CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`202324Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Deputy Division Director Review
`
`Summary Review for Regulatory Action
`
`26, 2012
`Jan .
`Amna Ibrahim NID
`From
`
`Subject
`Deputy Division Director Smnmary Review
`NDA/BLA #
`202324
`
`Su .lement #
`
`Applicant Name
`Date of Submission
`
`PDUFA Goal Date
`
`000
`
`Pfizer Pharmaceuticals, Inc.
`A iii] 14, 2011
`
`Feb
`
`.
`
`14, 2012
`
`Proprietary Name /
`Established
`S i
`
`Name
`
`Inlyta
`axitinib
`
`Dosa _e Forms / Stren_ h
`
`Tablet! 5 111
`
`Proposed Indication(s)
`
`For the treatment of patients with advanced renal cell
`carcinoma
`
`Recommended Action for NME:
`
`
`
`Material Reviewed/Consulted
`0ND Action Packa ' e, includin' :
`Medical Officer Review
`
`Names of discipline reviewers
`
`Am McKee/ John Johnson
`
`Somesh Chattmadh a / Shen- ui Tan- Ra'i Sridhara
`
`Pharmacolo 3 Toxicolo 3 Review
`
`Anwar Goheer/Todd Pahnb /John Lei- nton
`
`CMC Review/
`
`Amit Mitra and Jean Tang/Sarah Pope Miksinski;
`
`_—
`
`Robert Youn Te'ashri S Purohit—Sheth
`
`ONMflke ofNew Dmgs
`DDMAC=Division ofDrug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division ofMedication Em: Prevention and Analysis
`DSI=Division of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DRISK=Division ofRisk Management
`CDTIFCross-Discipline Team Leader
`
`Page 1 of 7
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`Reference ID: 3077799
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`Deputy Division Director Review
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`
`
`1. Introduction
`Renal cancer is one of the more common cancers in the US. According to the Seer database,
`about 61,000 men and women will be diagnosed with and 13,000 will have died from cancer
`of the kidney and renal pelvis in 2011. Prior to 2005, IL-2 and INF-α were used to treat
`advanced, inoperable renal cell cancer based on an improvement in response rates, which with
`IL-2 can be occasionally durable. Both these drugs have substantial toxicity.
`
`Since 2005, 6 agents have been approved for this disease. These include sorafenib, sunitinib,
`temsirolimus, everolimus, bevacizumab and pazopanib. All of these were approved based on
`an improvement in progression-free survival (PFS).The only exception is temsirolimus, which
`has demonstrated an improvement in overall survival (OS) in patients with pre-specified poor
`prognosis risk factors.
`
`NDA 202324 was submitted for the following proposed indication:
`
`
`“INLYTA is a kinase inhibitor indicated for the treatment of patients with advanced
`renal cell carcinoma”
`
`
`
`2. CMC/Device
`
`
`Kareen Riviere Ph.D. (Biopharmaceutics reviewer/ONDQA) stated that the proposed film coat
` is acceptable for the 1 mg and 5 mg tablet. This review was cosigned
`by Sandra Suarez Ph.D. CMC reviewers Amit Mitra Ph.D. and Zhe Tang Ph.D. recommend
`approval with respect to CMC. Their reviews are co-signed by Sarah Miksinski Ph.D. Richard
`Lostritto Ph.D. in his Division Director’s memo recommends approval of this NDA. He
`recommends one CMC-related PMC for this application which provides for the applicant to
`validate testing for
` within 90 (ninety) days. Dr Lostritto states that this is a test the
`applicant ultimately agreed to adopt late in the review cycle and for which they did not have a
`validated method. Because this is a well known test with a long and well characterized history,
`ONDQA is comfortable allowing this time to for validation which should be straightforward.
`
`All other CMC-related deficiencies have been resolved for this application, and all related
`reviews are complete. There are no outstanding review deficiencies from the CMC
`standpoint.
`
` concur with the conclusions reached by the chemistry reviewer regarding the acceptability of
`the manufacturing of the drug product and drug substance. Manufacturing site inspections
`were acceptable. Stability testing supports an expiry of 36 months 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).
`There are no outstanding issues.
`
`
` I
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`Reference ID: 3077799
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`Deputy Division Director Review
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`3. Nonclinical Pharmacology/Toxicology
`As stated by Anwar Goheer Ph.D. and Todd Palmby Ph.D. in their reviews, there are no non-
`clinical findings that would preclude the approval of axitinib for the proposed indication. I
`concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstanding pharm/tox issues that preclude approval.
