Analysis set (FAS) included all patients who were randomized, with study drug assignment designated according to initial randomization, regardless of whether patients received study drug or received a different drug from that to which they were randomized.  The FAS was the primary population for evaluating all efficacy endpoints, as well as patient characteristics. 2. The safety analysis (SA) set consisted of all patients who received at least 1 dose of study medication, with treatment assignments designated according to actual study treatment received.  This SA set was the primary population for evaluating treatment administration/compliance and safety. Efficacy and clinical benefit endpoints may have been evaluated in this population as well. PFS, based on Independent Review Committee (IRC) assessment, was the primary efficacy endpoint.  PFS was summarized for the FAS (i.e., all patients who were randomized) using Kaplan-Meier methods and displayed graphically, where appropriate.  The median event time for each treatment arm and corresponding 2-sided 95% confidence interval (CI) for the median were provided for PFS.  The hazard ratio and its 95% CI were estimated.  A stratified (i.e., ECOG PS and prior therapy) log-rank test (1-sided, α=0.025) was used to compare PFS between the 2 treatment arms. An unstratified log-rank test (1-sided, α=0.025) and Cox regression model were also used as secondary analyses for PFS.  Cox regression models were used to explore the potential influences of the stratification factors on the primary PFS endpoint.  In addition, the potential influences of baseline patient characteristics (e.g., age, ethnic origin, sex, geographic region, Memorial Sloan-Kettering Cancer Center [MSKCC] risk group) on the primary PFS endpoint were evaluated.  For each treatment arm, the median PFS and a 2-sided 95% CI were provided for each level of the stratification variables. MSKCC risk groups were derived using the following 4 risk factors: high lactate dehydrogenase (>1.5 × upper limit of normal [ULN]), low serum hemoglobin (less than the lower limit of normal [LLN]), high corrected serum calcium (>10 mg/dL), and absence of prior nephrectomy.  Risk groups were defined as favorable (0 factors), intermediate (1 or 2 factors), or poor (≥3 factors). Protocol A4061032 – Final 2 – 25 April 2017 FKSI-15 was the sum of the scores from the 15 FKSI questions.  FKSI-15 was summarized using means (with standard deviations) and medians at each assessment point, based on the observed values as well as changes from baseline both within group and between groups (with 95% CIs for mean changes).  Comparisons of the 2 treatments were based on a repeated measures analysis using a mixed effects model.  The variables in the model were treatment, time, and treatment-by-time, with baseline as a covariate and time assumed linear. FKSI-DRS was measured as the sum of the scores from the 9 FKSI-DRS questions.  Analysis of FKSI-DRS, EQ-5D index, and EQ-VAS followed the same methodology as FKSI-15. Genotype variables were treated as categorical variables.  For the TA repeat polymorphism in the UGT1A1 promoter only within each of the 3 possible genotype subsets for the most common variants , median event time and a 2-sided 95% CI were provided for the following efficacy endpoints: PFS, OS, and best overall tumor response.  Kaplan-Meier method was used to display the data graphically for PFS and OS. Descriptive statistics were provided for each hematology, biochemistry, and urinalysis test result and for change from baseline by visit. Triplicate, 12-lead ECGs were planned to be performed at screening and at Cycle 1, Day 15 for the first 50 patients randomized to Axitinib only.  At each time point, triplicate data were averaged and all summary statistics and data presentations used the triplicate averaged data. 3bdbc6a1\Approved\Approved On: 04-May-2017 09
RESULTS
Patient Disposition:
Overall summary of patient disposition by treatment is presented in Table 2.  A total of 116 patients (32.1%) in the Axitinib arm and 77 patients (21.3%) in the Sorafenib arm had started at least 15 cycles of treatment.  The most common reason for discontinuation from treatment in both treatment arms was objective progression or relapse (265 patients [73.4%] and 246 patients [68.0%] in the Axitinib and Sorafenib arms, respectively).  Cumulatively, the most common reason for discontinuation from the study start in both treatment arms was death (280 patients [78.0%] in the Axitinib arm and 276 patients [77.7%] in the Sorafenib arm).
