CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202324Orig1s000
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`MEDICAL REVIEW(S)
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`CLINICAL TEAM LEADER REVIEW OF NDA
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`NDA 202324
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`DRUG INLYTA® (axitinib) tablets for oral administration
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`APPLICANT Pfizer, Inc.
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`PROPOSED INDICATION INLYTA is indicated for the treatment of patients with
`advanced renal cell carcinoma (RCC).
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`REVIEW PRIORITY Standard
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`DATE RECEIVED April 14, 2011
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`DATE COMPLETED January 11, 2012
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`PDUFA DATE February 14, 2012
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`Reference ID: 3070090
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`Table of Contents
`PRODUCT INFORMATION............................................................................................. 4
`REGULATORY HISTORY ............................................................................................... 4
`CLINICAL TRIALS........................................................................................................... 6
`PIVOTAL RANDOMIZED PHASE 3 TRIAL .................................................................. 6
`Trial Design ................................................................................................................... 6
`Eligibility........................................................................................................................ 7
`Objectives....................................................................................................................... 7
`Treatment ...................................................................................................................... 8
`Demographics................................................................................................................ 9
`Efficacy......................................................................................................................... 12
`Progression-Free Survival...................................................................................... 12
`PFS in United States Subpopulation ..................................................................... 14
`Interim Overall Survival Analysis......................................................................... 15
`Final Overall Survival Analysis............................................................................. 16
`Objective Response ................................................................................................. 17
`Response Duration.................................................................................................. 18
`Safety............................................................................................................................ 19
`Exposure .................................................................................................................. 19
`Deaths....................................................................................................................... 20
`Discontinuations Due to Adverse Events .............................................................. 21
`Notable Adverse Events.......................................................................................... 23
`Safety Summary...................................................................................................... 27
`ONCOLOGY DRUGS ADVISORY COMMITTEE ....................................................... 27
`LABELING....................................................................................................................... 28
`CONCLUSION................................................................................................................. 28
`RECOMMENDATION .................................................................................................... 28
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`Table of Tables
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`Table 1 Approved Targeted Drugs for Advanced RRC...................................................... 5
`Table 2 Pivotal Phase 3 RC Study A4061032 and Supportive Phase 2 Studies A4061012,
`A4061035, and A4061023: Summary of Efficacy Results (Full Analysis Set) ................. 6
`Table 3 Demographic and Baseline Characteristics by Treatment; Full Analysis Set ...... 9
`Table 4 Summary of Disease Characteristics and Prior Treatment ................................. 10
`Table 5 Interim Overall Survival Analysis ....................................................................... 15
`Table 6 Final Overall Survival Analysis.......................................................................... 16
`Table 7 Best Overall Response by Treatment and Stratification...................................... 17
`Table 8 Exposure .............................................................................................................. 19
`Table 9 Summary of Axitinib Dose Escalations and Reductions..................................... 19
`Table 10 Summary of Deaths by Treatment: Safety Analysis Set................................... 20
`Table 11 Discontinuations Due to Adverse Events ......................................................... 21
`Table 12 Overall Summary of Treatment-Related Adverse Events by ........................... 23
`Table 13 Summary of Adverse Events by Treatment, MedDRA Preferred Term, and
`Maximum CTCAE Grade Experienced by ≥5% of Patients: Safety Analysis Set........... 23
`Table 14 Hypertension..................................................................................................... 24
`Table 15 Adverse Events Related to Hyperthyroidism and Hypothyroidism.................. 25
`Table 16 Bleeding Events ................................................................................................ 25
`Table 17 Arterial Thrombotic Events .............................................................................. 26
`Table 18 Venous Thrombotic Events .............................................................................. 26
`Table 19 Laboratory Adverse Events > 10% in Either Arm............................................ 27
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`Table of Figures
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`Figure 1: Structural Formula of Axitinib............................................................................ 4
`Figure 2 Progression-Free Survival ITT IRC Analysis .................................................. 12
`Figure 3 Kaplan-Meier Curve of Progression-Free Survival by Treatment and Prior
`Sunitinib-Containing Regimen; IRC Assessment............................................................. 13
`Figure 4 Kaplan-Meier Curve of Progression-Free Survival by Treatment and Prior
`Cytokine-Containing Regimen; IRC Assessment............................................................. 13
`Figure 5 PFS in United States Subpopulation.................................................................. 14
`Figure 6 Interim Overall Survival Analysis...................................................................... 15
`Figure 7 Final Overall Survival Analysis ........................................................................ 16
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`PRODUCT INFORMATION
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`Axitinib is chemically designated as N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-
`indazol- 400 6-ylsulfanyl]-benzamide. The molecular formula is C22H18N4OS, and the
`molecular weight is 386.47 Daltons. The structural formula is shown in Figure 1.
