CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202324Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`January 25, 2012
`From
`John R. Johnson, MD.
`m_ Cross-Disci line Team Leader Review
`NDA/BLA #
`202324
`
`Su u vlement#
`
`advanced renal cell carcinoma (RCC).
`
`Date of Submission
`
`PDUFA Goal Date
`
`Auril 14, 2011
`
`Feb
`
`.
`
`14, 2012
`
`Proprietary Name /
`Established
`S 1
`
`names
`
`INLYTA (Axitinib)
`
`Dosa_e forms / Stren_ h
`
`Tablets 1 m and 5 m
`
`Proposed Indication(s)
`
`INLYTA is indicated for the treatment of patients with
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`Table of Contents
`
`Introduction..........................................................................................................................4
`1.
`2. Background..........................................................................................................................4
`3. CMC/Device ........................................................................................................................6
`4. Nonclinical Pharmacology/Toxicology ...............................................................................9
`5. Clinical Pharmacology/Biopharmaceutics.........................................................................11
`6. Clinical Microbiology........................................................................................................12
`7. Clinical/Statistical- Efficacy ..............................................................................................12
`Progression-Free Survival..................................................................................................13
`PFS in United States Subpopulation..................................................................................16
`Final Overall Survival Analysis.........................................................................................16
`Objective Response............................................................................................................17
`Response Duration.............................................................................................................19
`8. Safety .................................................................................................................................19
`Exposure ............................................................................................................................19
`Deaths ................................................................................................................................21
`Discontinuations Due to Adverse Events ..........................................................................22
`Notable Adverse Events.....................................................................................................24
`Safety Summary.................................................................................................................28
`9. Advisory Committee Meeting............................................................................................29
`10. Pediatrics ............................................................................................................................29
`11. Other Relevant Regulatory Issues......................................................................................29
` Submission Quality and Integrity ......................................................................................29
` Compliance with Good Clinical Practices .........................................................................29
` DSI Inspections at Clinical Sites...................................................................................31
` Financial Disclosures.........................................................................................................31
`12. Labeling .............................................................................................................................32
`13. Recommendations/Risk Benefit Assessment.....................................................................33
`
`Recommended Regulatory Action.................................................................................33
`
`Risk Benefit Assessment................................................................................................33
`
`Recommendation for Postmarketing Risk Evaluation and Management Strategies .....33
`
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`
`Table of Tables
`
`Table 1 Approved Targeted Drugs for Advanced RRC..............................................................5
`Table 2 Final Overall Survival Analysis...................................................................................16
`Table 3 Best Overall Response by Treatment and Stratification..............................................17
`Table 4 Exposure .......................................................................................................................19
`Table 5 Summary of Axitinib Dose Escalations and Reductions..............................................20
`Table 6 Summary of Deaths by Treatment: Safety Analysis Set..............................................21
`Table 7 Discontinuations Due to Adverse Events ....................................................................22
`Table 8 Overall Summary of Treatment-Related Adverse Events by ......................................24
`Table 9 Summary of Adverse Events by Treatment, MedDRA Preferred Term, and Maximum
`CTCAE Grade Experienced by ≥5% of Patients: Safety Analysis Set......................................24
`Table 10 Hypertension..............................................................................................................25
`Table 11 Adverse Events Related to Hyperthyroidism and Hypothyroidism...........................26
`Table 12 Bleeding Events .........................................................................................................26
`Table 13 Arterial Thrombotic Events .......................................................................................27
`Table 14 Venous Thrombotic Events .......................................................................................27
`Table 15 Laboratory Adverse Events > 10% in Either Arm.....................................................28
`
`
`Table of Figures
`
`Figure 1 Progression-Free Survival ITT IRC Analysis ...........................................................13
`Figure 2 Kaplan-Meier Curve of Progression-Free Survival by Treatment and Prior Sunitinib-
`Containing Regimen; IRC Assessment......................................................................................15
`Figure 3 Kaplan-Meier Curve of Progression-Free Survival by Treatment and Prior Cytokine-
`Containing Regimen; IRC Assessment......................................................................................15
`Figure 4 PFS in United States Subpopulation...........................................................................16
`Figure 5 Final Overall Survival Analysis .................................................................................16
`
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`1. Introduction
`
`
`
`
`Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth
`factor (VEGFR)-1, VEGFR-2, and VEGFR-3. The Applicant requests approval for the
`treatment of patients with advanced renal cell carcinoma (RCC) regardless of whether the
`patients have had prior chemotherapy. However, all of the patients in their only randomized
`trial have had prior chemotherapy. Other issues are that there is only one randomized trial, that
`the Axitinib effect on the primary endpoint, progression-free survival (PFS), is modest and that
`the modest PFS effect is not reflected by any favorable effect on overall survival. Axitinib
`toxicity is similar in severity to other approved drugs for this indication, but the toxicity profile
`is different. Another issue is that most of the Axitinib effect on PFS was in the prior cytokine
`subgroup. Most patients in the United States will have had prior sunitinib instead of prior
`cytokines.