a Full Analysis Set includes all patients who were randomized, with study treatment assignment designated according to initial randomization, regardless of whether patients received study treatment or received a different drug from that to which they were randomized. b Safety Analysis Set consists of all patients who received at least 1 dose of study drug with treatment assignments designated according to actual study treatment received. c A patient was considered to have started a cycle if the patient took at least 1 dose of Axitinib or Sorafenib Protocol A4061032 – Final 2 – 25 April 2017 Public Disclosure Synopsis
Abbreviations: N = number of patients; n = number of patients meeting specified criteria a Full Analysis Set includes all patients who were randomized, with study treatment assignment designated according to initial randomization, regardless of whether patients received study treatment or received a different drug from that to which they were randomized. b Safety Analysis Set consists of all patients who received at least 1 dose of study drug with treatment assignments designated according to actual study treatment received. c A patient was considered to have started a cycle if the patient took at least 1 dose of Axitinib or Sorafenib.
Patient Demography:
The data cutoff date for Demographic and baseline characteristics was 31 Aug 2010. Demographic and baseline characteristics are summarized in Table 3.  The demographic and baseline characteristics were similar between the treatment arms.  The majority of patients in each treatment arm were <65 years of age (238 [65.9%] patients in the Axitinib arm; 238 [65.7%] patients in the Sorafenib arm), male (265 [73.4%] patients in the Axitinib arm; 258 [71.3%] patients in the Sorafenib arm), and white (278 [77.0%] patients in the Axitinib arm; 269 [74.3%] patients in the Sorafenib arm).  Approximately half of the patients in each treatment arm had an ECOG PS score of 0 (195 [54.0%] patients in the Axitinib arm; 200 [55.2%] patients in the Sorafenib arm) and were in the intermediate MSKCC risk group (199 [55.1%] patients in the Axitinib arm; 210 (58.0%] patients in the Sorafenib arm). e18bdbc6a1\Approved\Approved On: 04-May-2017 09
7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:36 European Union: Austria, Germany, France, Great Britain, Greece, Ireland, Italy, Poland, Russia, Slovakia, Spain, and Sweden; North America: Canada and United States; and Other: Australia and Brazil. Abbreviations:  ECOG = Eastern Cooperative Oncology Group, MSKCC = Memorial Sloan-Kettering Cancer Center, N = number of patients, n = number of patients meeting specified criteria, SD = standard deviation a ECOG Performance Status was taken from case report forms and was the last measure obtained before dosing. b MSKCC Risk Categorization Based on Criteria for Previously Treated Patients With RCC Using ECOG Performance Status of 1 as a Risk Factor. Using MSKCC risk factors for previously treated patients (hemoglobin, corrected calcium, and ECOG status). ECOG status 0 vs 1. ECOG performance status taken from case report forms and was the last measure taken prior to dosing. ° These patients were missing data on some or all of the risk factors (hemoglobin, corrected calcium, and ECOG status) that were used to derive the MSKCC risk groups. Primary endpoint Results: Progression-Free Survival (PFS) The data cutoff date for PFS was 31 Aug 2010.  Table 4 presents a summary of PFS by treatment (stratified analysis) based on IRC assessment for the FAS. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:36 (C
Presentation of PFS for subgroups based on prior bevacizumab and temsirolimus regimens were not included in this document based on the low number of patients with these prior regimens (59 and 24 patients, respectively), and which resulted in wide confidence intervals.  Data cutoff date:  31  Aug 2010. Abbreviations:  CI = confidence interval, ECOG = Eastern Cooperative Oncology Group, IRC = Independent Review Committee, N = number of patients, n = number of patients meeting prespecified criteria, NE = not evaluable, PFS = progression-free survival ² On-study included treatment plus 28-day follow-up period. b The denominator for type of event (Objective progression and Death without objective progression) was based on the number of patients observed to have progressed or died due to any cause while on-study. c The denominator for reason of objective progression was based on the number of patients with Objective progression d The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. c Based on the Brookmeyer and Crowley method. f Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Sorafenib.  Hazard ratio was adjusted for same stratification factors as log-rank test. § For overall stratified analysis, p-value was from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.  For the population with prior sunitinib-containing regimen or cytokine-containing regimen, the p-value was from a 1-sided log-rank test stratified by ECOG performance status. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:30
7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:3 Presentation of PFS for subgroups based on prior bevacizumab and temsirolimus regimens were not included in this document based on the low number of patients with these prior regimens (59 and 24 patients, respectively), and which resulted in wide confidence intervals.  Data cutoff date:  31  Aug 2010. Abbreviations:  CI = confidence interval, ECOG = Eastern Cooperative Oncology Group, IRC = Independent Review Committee, N = number of patients, n = number of patients meeting prespecified criteria, NE = not evaluable, PD = progressive disease, PFS = progression-free survival a On-study included treatment plus 28-day follow-up period. b The denominator for type of event (Objective progression and Death without objective progression) was based on the number of patients observed to have progressed or died due to any cause while on-study. c The denominator for reason of objective progression was based on the number of patients with Objective progression d The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. c Based on the Brookmeyer and Crowley method. f Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Sorafenib.  Hazard ratio was adjusted for same stratification factors as log-rank test. § For overall stratified analysis, p-value was from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.  For the population with prior sunitinib-containing regimen or cytokine-containing regimen, the p-value was from a 1-sided log-rank test stratified by ECOG performance status.