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`Figure 1: Structural Formula of Axitinib
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` applicant figure
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`REGULATORY HISTORY
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`Il-2 and INF alpha are approved for treatment of advanced renal cell cancer (RCC).
`More recently the 6 targeted drugs in Table 1 were approved. Table 1 shows for each
`targeted drug the patient population studied and the efficacy results. The only drug
`shown to improve overall survival is Temserolimus in poor risk treatment naïve patients.
`An SPA was granted in April 2008 with caveat that improvements in the primary
`endpoint of PFS must be both clinically and statistically significant.
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`Table 1 Approved Targeted Drugs for Advanced RRC
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`CLINICAL TRIALS
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`As shown in Table 2, the NDA is supported by a pivotal randomized Phase 3 trial and 3
`single arm Phase 2 trials.
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`Table 2 Pivotal Phase 3 RC Study A4061032 and Supportive Phase 2 Studies
`A4061012, A4061035, and A4061023: Summary of Efficacy Results (Full Analysis
`Set)
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`Abbreviations: CI=confidence interval; DR=duration of response; HR=hazard ratio; IRC=independent
`review committee; NA=not available/not applicable, N = number of subjects
`randomized in Study A4061032 or treated in all other studies, NE=not estimable; ORR=objective response
`rate; OS=overall survival; PFS=progression-free survival; RR=risk ratio
`Data cut-off as of date 31 August 2011 for A4061032 and as per cut-off date of CSR for A4061012,
`A4061023, and A4061035.
`*OS in Study A4061032 reflects immature results.
`a Hazard ratio used for PFS. HR <1 indicates a reduction in HR in favor of axitinib; HR >1 indicates a
`reduction in HR in favor of sorafenib. Risk ratio is used for ORR. RR >1
`indicated a higher likelihood of responding in the axitinib arm; RR <1 indicated a higher likelihood of
`responding in the sorafenib arm.
`b Analyzed as a post-hoc efficacy endpoint applicant table
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`PIVOTAL RANDOMIZED PHASE 3 TRIAL
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`Trial Design
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`Patients were randomized in a 1:1 ratio to axitinib at a starting dose of 5 mg BID
`administered orally with food, or sorafenib at a starting dose of 400 mg BID administered
`orally without food.
`Patients who tolerated axitinib (no related AEs above CTCAE Grade 2 for a consecutive
`2-week period) were recommended to have their dose increased by 1 dose level to a
`maximum of 10 mg BID (unless the patient’s BP was >150/90 mm Hg or the patient was
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`receiving antihypertensive medication). Axitinib could be decreased for toxicity to 3 mg
`BID and then 2 mg BID as necessary.
`The sorafenib dose could be reduced to 400 mg once daily (QD) to manage sorafenib-
`related adverse drug reactions and then to a single 400 mg dose every other day, if
`further reduction was required.
`Eligible subjects were stratified prior to randomization by baseline ECOG performance
`status (0 vs. 1) and prior systemic regimen: sunitinib-containing vs. bevacizumab-
`containing vs. temsirolimus containing vs. cytokine-containing.