`Provide an overview of the basic regulatory and scientific facts of the application and, in
`particular, an explanation of what issues this review will consider in greater detail.
`2. Background
`
`
`THE FOLLOWING IS EXCERPTED FROM THE MEDICAL OFFICER REVIEW
`
`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 for Axitinib
`for treatment of advanced RCC was granted in April 2008 with caveat that improvements in
`the primary endpoint of PFS must be both clinically and statistically significant.
`
`
`Renal cell carcinoma (RCC) is the seventh leading cancer type in men and the eighth leading
`cancer type in women, with an estimated total of 58,240 new cases and 13,040 deaths due to
`RCC in 2010.i Localized RCC can be treated with surgery with excellent long-term survival
`results. However, the prognosis for patients with locally advanced or metastatic disease
`remains poor, with median overall survival prior to the introduction of Surgery and traditional
`chemotherapy have not played a role in advanced or metastatic RCC, as their use has not been
`shown to affect survival in this population. Cytokines such as interferon-α (IFN-α) and
`interleukin-2 (IL-2) have response rates ranging from 7% to 23%,ii,iii and high-dose IL-2 has
`been shown to induce durable complete responses in approximately five percent of treated
`patients.iv However, the toxicity associated with both of these agents has diminished their use,
`especially with the newer agents that have been developed in the last decade.
`
`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
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`and VEGF antibody bevacizumab; and mammalian target of rapamycin (mTOR) inhibitors
`temsirolimus and everolimus (Table 1).
`
`
`Table 1 Approved Targeted Drugs for Advanced RRC
`
`
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`
`3. CMC/Device
`
`• Drug Substance
`
`In the CMC review by Jean Tang entered into DARRTS on 12/12/11 there were 8
`deficiencies. The following is excerpted from the CMC reviewed entered into
`DARRTS on 1/24/12.
`
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The application is recommended for APPROVAL with respect to CMC
`
`Include the following language in the action letter:
`Based on the provided stability data, an expiration dating period of 36 months is
`granted
`for the drug product when stored at 20-25°C (68-77°F); excursions permitted between
`15°C and 30°C (59°F and 86°F).
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`The method and method validation data used to detect
`level in Drug Substance will be provided post-approval.
`
` and
`
`
`
`• Drug Product
`
`In the CMC review by Amit Mitra entered into DARRTS on 12/12/11 there were 5
`deficiencies. The following is excerpted from the CMC reviewed entered into
`DARRTS on 1/24/12.
`
`Recommendations
`
`A. Recommendation and Conclusion on Approvability
`
`The application is recommended for approval with respect to CMC.
`Include the following language in the action letter:
`Based on the provided stability data, an expiration dating period of 36 months is
`granted for the drug product when stored at 20-25°C (68-77°F); excursions permitted
`between 15°C and 30°C (59°F and 86°F).