Presentation of PFS for subgroups based on prior bevacizumab and temsirolimus regimens were not included in this document based on the low number of patients with these prior regimens (59 and 24 patients, respectively), and which resulted in wide confidence intervals.  Data cutoff date:  31  Aug 2010. Abbreviations:   CI = confidence interval, ECOG = Eastern Cooperative Oncology Group, IRC = Independent Review Committee, N = number of patients, n = number of patients meeting prespecified criteria, NE = not evaluable, PD = progressive disease, PFS = progression-free survival a On-study included treatment plus 28-day follow-up period. b The denominator for type of event (Objective progression and Death without objective progression) was based on the number of patients observed to have progressed or died due to any cause while on-study. c The denominator for reason of objective progression was based on the number of patients with Objective progression d The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. c Based on the Brookmeyer and Crowley method. f Assuming proportional hazards, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Sorafenib.  Hazard ratio was adjusted for same stratification factors as log-rank test. 8 For overall stratified analysis, p-value was from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.  For the population with prior sunitinib-containing regimen or cytokine-containing regimen, the p-value was from a 1-sided log-rank test stratified by ECOG performance status. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:3 Protocol A4061032 – Final 2 – 25 April 2017
Secondary Endpoints Results:
Overall Survival (OS)
The data cutoff date for the final OS analysis was 01 Nov 2011.  Following the final PFS analysis, patients remained in the treatment arms to which they had been randomized and were followed for evaluation of safety and efficacy, including OS.  As of the 01 Nov 2011 cutoff date for the final OS analysis, there were 211 deaths (58.4%) in the Axitinib arm and 214 deaths (59.1%) in the Sorafenib arm.  The final OS results for the overall study population were largely consistent with the interim results.  Based on the final analysis, there was no significant difference in final OS between Axitinib and the active comparator, Sorafenib.  A summary of OS by treatment (stratified analysis) for the FAS is presented in Table 5. 8bdbc6a1\Approved\Approved On: 04-May-2017 09:36

Summary of Final Analysis of Overall Survival by Treatment and

a The denominator for cause of death was based on the number of patients who died. b Patients who were not known to be dead at the time the database was closed for analysis were censored on the date they were last known to be alive. c The denominator for reason of censorship was based on the number of patients censored. d Calculated from the log(-log[12-month survival probability]) using a normal approximation and back transformation. c Based on the Brookmeyer and Crowley method. f Assuming proportional hazards model, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Sorafenib.  Hazard ratio was adjusted for same stratification factors as log-rank test. § For overall stratified analysis, p-value was from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.  For the population with prior treatment, the p-value was from a 1-sided log-rank test stratified by ECOG performance status. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09: Protocol A4061032 – Final 2 – 25 April 2017
a The denominator for cause of death was based on the number of patients who died. b Patients who were not known to be dead at the time the database was closed for analysis were censored on the date they were last known to be alive. c The denominator for reason of censorship was based on the number of patients censored. d Calculated from the log(-log[12-month survival probability]) using a normal approximation and back transformation. c Based on the Brookmeyer and Crowley method. f Assuming proportional hazards model, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Sorafenib.  Hazard ratio was adjusted for same stratification factors as log-rank test. 8 For overall stratified analysis, p-value was from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.  For the population with prior treatment, the p-value was from a 1-sided log-rank test stratified by ECOG performance status. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09: Protocol A4061032 – Final 2 – 25 April 2017