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`Eligibility
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`Key eligibility criteria included histologically- or cytologically-confirmed diagnosis of
`RCC with a component of clear cell subtype, and with evidence of metastatic disease;
`one prior systemic first-line regimen for metastatic RCC; no evidence of uncontrolled
`hypertension; adequate organ function; an Eastern Cooperative Oncology Group (ECOG)
`performance status of 0 or 1; and a life expectancy of 12 weeks.
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`Objectives
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`The primary objective of this study was to compare the PFS of patients with mRCC
`receiving axitinib vs. sorafenib following failure of one prior systemic first-line regimen
`containing 1 or more of the following: sunitinib, bevacizumab + IFN, temsirolimus, or
`cytokine(s).
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`The secondary objectives were to
`(cid:31)Compare the OS of patients in each arm;
`(cid:31)Compare the ORR of patients in each arm;
`(cid:31)Evaluate the safety and tolerability of axitinib;
`(cid:31)Estimate the duration of response (DR) of patients in each arm.
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`Treatment
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`Treatment was administered continuously in 4-week cycles. In Arm A, the starting dose
`of axitinib was 5 mg twice daily (BID) administered orally with food.
` tablets of axitinib were used in the study. In Arm B, sorafenib was
`administered orally without food at a starting dose of 400 mg BID. In both arms, doses
`were to be taken as close to 12 hours apart as possible and at approximately the same
`times each day. Subjects who tolerated axitinib with no related adverse events above
`CTCAE Grade 2 for a consecutive 2 week period were recommended to have their dose
`increased by one dose level to 7 mg BID and subsequently to a maximum of 10 mg BID
`(unless the subject’s blood pressure [BP] was >150/90 mm Hg or the subject was
`receiving antihypertensive medication). The clinical judgments of the treating physician
`were to be exercised when titrating the axitinib dose.
`Except for hypertension and proteinuria, a dose reduction to one lower dose level to 3 mg
`BID and subsequently to a minimum of 2 mg BID was recommended in subjects
`experiencing axitinib-related Grade 3 non-hematologic toxicity.
`For treatment related Grade 4 non-hematologic or hematologic toxicity, the axitinib dose
`was interrupted and restarted at one lower dose level as soon as improvement to CTCAE
`Grade 2 or less occurred. Dose reductions below 2 mg BID were not to be implemented
`prior to discussion with the Sponsor. In Arm B, when dose reduction was necessary to
`manage sorafenib-related adverse drug reactions, the sorafenib dose was reduced to 400
`mg once daily (QD). If additional dose reduction was required, sorafenib was reduced to
`a single 400 mg dose every other day.
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`Demographics
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`Treatment groups are reasonably balanced for demographic and disease characteristics as
`shown in Tables 3 and 4.
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`Table 3 Demographic and Baseline Characteristics by Treatment; Full Analysis Set
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` applicant table
`Countries included in each geographic region are as follows: Asia: China, India, Japan, Korea, Singapore, and Taiwan;
`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, kg = kilogram, mg = milligram, 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 groups were derived using the following 4 risk factors: high lactate dehydrogenase (>1.5 × upper limit
`of normal), low serum hemoglobin (less than the lower limit of normal), high corrected serum calcium (>10 mg/dL),
`and absence of prior nephrectomy.
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`Table 4 Summary of Disease Characteristics and Prior Treatment
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` Abbreviations: CT = computed tomography, N = number of patients, n = number of patients meeting specified
` criteria, SD = standard deviation
` a Protocol Amendment 3 (dated 10 February 2009) removed the requirement for documentation of progressive
` disease with prestudy scans
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`Efficacy
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`Progression-Free Survival
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`The primary efficacy endpoint is PFS as determined by an independent radiology review
`committee (IRC).
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`Figure 2 Progression-Free Survival ITT IRC Analysis
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` applicant figure
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`As shown in Figure 2, the ITT IRC PFS analysis demonstrates an axitinib advantage with
`HR=0.655 (95% CI=0.544—0.812), stratified Log Rank p<0.0001, axitinib median PFS
`6.7 months and sorafenib median PFS 4.7 months.