`
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`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`None
`
`
`
`• General Product Quality Considerations
`
`THE FOLLOWING IS EXCERPTED FROM THE CHEMISTRY REVIEW
`
`Overall Recommendation: The development and validation results for the analytical
`sections involved in this NDA are acceptable
`
` •
`
` Biopharmaceutics Review
`
`
`THE FOLLOWING IS EXCERPTED FROM THE BIOPHARMACEUTICS REVIEW
`
`
`1. Axitinib 1 mg and 5 mg tablets are recommended for approval from a
`Biopharmaceutics standpoint.
`• The following dissolution method and acceptance criterion for the 1 mg and
`5 mg strength tablets have been agreed upon with the Applicant on a
`teleconference dated December 5, 2011:
`i. Dissolution method: Apparatus II, 75 rpm agitation rate, 900 mL
`media volume, 37 °C, 0.01 N HCl (pH 2.2) medium.
`ii. Dissolution acceptance criterion: Q=
` at 30 minutes.
`
`2. The Applicant’s design space for axitinib tablets is questionable from a
`Biopharmaceutics standpoint since the submitted data provides insufficient
`evidence supporting consistent in vivo performance of drug product manufactured
`within the ranges of the proposed design space.
`• The FDA’s recommendation accepted by the Applicant on a teleconference
`dated December 5, 2011 to conduct f2 testing for any movements outside
`the NOR and within the proposed design space may alleviate this
`uncertainty provided an action is taken to ensure consistent quality
`throughout the drug product marketing phase for those instances were f2
`fails.
`
`3. The Applicant should maintain a maximum film coat percentage of
`.
`• At a teleconference on December 5, 2011, the Applicant stated that they
`will further review FDA’s recommendation. As of December 9, 2011, the
`Applicant has not provided agreement on this recommendation or proposed
`a maximum film coat percentage.
`
`
`
`• Biostatistics Review
`
`
`
`
`
`
`
`
`
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`Conclusions and Recommendation
`
`In conclusion, we made the following comments:
`
`THE FOLLOWING IS EXCERPTED FROM THE BIOSTATISTICS REVIEW
`
`
`
`I Analytical QbD
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`
`
`0 Facilities review/inspection
`
`Approved 12/4 11.
`
`0 Environmental Assessment 01' Claim Of Categorical Exclusion
`
`THE FOLLOWING IS EXCERPTED FROM THE CHEMISTRY REVIEW
`
`The applicant stated that EIC is below 1 ppb- and requested a
`categorical exclusion based according to 21CFR §25.31(b) without the EIC
`calculation. Therefore, the applicant was requested to provide calculation to
`show that the EIC is below 1 ppb to justify the EA waiver re uest. In an
`
`amendment, the provided the calculation for EICh
`
`which is below the less than 1 ppb required for granting the waiver. Therefore,
`no further information is necessary.
`
`4. Nonclinical Pharmacology/Toxicology
`
`THE FOLLOWING IS EXCERPTED FROM THE PHARMACOLOGY/TOXICOLOGY
`REVIEW
`
`Non-clinical pharmacology and toxicology studies to support axitinib NDA 202324
`for the treatment of renal cell carcinoma after failure of one prior systemic
`therapy were reviewed by Anwar Goheer, PhD, Alexander H. Putman, Ph.D.,
`and Robeena Aziz, MPH, Ph.D. Information included studies conducted with
`orally administered axitinib investigating the drug’s pharmacology, toxicokinetics
`and ADME, safety pharmacology, general toxicology (mouse and dog), and
`genetic toxicity (in vivo and in vitro). Reproductive and developmental toxicology
`studies were conducted in mice to assess the effects of axitinib on fertility and
`embryo-fetal development. The studies cited in the review consist primarily of
`original research studies conducted by the applicant.