a The denominator for cause of death was based on the number of patients who died. b Patients who were not known to be dead at the time the database was closed for analysis were censored on the date they were last known to be alive. c The denominator for reason of censorship was based on the number of patients censored. d Calculated from the log(-log[12-month survival probability]) using a normal approximation and back transformation. c Based on the Brookmeyer and Crowley method. f Assuming proportional hazards model, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Sorafenib.  Hazard ratio was adjusted for same stratification factors as log-rank test. § For overall stratified analysis, p-value was from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.  For the population with prior treatment, the p-value was from a 1-sided log-rank test stratified by ECOG performance status. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09: Protocol A4061032 – Final 2 – 25 April 2017
a The denominator for cause of death was based on the number of patients who died. b Patients who were not known to be dead at the time the database was closed for analysis were censored on the date they were last known to be alive. c The denominator for reason of censorship was based on the number of patients censored. d Calculated from the log(-log[12-month survival probability]) using a normal approximation and back transformation. c Based on the Brookmeyer and Crowley method. f Assuming proportional hazards model, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Sorafenib.  Hazard ratio was adjusted for same stratification factors as log-rank test. 8 For overall stratified analysis, p-value was from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.  For the population with prior treatment, the p-value was from a 1-sided log-rank test stratified by ECOG performance status. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:
a The denominator for cause of death was based on the number of patients who died. b Patients who were not known to be dead at the time the database was closed for analysis were censored on the date they were last known to be alive. c The denominator for reason of censorship was based on the number of patients censored. d Calculated from the log(-log[12-month survival probability]) using a normal approximation and back transformation. c Based on the Brookmeyer and Crowley method. f Assuming proportional hazards model, a hazard ratio <1 indicated a reduction in hazard rate in favor of Axitinib; a hazard ratio >1 indicated a reduction in favor of Sorafenib.  Hazard ratio was adjusted for same stratification factors as log-rank test. 8 For overall stratified analysis, p-value was from a 1-sided log-rank test of treatment stratified by ECOG performance status and prior treatment.  For the population with prior treatment, the p-value was from a 1-sided log-rank test stratified by ECOG performance status.
Objective Response Rate (ORR)
The data cutoff date for ORR was 31 Aug 2010.  A summary of the best overall response by treatment (stratified analysis) is presented in Table 6. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:
Abbreviations: CI = confidence interval, CR = complete response, ECOG = Eastern Cooperative Oncology Group, IRC = Independent Review Committee, N = number of patients, n = number of patients meeting prespecified criteria, PR = partial response a Using exact method based on F-distribution. b Risk ratio and CI based on the Mantel-Haenszel estimator, risk ratio is adjusted for same stratification factors as Cochran-Mantel-Haenszel test. c For the overall stratified analysis, the p-value was from a 1-sided Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status and prior treatment. d P-value is from a 1-sided Cochran-Mantel-Haenszel test stratified by ECOG performance status. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:3 Public Disclosure Synopsis
Abbreviations: CI = confidence interval, CR = complete response, ECOG = Eastern Cooperative Oncology Group, IRC = Independent Review Committee, N = number of patients, n = number of patients meeting prespecified criteria, PR = partial response a Using exact method based on F-distribution. b Risk ratio and CI based on the Mantel-Haenszel estimator; risk ratio is adjusted for same stratification factors as Cochran-Mantel-Haenszel test. c For the overall stratified analysis, the p-value was from a 1-sided Cochran-Mantel-Haenszel test of treatment stratified by ECOG performance status and prior treatment. d P-value is from a 1-sided Cochran-Mantel-Haenszel test stratified by ECOG performance status.