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`As shown in Figure 3 and Figure 4, most of the PFS benefit comes from the subgroup
`with prior cytokine treatment. PFS benefit is much less in the subgroup with prior
`sunitinib treatment. Most patients in the United States will have had prior sunitinib
`treatment.
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`On the other hand, as shown in Figure 5, an unplanned subgroup PFS analysis in the U.S
`population shows an axitinib benefit with stratified HR =0.613 (95% CI 0.401-0.938),
`p=0.0115 Log Rank, one-sided, axitinib median PFS 6.7 months and sorafenib median
`PFS 3.5 months.
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`Figure 3 Kaplan-Meier Curve of Progression-Free Survival by Treatment and
`Prior Sunitinib-Containing Regimen; IRC Assessment
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`Figure 4 Kaplan-Meier Curve of Progression-Free Survival by Treatment and
`Prior Cytokine-Containing Regimen; IRC Assessment
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`PFS in United States Subpopulation
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`Figure 5 PFS in United States Subpopulation
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`Interim Overall Survival Analysis
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`As shown in Table 5 and Figure 6, there was no axitinib effect on interim overall
`survival. There was no crossover to the other treatment after progression.
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`Table 5 Interim Overall Survival Analysis
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`-
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`I
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`o
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`lé/Iedlan OS in months (95 A)
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`Hazard Ratlo 95%C
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`Axitinib
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`N=361
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`113 31-2
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`NR (159’ NR)
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`Sorafenib
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`N=362
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`110 30.4
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`189 (13, NR)
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`1.009 0.77-1.31
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`0-53
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`Figure 6 Interim Overall Survival Analysis
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`—Axitinib
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`—Sorafenib
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`withoutOSevent
`Proportion
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`"0
`Overall Survival (Months)-
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`Final Overall Survival Analysis
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`As shown in Table 6 and Figure 7, there was no axitinib effect on final overall survival.
`There was no crossover to the other treatment after progression
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`Table 6 Final Overall Survival Analysis
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`Sorafenib
`Axitinib
`N=362
`N=361
`213 (358.8)
`210 (58.2)
`19.4 (17.5, 21.6)
`20.1 (16.7, 23.4)
`0.97 (0.8-1.17)
`0.37
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`Figure 7 Final Overall Survival Analysis
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` Axitinib
` Sorafenib
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`10
`15
`20
`25
`Overall Survival (Months)
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`30
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`35
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`Deaths (%)
`Median OS in months (95% CI)
`Hazard Ratio (95% CI)
`P-value
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`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
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`Proportion without OS event
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`Objective Response
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`Table 7 Best Overall Response by Treatment and Stratification
`Factor; Stratified Analysis; IRC Assessment
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` applicant table
`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.
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`Response Duration
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`Based on blinded IRC assessment, the median DR in the axitinib arm was 11 months
`(95% CI [7.4, not estimatable]) compared with 10.6 months in the sorafenib arm
`(95% CI [8.8, 11.5]). Based on blinded IRC assessment, the median DR in the prior
`sunitinib-containing regimen in the axitinib arm was 11.0 months (95% CI [5.2, not
`estimatable]) compared with 11.1 months in the sorafenib arm (95% CI [not estimatable,
`not estimatable]). Based on blinded IRC assessment, the median DR in the prior
`cytokine-containing regimen in the axitinib arm was 11.0 months (95% CI [7.4, not
`estimatable]) compared with 10.6 months in the sorafenib arm (95% CI [5.9, 11.5]).
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`Safety
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`Exposure
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`As shown in Table 8, the median number of days on treatment was axitinib 196 and
`sorafenib 152. The median relative dose intensity was axitinib 98.6% and sorafenib
`91.7%. There was dose reduction in 30.6% of axitinib patients and 52.1% of sorafenib
`patients. There was dose interruption in 76.9% of axitinib patients and 80.3% of
`sorafenib patients.