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`Pharmacology studies submitted to the NDA support that axitinib is a kinase
`inhibitor which binds to and inhibits the activity of multiple receptor tyrosine
`kinases including vascular endothelial growth factor receptor (VEGFR)-1,
`VEGFR-2 and VEGFR-3.
`The most common adverse reactions observed with axitinib in patients (≥20%
`according to Highlights section of the label) were diarrhea, hypertension, fatigue,
`decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia
`(hand-foot) syndrome, weight decrease, vomiting, asthenia, and constipation.
`Safety pharmacology studies conducted with axitinib in mice, rats and dogs
`identified the potential for increased systolic blood pressure and decreased heart
`rate. In repeat-dose studies, toxicities in bone and teeth, spleen and thymus (in
`mice), and elevated cholesterol and triglycerides (in dogs) were not observed
`clinically, but may be relevant to patient risk under certain circumstances.
`Toxicities were observed throughout the gastrointestinal tract in mice and dogs.
`Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay
`and was not clastogenic in the in vitro human lymphocyte chromosome
`aberration assay. However, axitinib was genotoxic in the in vivo mouse bone
`marrow micronucleus assay. Kinetochore staining results from the in vivo
`micronucleus assay indicated that the increases in micronucleated polychromatic
`erythrocytes were due to an aneugenic mechanism.
`Axitinib may impair reproductive function and fertility in males and females. In
`repeat-dose toxicology studies in mice and dogs, findings in the male
`reproductive tract were observed in the testes/epididymis at exposures
`approximately equivalent to and lower than patient exposure, respectively.
`Findings in the female reproductive tract in mice and dogs included signs of
`delayed sexual maturity, reduced or absent corpora lutea, decreased uterine
`weights and uterine atrophy at exposures approximately equivalent to exposure
`in patients.
`In a fertility study in mice, axitinib did not affect mating or fertility rate when
`administered to males at any dose tested. Reduced fertility and embryonic
`viability were observed in female mice at all doses tested. Doses in this study
`resulted in systemic exposures greater than exposures in patients.
`Axitinib is embryotoxic, fetotoxic, and teratogenic to mice, at exposures lower
`than human exposures at the recommended human starting dose. During a
`fertility and early embryonic development study, axitinib administered to female
`mice prior to mating and through the first week of pregnancy caused an increase
`in post-implantation loss. In an embryo-fetal developmental toxicity study,
`pregnant mice received oral axitinib twice daily during the period of
`organogenesis. Embryo-fetal toxicities observed in the absence of maternal
`toxicity included malformations (cleft palate) and variations in skeletal ossification
`(interfrontal ossification sites, incomplete ossification of the supraoccipitals). A
`no effect level for adverse embryo-fetal effects was not identified in this study.
`The potential benefit of axitinib in pregnant women in this patient population may
`outweigh the potential risk to the developing fetus. Therefore, Pregnancy
`Category D is recommended for the use of axitinib in this patient population.
`Recommendations: I concur with Drs. Goheer’s, Putman’s and Aziz’s
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`
`conclusion that pharmacology and toxicology data support the approval of NDA
`202324 for axitinib. There are no outstanding nonclinical issues that would
`preclude the approval of axitinib for the proposed indication.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`THE FOLLOWING IS ABSTRACTED FROM THE CLINICAL PHARMACOLOGY
`BIOPHARMACEUTICS REVIEW.
`
`Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor (VEGFR)-1, -2,
`and -3. The current submission is the original NDA for axitinib for the treatment of
`advanced renal cell carcinoma (RCC). To support the efficacy in advanced renal cell
`carcinoma, the sponsor conducted one randomized, controlled phase 3 trial. Patients in the
`phase 3 trial were randomized to receive axitinib tablets 5 mg twice daily or sorafenib 400
`mg twice daily. Progression free survival (PFS) was the primary endpoint. The median
`PFS for the axitinib treatment arm was 6.7 months compared to 4.7 months for patients
`receiving sorafenib.