Duration of Response (DR)
The data cutoff date for the blinded IRC assessment of DR was 31 Aug 2010.  Table 7 presents a summary of the median DR among responders (Complete Responders or Partial Responders) by treatment based on IRC assessment for the FAS. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:

Summary of Duration of Tumor Response among Responders by

The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. Abbreviations:  CI = confidence interval, IRC = Independent Review Committee, N = number of patients, n = number of patients meeting specified criteria, NE = not estimable, PD = progressive disease ² On-study included treatment plus 28-day follow-up period. b The denominator for type of event (Objective progression and Death without objective progression) was based on the number of patients observed to have progressed or died due to any cause while on-study. c The denominator for reason of objective progression was based on the number of patients with Objective progression d The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. c Based on the Brookmeyer and Crowley method. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:3
The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. Abbreviations:  CI = confidence interval, IRC = Independent Review Committee, N = number of patients, n = number of patients meeting specified criteria, NE = not estimable, PD = progressive disease a On-study included treatment plus 28-day follow-up period. b The denominator for type of event (Objective progression and Death without objective progression) was based on the number of patients observed to have progressed or died due to any cause while on-study. ° The denominator for reason of objective progression was based on the number of patients with Objective progression d The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. c Based on the Brookmeyer and Crowley method. e18bdbc6a1\Approved\Approved On: 04-May-2017 09 Public Disclosure Synopsis
The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. Abbreviations:  CI = confidence interval, IRC = Independent Review Committee, N = number of patients, n = number of patients meeting specified criteria, NE = not estimable, PD = progressive disease ² On-study included treatment plus 28-day follow-up period. b The denominator for type of event (Objective progression and Death without objective progression) was based on the number of patients observed to have progressed or died due to any cause while on-study. c The denominator for reason of objective progression was based on the number of patients with Objective progression d The denominator for reason for censorship was based on the number of patients who did not progress or die due to any cause while on-study. c Based on the Brookmeyer and Crowley method.
Percentage of Participants with Treatment-Emergent Adverse Events (AEs) and
Serious Adverse Events (SAEs)
The safety results include the cumulative safety results for all patients until 25 Feb 2016. The Safety Analysis Set consisted of all patients who received at least 1 dose of study drug with treatment assignments designated according to actual study treatment received.  More than 95% of patients in either treatment arms experienced at least 1 all causality AE. Percentage of Participants with Treatment-Emergent AEs and SAEs is shown in Table 8. e18bdbc6a1\Approved\Approved On: 04-May-2017 09:
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; MedDRA = Medical Dictionary for Regulatory Activities; N = number of patients; n = number of patients meeting specified criteria. Includes data up to 28 days after last dose of study treatment. Except for the number of adverse events, patients are counted only once per treatment in each row. CTCAE Grade Version 3.0. MedDRA (v18.1) coding dictionary applied.
Percentage of Participants with Adverse Events (All Causality) by Severity
This includes the cumulative results for all patients until 25 Feb 2016.  Percentage of Participants with AEs by Severity is shown in Table 9.
CTCAE Grade Version 3.0 MedDRA (v18.1) coding dictionary applied.
Percentage of Participants with Treatment-Related Adverse Events and Serious
Adverse Events
This includes the cumulative results for all patients until 25 Feb 2016.  A summary of Treatment-Related Adverse Events and SAE is presented in Table 10. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:30 Protocol A4061032 – Final 2 – 25 April 2017
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Number of Participants with Clinically Significant Laboratory Abnormalities: Hematology
The data cutoff date for the clinically significant laboratory abnormalities in hematology was 31 Aug 2010.  Similar proportions of patients in the Axitinib and Sorafenib arms experienced Grade 3 or 4 hematology laboratory values; the exception to this was decreased hemoglobin, with a lower number of patients in the Axitinib arm compared with patients in the Sorafenib arm with Grade 3 values. Participants with Clinically Significant Laboratory Abnormalities: Hematology is shown in Table 11.
%= (n/N)*100, where N=number of patients with baseline measurement and at least 1 postbaseline value. Abbreviations:  CTCAE = Common Terminology for Adverse Events, N/n = number of patients a Does not include baseline. Protocol A4061032 – Final 2 – 25 April 2017 Number of Participants with Clinically Significant Laboratory Abnormalities: Biochemistry The data cutoff date for clinically significant laboratory abnormalities in biochemistry was 31 Aug 2010.  In general, similar proportions of patients in the Axitinib and Sorafenib arms experienced Grade 3 or 4 biochemistry laboratory values.  For lipase and hypophosphatemia, there were a lower number of patients in the Axitinib arm compared with patients in the Sorafenib arm with Grade 3 biochemistry results or Grade 4 biochemistry results. Participants with Clinically Significant Laboratory Abnormalities: Biochemistry is shown in Table 12. 18bdbc6a1\Approved\Approved On: 04-May-2017 09:36
CTCAE Grade Version 2 used for this analysis.  Data cutoff date:  31 Aug 2010.  Data source: central laboratory. %= (n/N)*100, where N=number of patients with baseline measurement and at least 1 postbaseline value. Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events, N/n = number of patients a Does not include baseline.