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`Table 8 Exposure
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`Number of Days on Treatment
` Median
`Total Cumulative Dose
` Median
`Number of patients with dose escalation (%)
`Dose Per Day
` Median
`Relative Dose Intensity (%)
` Median
`Number of patients with dose reduction (%)
`Number of patients with dose interruption (%)
`Reason
` AE
` Other
`from medical officer review
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`Axitinib
`N = 359
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`196
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`1896 mg
`132 (36.8)
`Planned: 10 mg
`9.9 mg
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`98.6
`110 (30.6%)
`276 (76.9%)
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`194 (54%)
`202 (56.3)
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`Sorafenib
`N = 355
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`152
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`89600 mg
`NA
`Planned: 800 mg
`773.9 mg
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`91.7
`185 (52.1%)
`285 (80.3%)
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`224 (63.1%)
`183 (51.5%)
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`Table 9 Summary of Axitinib Dose Escalations and Reductions
`Axitinib
`N=359
`n (%)
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`Axitinib dose levels
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`Total daily dose
` < 6 mg
` 6-8 mg
` 10 mg
` 12-14 mg
` 20 mg
`Number of patients escalated and then reduced
` modified from medical officer review
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` 30 (8.4)
` 58 (16.2)
` 139 (38.7)
` 60 (16.7)
` 71 (19.8)
` 71 (19.8)
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`Deaths
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`Table 10 shows a summary of deaths by treatment. Deaths while on study drug or within
`28 days of study drug discontinuation were 9.7% for axitinib and 6.5% for sorafenib.
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`Table 10 Summary of Deaths by Treatment: Safety Analysis Set
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`Discontinuations Due to Adverse Events
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`Table 11 shows the discontinuations due to adverse events by treatment group. Axitinib
`had 9.7% of patients discontinued due to adverse events and sorafenib had 13%.
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`Any Adverse Event
`Disease progression
`Fatigue
`Transient ischemic attack
`Asthenia
`Pleural effusion
`Decreased appetite
`Palmar-plantar erythrodysaesthesia syndrome
`Dyspnea
`Anemia
`Vomiting
`Retinal vein thrombosis
`Ascites
`Blood creatinine increased
`Hypoglycemia
`Altered state of consciousness
`Cerebral hemorrhage
`Dyspnea exertional
`Pneumothorax
`Hypertension
`Diarrhea
`Nausea
`Erythema multiforme
`Rash
`Angina pectoris
`Myocardial infarction
`Duodenal ulcer hemorrhage
`Enterocolitis
`Gastrointestinal hemorrhage
`Periodontitis
`Upper gastrointestinal hemorrhage
`Cholangitis
`Hepatic function abnormal
`Sepsis
`Fall
`Blood bilirubin increased
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`Table 11 Discontinuations Due to Adverse Events
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`Axitinib
`N=359
`35 (9.7%)
`11
`4
`3
`2
`2
`2
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`Sorafenib
`N=355
`46 (13%)
`4
`1
`0
`3
`1
`0
`4
`2
`1
`1
`0
`0
`0
`0
`0
`0
`0
`0
`0
`3
`2
`2
`2
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
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`Weight decreased
`Renal cell carcinoma
`Hemiparesis
`Hyperaesthesia
`Ischemic stroke
`Renal failure acute
`Pruritus
`Pruritus generalized
`Rash generalized
`Hemorrhage
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`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`from medical officer review
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`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
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`Table 12 Overall Summary of Treatment-Related Adverse Events by
`Treatment: Safety Analysis Set
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` Abbreviations: AE = adverse event, CTCAE = Common Terminology Criteria for Adverse Events,
` MedDRA = Medical Dictionary for Regulatory Activities, n = number of patients fitting specified
` criteria, No. = number
` a MedDRA (version 13.1) coding dictionary applied.