`
`Exposure-safety analysis demonstrated that there was exposure dependent increase in
`hypertension, proteinuria, fatigue, and diarrhea. The proposed dose reduction strategy (5 to
`3 to 2 mg bid) to manage hypertension and proteinuria is acceptable. Additionally, the dose
`titration scheme, which is the same as that used in the phase 3 trial (5 to 7 to 10 mg based
`on tolerability),is reasonable and can reduce variability in axitinib exposures based on
`observed pharmacokinetic data.
`
`The pharmacokinetics of axitinib has been evaluated in twenty studies in healthy
`volunteers and cancer patients. Following oral administration, the median axitinib plasma
`Tmax ranges between .5 – 4.1 hours and the mean half-life ranges between 2.5 – 6.1 hours.
`The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%. A clinically
`significant effect of food was not observed; axitinib may be administered with or without
`food.
`
`The results of the hepatic impairment study support the labeling recommendations of
`reducing the axitinib dose by half for patients with moderate hepatic impairment. No dose
`adjustment is warranted for patients with mild hepatic impairment. Patients with severe
`hepatic impairment have not been studied. Based on the population pharmacokinetic
`analysis, no adjustment to the starting dose is needed for patients with pre-existing mild,
`moderate, or severe renal impairment.
`
`As only one subject was enrolled with end-stage renal impairment, a definitive conclusion
`regarding the effect of end-stage renal impairment on axitinib exposure cannot be made.
`
`In vitro data indicate that axitinib is primarily metabolized by CYP3A4/5. In drug-drug
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`interaction studies, ketoconazole (a strong CYP3A4/5 inhibitor) increased axitinib
`exposure by 106%, while rifampin (a strong CYP3A4/5 inducer) decreased axitinib
`exposure by 80%. Therefore, concomitant use of strong inhibitors or inducers of
`CYP3A4/5 should be avoided. However, if a strong CYP3A4/5 inhibitor must be co-
`administered, the axitinib dose should be reduced by half.
`
`Recommendations
`
`The Office of Clinical Pharmacology Divisions of Clinical Pharmacology 5,
`Pharmacometrics,
`and Pharmacogenomics have reviewed the information contained in NDA 202324. This
`NDA is considered acceptable from a clinical pharmacology perspective.
`
`6. Clinical Microbiology
`
`THE FOLLOWING IS ABSTRACTED FROM THE PRODUCT QUALITY
`MICROBIOLOGY REVIEW
`
`A. Recommendation on Approvability – The recommendation is to
`approve this submission from a quality microbiology standpoint.
`
`B. Recommendations on Phase 4 Commitments and/or
`Agreements, if Approvable - NA
`
`II. Summary of Microbiology Assessments
`
`A. Brief Description of the Manufacturing Processes that relate to
`Product Quality Microbiology – Formulated powders are
`
` film coated and packaged. This is a nonsterile
`
`drug product.
`
`B. Brief Description of Microbiology Deficiencies – None
`
`C. Assessment of Risk Due to Microbiology Deficiencies – NA
`7. Clinical/Statistical- Efficacy
`
` A
`
` single RCT was submitted, comparing 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). Patients were
`randomized one to one to receive axitinib was 5 mg twice daily (BID) administered orally with
`food or sorafenib administered orally without food at a starting dose of 400 mg BID. Subjects
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`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). 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 reduction below 2 mg BID were not to be implemented prior to discussion with the
`Sponsor. When dose reduction was necessary to manage sorafenib-related adverse drug
`reactions, the sorafenib dose was reduced to 400 mg once daily (QD). Ifadditional dose
`reduction was required, sorafenib was reduced to a single 400 mg dose every other day.
`
`Progression-Free Survival
`
`The primary efficacy endpoint was PFS as determined by an independent radiology review
`committee (IRC).