Number of Participants with Clinically Significant Laboratory Abnormalities: Urinalysis; Safety Analysis Set
The data cutoff date for Urinalysis was 31 Aug 2010.  Similar proportions of patients in the Axitinib arm and the Sorafenib arm had 3+ or 4+ protein in urine on-study.  A summary of urinalysis results by treatment is presented in Table 13.
each patient was counted once with maximum severity within each urinalysis test.  Data cutoff date: 31 Aug 2010. Abbreviations:  N = number of patients, n = number of patients meeting prespecified criteria, Note: 1+/2+/3+/4+ = indicates the amount of blood/hemoglobin, glucose and protein in urine. a Does not include baseline.
Patient Related Outcomes:
Functional Assessment of Cancer Therapy Kidney Symptom Index-15 (FKSI-15) Score
The data cutoff date for FKSI-15 score assessment was 31 Aug 2010.  At baseline, 312 (86.4%) of 361 patients in the Axitinib arm and 305 (85.9%) of 355 patients in the Sorafenib arm who were eligible completed all items of the FKSI-15. A repeated measures mixed-effects model showed the difference between the 2 treatment arms for FKSI-15 observed summary scores by treatment cycle, and are presented together with the medians, SDs, and 95% CIs in Table 14.  The sample sizes decreased over time.  At Cycle 13, 99 patients remained in the Axitinib arm compared with only 65 patients in the Sorafenib arm.  The mean FKSI-15 values were almost identical at baseline (43.199 and 43.339 for Axitinib and Sorafenib, respectively) and remained similar though the study; however, fewer patients remained in the Sorafenib arm over time.
Protocol A4061032 – Final 2 – 25 April 2017
questions were reverse coded as appropriate).  P-value was based on 2 sample t-test (2-sided p-values).  Data cutoff: 31 Aug 2010. Abbreviations:  CI = confidence interval, FKSI = Functional Assessment of Cancer Therapy Kidney Symptom Index, FKSI-1S = sum of the scores from the 1S FKSI questions, N = number of patients, n = number of patients meeting prespecified criteria, SD = standard deviation Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS) Score The data cutoff date for FKSI-DRS score assessment was 31 Aug 2010.  Baseline FKSI-DRS assessments were available for 716 patients (i.e., 361 patients in the Axitinib arm and 355 patients in the Sorafenib arm).  At baseline, 332 (92.0%) of 361 patients in the Axitinib arm and 327 (92.1%) of 355 patients in the Sorafenib arm completed all items of the FKSI-DRS. A repeated measures mixed-effects model was used to compare the differences in FKSI-DRS scores between the Axitinib and the Sorafenib arms (Table 15).  All results were similar to those obtained based on the full 15 items of FKSI-15 described previously.
Protocol A4061032 – Final 2 – 25 April 2017
questions were reverse coded as appropriate).  P-value was based on 2 sample t-test (2-sided p-values).  Data cutoff: 31 Aug 2010. Abbreviations:  CI = confidence interval, FKSI-DRS = Functional Assessment of Cancer Therapy Kidney Symptom Index -Disease Related Symptoms, N = number of patients, n = number of patients meeting pre specified criteria, SD = standard deviation:
Euro Quality of Life Questionnaire- 5 Dimension (EQ-5D): Health State Profile Utility Score
The data cutoff date for EQ-5D assessment was 31 Aug 2010.  A repeated measures mixed-effects model was used to compare the differences in EQ-5D scores between Axitinib and Sorafenib arms.  Table 16 presents the comparison in EQ-5D scores between the two arms.  The overall between-treatment comparison for Axitinib vs Sorafenib based on the repeated measures mixed effects model was not statistically significant.
Protocol A4061032 – Final 2 – 25 April 2017
Larger values are associated with better health states P-value is based on two sample t-test (2 sided P-values) Data cutoff date: 31 Aug 2010 Abbreviations:  CI = confidence interval, N = number of patients, n = number of patients meeting pre specified criteria, SD = standard deviation: Euro Quality of Life Questionnaire- 5 Dimension (EQ-5D): Visual Analog Scale (VAS); Full Analysis Set The data cutoff date for EQ-5D VAS assessment was 31 Aug 2010.  A repeated measures mixed effects model was used to compare differences between treatment arms, as reported in Table 17.