` b CTCAE Grade Version 3.0. applicant table
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`Table 13 Summary of Adverse Events by Treatment, MedDRA Preferred Term, and
`Maximum CTCAE Grade Experienced by ≥5% of Patients: Safety Analysis Set
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` 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 fitting specified criteria
`a MedDRA (version 13.1) coding dictionary applied.
`b CTCAE Grade Version 3.0.
`c Total of all CTCAE Grade events.
`modified applicant table
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`Notable Adverse Events
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`Hypertension
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`Table 14 Hypertension
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`Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, N = number of patients, n =
`number of patients meeting prespecified criteria, No. = number
`a MedDRA (version 13.1) coding dictionary applied. applicant table.
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`Thyroid Events
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`In the axitinib arm 95 (26.5%) patients and in the sorafenib arm 48 (13.5%) patients
`started or increased their dose of existing thyroid medications after the first dose of study
`drug.
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`Table 15 Adverse Events Related to Hyperthyroidism and Hypothyroidism
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`Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, N = number of patients, n = number of
`patients meeting prespecified criteria, No. = number, SOC = system organ class
`a MedDRA (version 13.1) coding dictionary applied. applicant table
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`Bleeding Events
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`Table 16 Bleeding Events
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`Gastrointestinal Tract Hemorrhages
` Anal
` Duodenal Ulcer
` Gastric
` Gastrointestinal
` Hemorrhoidal
` Lower gastrointestinal
` Rectal
` Retroperitoneal
` Tongue
` Upper gastrointestinal
`Epistaxis
`Hematuria
`Hemoptysis
`Cerebral Hemorrhage
`Urinary Tract Hemorrhage
`Urethral Hemorrhage
`Gingival Bleeding
`Pharyngeal Hemorrhage
`
`Sorafenib
`Axitinib
`N=355
`N=359
`All Grades
`Gr 3-5 (%) All Grades
`Gr 3-5 (%)
`(%)
`(%)
`16 (4.5)
`2 (<1)
`12 (3.4)
`7 (2)
`1
`0
`0
`0
`0
`0
`1
`1
`1
`1
`0
`0
`1
`0
`3
`3
`3
`0
`0
`0
`1
`1
`1
`1
`8
`0
`5
`0
`0
`0
`1
`1
`1
`0
`0
`0
`0
`0
`1
`1
`22 (6.1)
`0
`15 (4.2)
`0
`12 (3.3)
`1 (<1)
`7 (2)
`0
`9 (2.5)
`1 (<1)
`16 (4.5)
`2 (<1)
`1 (<1)
`1 (<1)
`0
`0
`1 (<1)
`0
`2 (<1)
`0
`0
`0
`1 (<1)
`0
`4 (1.1)
`0
`8 (2.3)
`0
`1 (<1)
`0
`0
`0
`
`
`
`Reference ID: 3070090
`
`25
`
`

`

`Pulmonary Hemorrhage
`Respiratory Tract Hemorrhage