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`Figure 1 Progression-Free Survival ITT IRC Analysis
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`[.0
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`[1.8
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`Ail-0137.30: 152 event: [N-JM. Med: 6.7 months (9&0: Id - 5.5)]
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`Surat-III: 21° mt- [N-JSZ. Mort: 4.7 month (85- CI: 4.! — 5.6)]
`Hazard Ratla 0.! 55 (05- crow—um]
`p—vuhl lac-d an urn-dun! ltmtfld Its—rut ht: «.0001
`
`
`
`
`
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`applicant figure
`
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`ARC—(115756
`—————— Somfenlb
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`Time (Months)
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`As shown in Figure 1, 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.
`
`As shown in Figure 2 and Figure 3, 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 4, 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 2 Kaplan-Meier Curve of Progression-Free Survival by Treatment and Prior
`Sunitinib-Containing Regimen; IRC Assessment
`
` applicant figure
`
`
`Figure 3 Kaplan-Meier Curve of Progression-Free Survival by Treatment and Prior
`Cytokine-Containing Regimen; IRC Assessment
`
`
`
` applicant figure
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`PFS in United States Subpopulation
`
`
`Figure 4 PFS in United States Subpopulation
`
`
`applicant figure
`
`
`Final Overall Survival Analysis
`
`As shown in Table 2 and Figure 5, there was no axitinib effect on final overall survival. There
`was no crossover to the other treatment after progression
`
`
`
`
`Table 2 Final Overall Survival Analysis
`
`
`
`Deaths (%)
`Median OS in months (95% CI)
`Hazard Ratio (95% CI)
`P-value
`applicant table
`
`
`Figure 5 Final Overall Survival Analysis
`
`
`
`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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` Axitinib
` Sorafenib
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`10
`15
`20
`25
`Overall Survival (Months)
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`0.4
`0.3
`0.2
`0.1
`0.0
`
`Proportion without OS event
`
` applicant figure
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`Objective Response
`
`Table 3 Best Overall Response by Treatment and Stratification
`Factor; Stratified Analysis; IRC Assessment
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`18
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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.
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`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
`
`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]).
`
`
`Discuss the background of the clinical program, highlighting agreements with the Sponsor
`prior to NDA submission, and subsequent review issues such as those regarding endpoints,
`number of trials, other departures from standard clinical evaluations, adverse events,
`risk/benefit, etc. Include the basic design of the efficacy studies, qualitative issues, key tables
`and figures that are intended to appear in the clinical sections of labeling. Even if there are
`no major issues, provide a brief overview of these critical aspects of the basis for the
`regulatory action being recommended. Greater detail should be provided if notable issues or
`findings exist or if other final documentation in the action package is lacking.
`
`
`•
`
`Includes discussion of both the statistical reviewer review and the clinical efficacy
`review with explanation for CDTL’s conclusions and ways that any disagreements
`were addressed.
`
`
`
`
`
`•
`
`Includes discussion of notable efficacy issues both resolved and outstanding
`
`
`8. Safety
`
`
`The submitted Safety Database is satisfactory. No special safety measures are needed other
`than the usual post marketing safety monitoring.
`
`Exposure
`
`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.
`
`
`Table 4 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
`
`
`Axitinib dose levels
`
`Axitinib
`N = 359
`
`196
`
`1896 mg
`132 (36.8)
`Planned: 10 mg
`9.9 mg
`
`98.6
`110 (30.6%)
`276 (76.9%)
`
`194 (54%)
`202 (56.3)
`
`
`
`Sorafenib
`N = 355
`
`152
`
`89600 mg
`NA
`Planned: 800 mg
`773.9 mg
`
`91.7
`185 (52.1%)
`285 (80.3%)
`
`224 (63.1%)
`183 (51.5%)
`
`
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`Table 5 Summary of Axitinib Dose Escalations and Reductions
`Axitinib
`N=359
`n (%)
`
`Total daily dose
` < 6 mg
` 6-8 mg
` 10 mg
` 12-14 mg
` 20 mg
`Number of patients escalated and then reduced
`