Protocol A4061032 – Final 2 – 25 April 2017
P-value is based on two sample t-test (2 sided P-values) Data cutoff date: 31 Aug 2010 Abbreviations:  CI = confidence interval, N = number of patients, n = number of patients meeting pre specified criteria, SD = standard deviation Public Disclosure Synopsis
Additional Safety Results:
SAEs: This includes the cumulative results for all patients until 25 Feb 2016.  All causality and treatment-related serious AEs are presented in Table 18.  General disorders and administration side conditions and gastrointestinal disorders were the most commonly reported SAEs among patients.
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AEs: This includes the cumulative results for all patients until 25 Feb 2016.  Gastrointestinal disorders and general disorders and administration site conditions were the most common treatment-emergent non-serious AEs occurring in ≥5% of patients.  All causality and treatment-related non-serious AEs are presented in Table 19.
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PERMANENT DISCONTINUATION DUE TO ADVERSE EVENTS: This includes the cumulative results for all patients until 25 Feb 2016.  Overall 17 (4.7%) patients in the Axitinib group and 28 (7.9%) patients in the Sorafenib group discontinued permanently from the study due to AEs related to study drug.  In addition, 6 (1.7%) and 5 (1.4%) patients from Axitinib and Sorafenib groups, respectively permanently discontinued from the study due to AEs that were judged as not related to study drug. DEATHS: This includes the cumulative results for all patients until 25 Feb 2016.  In the Axitinib arm, 280 (78.0%) patients died in total; 48 (13.4%) patients died on-study and 232 (64.6%) patients died during follow-up.  In the Sorafenib arm, 276 (77.7%) patients died in total; 32 (9.0%) patients died on-study and 244 (68.7%) patients died during follow-up.  A summary of deaths reported is presented in Table 20. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:36 Public Disclosure Synopsis
poss = possible. a On-study deaths are those that occurred after the first dose of study drug and within 28 days of the last dose of study drug. b Death data were collected from 2 sources, the AE CRF (Grade 5 AEs) and Notice of Death CRF.  Deaths reported in this table are based on dates reported in the Notice of Death CRF page. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:36

Protocol A4061032 – Final 2 – 25 April 2017

poss = possible. c Follow-up deaths are those that occurred more than 28 days after the last dose of study drug. 7e18bdbc6a1\Approved\Approved On: 04-May-2017 09:5
CONCLUSIONS
. This Phase 3 study met the primary endpoint, demonstrating statistically significant improvement in the PFS, as determined by the IRC.  The 33.5% reduction in the hazard of disease progression or death (HR = 0.665; p-value <0.0001) for the Axitinib arm vs the active comparator, Sorafenib, is clinically meaningful. . The efficacy results are robust, as indicated by the sensitivity analyses that confirmed the primary analysis of the PFS endpoint.  In addition, the secondary efficacy endpoint, ORR, also confirmed the superiority of Axitinib treatment over Sorafenib; another secondary endpoint, OS, was immature at the time of the final PFS analysis and the interim OS result will be updated at a later date. . . For the patients in the prior sunitinib stratum, there was a 25.9% reduction in the hazard of disease progression or death (HR = 0.741; p-value <0.0107) for the Axitinib arm vs the active comparator, Sorafenib. For the patients in the prior cytokine stratum, there was a 53.6% reduction in the hazard of disease progression or death (HR = 0.464; p-value <0.0001) for the Axitinib arm versus the active comparator, Sorafenib. . AEs were generally tolerable and clinically manageable.  There was an increased incidence of hypertension, nausea, dysphonia, and hypothyroidism for patients in the Axitinib arm compared with the Sorafenib arm, and an increased incidence of palmar plantar erythrodysesthesia syndrome, rash, and alopecia for patients in the Sorafenib arm compared with the Axitinib arm. . In general, the patient-reported outcome data suggest that Axitinib provides patients with a benefit in PFS, while generally enabling them to maintain their quality of life as compared with Sorafenib.  There was no difference in the overall FKSI-15 scores between the 2 treatment arms over time. . No new important safety signals were observed. 3bdbc6a1\Approved\Approved On: 04-May-2017 09:36