`Hemorrhage
`Hematoma
`Periorbital Hematoma
`from medical officer review
`
`Arterial Thrombotic Events
`
`
`
`
`
`Myocardial infarction
`Retinal artery occlusion
`Cerebral ischemia
`Ischemic stroke
`Transient ischemic attack
`from medical officer review
`
`0
`0
`0
`0
`0
`
`0
`0
`4 (1.1)
`0
`0
`
`
`
`
`2 (<1)
`2 (<1)
`4 (1.1)
`1 (<1)
`2 (<1)
`
`1 (<1)
`0
`1 (<1)
`0
`0
`
`Sorafenib
`N=355
`Gr 1-4 (%)
`Gr 3-4 (%)
`2 (<1)
`1 (<1)
`0
`0
`1 (<1)
`1 (<1)
`1 (<1)
`1 (<1)
`0
`0
`
`Table 17 Arterial Thrombotic Events
`
`Axitinib
`N=359
`Gr 1-4 (%)
`Gr 3-4 (%)
`0
`0
`1 (<1)
`1 (<1)
`0
`0
`0
`0
`3 (<1)
`3 (<1)
`
`
`
`Table 18 Venous Thrombotic Events
`
`Venous Thrombotic Events
`
`
`
`
`
`
`
`Retinal vein occlusion
`Retinal vein thrombosis
`Pulmonary embolism
`Deep vein thrombosis
`Jugular vein thrombosis
`Subclavian vein thrombosis
`Thrombosis
`Venous thrombosis
`from medical officer review
`
`
`Axitinib
`N=359
`All Gr (%)
`Gr 3-5 (%)
`1 (<1)
`1 (<1)
`1 (<1)
`1 (<1)
`7 (1.9)
`7 (1.9)
`2 (<1)
`2 (<1)
`1 (<1)
`0
`1 (<1)
`0
`1 (<1)
`0
`1 (<1)
`0
`
`Sorafenib
`N=355
`All Gr (%)
`Gr 3-5 (%)
`0
`0
`0
`0
`2 (<1)
`2 (<1)
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`
`
`Reference ID: 3070090
`
`26
`
`

`

`Laboratory Adverse Events > 10% in Either Arm
`
`
`Table 19 Laboratory Adverse Events > 10% in Either Arm
`
`
`
`
`Sorafenib
`N=355
`Gr 1-4 (%)
`Gr 3-4 (%)
`68 (21.7)
`7 (2.2)
`107 (33.5)
`5 (1.6)
`77 (24.8)
`5 (1.6)
`142 (48.8)
`0
`130 (40.9)
`4 (1.3)
`72 (22.6)
`0
`72 (22.6)
`5 (1.6)
`46 (14.6)
`11 (3.5)
`41 (12.9)
`3 (<1)
`56 (17.6)
`2 (<1)
`146 (45.7)
`47 (14.7)
`104 (32.6)
`5 (1.6)
`29 (9.1)
`1 (<1)
`53 (14.9)
`14 (3.9)
`166 (46.8)
`55 (15.5)
`101 (28.4)
`10 (2.8)
`163 (51.6)
`12 (3.8)
`145 (40.8)
`21 (5.9)
`53 (14.9)
`1 (<1)
`55 (15.5)
`1 (<1)
`
`Axitinib
`N=359
`Gr 1-4 (%)
`Gr 3-4 (%)
`
`72 (21.8)
`2 (<1)
`ALT Increased
`100 (29.8)
`5 (1.5)
`ALP Increased
`67 (20.2)
`2 (<1)
`AST Increased
`156 (49.8)
`1 (<1)
`Bicarbonate decreased
`184 (54.8)
`0
`Creatinine Increased
`100 (29.8)
`1 (<1)
`Hypercalcemia
`93 (27.6)
`7 (2.1)
`Hyperglycemia
`60 (18)
`12 (3.6)
`Hyperkalemia
`58 (17.1)
`3 (<1)
`Hypernatremia
`50 (14.8)
`1 (<1)
`Hypoalbuminemia
`90 (26.6)
`16 (4.7)
`Lipase increased
`84 (24.9)
`6 (1.8)
`Amylase Increased
`39 (13.1)
`2 (<1)
`Hypoglycemia
`68 (18.9)
`17 (4.8)
`Hyponatremia
`51 (14.2)
`8 (2.2)
`Hypophosphatemia
`44 (12.2)
`7 (1.9)
`Hypocalcemia
`111 (34.7)
`2 (<1)
`Hemoglobin Decreased
`Lymphocytes Decreased 130 (36.2)
`18 (5)
`Platelets Decreased
`54 (15)
`1 (<1)
`White blood cells
`38 (10.6)
`0
`Decreased
`from medical officer review
`
`Safety Summary
`
`
`Hypertension, dysphonia, and hypothyroidism are more frequent for axitinib than
`sorafenib.
`
`Hand-foot syndrome, rash, and alopecia are more frequent for sorafenib
`than axitinib.
`
`
`ONCOLOGY DRUGS ADVISORY COMMITTEE
`
`This NDA was presented to and discussed by the FDA Oncology Drugs Advisory
`Committee on December 7, 2011. There was one question posed to the Committee as
`follows.
`
`
`
`
`Reference ID: 3070090
`
`27
`
`

`

`Is the benefit:risk evaluation favorable for axitinib treatment in patients with advanced
`RCC after failure of a first-line systemic therapy? [Voting Question] Yes, No, or Abstain
`
`The Committee vote was YES: 13, NO: 0, ABSTAIN: 0.
`
`
`LABELING
`
`See revised labeling by the FDA review team.
`
`
`CONCLUSION
`
`In a Phase 3 randomized controlled trial comparing axitinib with sorafinib in patients
`with progression after one prior treatment, axitinib was modestly superior to sorafinib for
`PFS with a HR=0.655 (95% CI=0.544—0.812), stratified Log Rank p<0.0001, axitinib
`median PFS 6.7 months and sorafenib median PFS 4.7 months. There was no survival
`effect. Patients were not crossed over to the other treatment after progression.
`
`If sorafenib has PFS benefit in this setting, it should be added to the axitinib PFS benefit.
`However, there is no prospective randomized trial showing whether sorafenib has PFS
`benefit in this setting and, if so, the amount of such benefit.
`
`Most of the axitinib PFS benefit is in the subgroup of patients with prior cytokine
`treatment. Most of the U.S. population will have had prior sutinitib. On the other hand,
`an unplanned subgroup analysis in the U.S. patients in the Phase 3 trial showed a PFS
`benefit similar to the study as a whole.
`
`The frequency and severity of adverse reactions was similar for axitinib and sorafenib.
`However, the adverse reaction profile was different. Hypertension, dysphonia, and
`hypothyroidism are more frequent for axitinib than sorafenib. Hand-foot syndrome, rash,
`and alopecia are more frequent for sorafenib than axitinib.
`
`The Applicant requested axitinib full approval “for the treatment of patients with
`advanced renal cell carcinoma (RCC)”. All patients in the randomized Phase 3 trial had
`one prior treatment for advanced renal cell carcinoma (RCC). FDA policy is that the
`indication is defined by the characteristics of the trial patients.
`
`RECOMMENDATION
`
`Axitinib should be approved for treatment of patients with advanced renal cell carcinoma
`(RCC) after failure of one first-line systemic therapy. Labeling should be revised as per
`the FDA review team. Standard post marketing safety monitoring is sufficient.
`
`
` John R. Johnson, M.D.
`
`
`
`Reference ID: 3070090
`
`28
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN R JOHNSON
`01/11/2012
`
`Reference ID: 3070090
`
`

`

`CLINICAL REVIEW
`
`Application Type NME
`Application Number(s) 202324
`Priority or Standard Standard
`
`Submit Date(s) 04/13/2011
`Received Date(s) 04/14/2011
`PDUFA Goal Date 02/14/2012
`Division / Office OHOP/DOP1
`
`Reviewer Name(s) Amy McKee, M.D.
`Review Completion Date 01/09/2012
`
`Established Name axitinib
`(Proposed) Trade Name Inlyta
`Therapeutic Class Tyrosine kinase inhibitor
`Applicant Pfizer, Inc.
`
`Formulation(s) oral
`Dosing Regimen 5 mg BID
`Indication(s) Second-Line Therapy for
`Metastatic Renal Cell Cancer
`
`
`
`
`Template Version: March 6, 2009
`
`Reference ID: 3069205
`
`

`

`Clinical Review
`Amy McKee, M.D.
`NDA 202324
`Inlyta® (axitinib)
`
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 8
`1.1 Recommendation on Regulatory Action ............................................................. 8
`1.2 Risk Benefit Assessment.................................................................................... 8
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 9
`INTRODUCTION AND REGULATORY BACKGROUND ......................