`4. Clinical Pharmacology/Biopharmaceutics
`Sarah Schrieber Ph.D., Nitin Mehrotra Ph.D. and Rosane Orbach Ph.D. in their review
`cosigned by Christine Garnett PhD, Issam Zineh Ph.D., Qi Liu Ph.D. and Nam Atiqur Rahman
`Ph.D., state that this NDA is considered acceptable from a clinical pharmacology perspective.
`I concur with the conclusions reached by the clinical pharmacology and biopharmaceutics
`reviewers that there are no outstanding clinical pharmacology issues that preclude approval.
`5. Clinical Microbiology
`Denise A. Miller and Stephen Langille recommend approval from the clinical microbiology
`perspective. They state that formulated powders are
` film coated
`and packaged. This is a non-sterile drug product. I concur with the conclusions reached by the
`clinical microbiology reviewer that there are no outstanding clinical microbiology or sterility
`issues that preclude approval.
`
`
`6. Clinical/Statistical-Efficacy
`Efficacy of axitinib is based on a single randomized, open-label, multicenter Phase 3 trial
`comparing axitinib to sorafenib as second-line systemic therapy in patients with metastatic
`renal cell carcinoma. Patients were randomized to receive either axitinib 5 mg po BID or
`sorafenib 400 mg po BID. The primary efficacy endpoint was PFS as assessed by a blinded
`Independent Review Committee. Secondary endpoints included overall survival and objective
`response rate (ORR), and safety of axitinib. This protocol was granted an SPA.
`
` A
`
` total of 723 patients were randomized to receive axitinib or sorafenib. Of the patients
`enrolled in this study, 389 patients (54%) had received 1 prior sunitinib-based therapy, 251
`patients (35%) had received 1 prior cytokine-based therapy (interleukin-2 or IFN-α), 59
`patients (8%) had received 1 prior bevacizumab-based therapy, and 24 patients (3%) had
`received 1 prior temsirolimus-based therapy. The baseline demographic and disease
`characteristics were similar between the axitinib and sorafenib groups
`
` A
`
` statistically significant improvement in PFS was demonstrated in patients receiving axitinib
`compared to patients receiving sorafenib (HR=0.67; 95% CI: 0.54, 0.81; p< 0.0001, log-rank
`test). The median PFS of patients receiving axitinib was 6.7 months (95% CI: 6.3, 8.6)
`compared to a median PFS of 4.7 months (95% CI: 4.6, 5.6) for patients on the sorafenib arm.
`This improvement in PFS was greater in the cytokine-treated subgroup compared to the
`sunitinib-refractory subgroup. There was no difference in the final overall survival analysis
`between the two arms with a hazard ratio of 0.97 (95% CI 0.8-1.17). Please see table below.
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`Deputy Division Director Review
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`Axitinib
`N= 361
`6.7 (6.3, 8.6)
`
`Sorafenib
`N = 362
`4.7 (4.6, 5.6)
`
`P-value
`HR (95% CI)
`
`
` 0.67 (0.54, 0.81) <0.0001c
`
`Table 1: Table 3. Efficacy Results
`(from Package Insert)
`Endpoint/Study Population
`Overall ITT
`Median PFSa,b in months (95%
`CI)
`0.97 (0.80, 1.17)
`19.2 (17.5, 22.3)
`20.1 (16.7, 23.4)
`Median OS in months (95% CI)
`2.06d (1.41, 3.00)
`9.4 (6.6, 12.9)
`19.4 (15.4, 23.9)
`ORR % (95% CI)
`PFS by prior treatment
`
`
`
`
`N=195
`N=194
`Sunitinib-refractory subgroup
`0.74 (0.57, 0.96)
`3.4 (2.8, 4.7)
`4.8 (4.5, 6.4)
`Median, months (95% CI)
`
`N=125
`N=126
`Cytokine-refractory subgroup
`0.46 (0.32, 0.68)
`6.5 (6.3, 8.3)
`12.1 (10.1, 13.9)
`Median, months (95% CI)
`CI: Confidence interval; HR: Hazard ratio (axitinib/sorafenib); ITT: Intent to treat; ORR: Objective response rate;
`NS: Not significant; OS: Overall survival; PFS: Progression-free survival
`a Time from randomization to progression or death due to any cause, whichever occurs first.
`b Assessed by independent radiology review according to RECIST.
`c One-sided p-value from a log-rank test of treatment stratified by ECOG performance status and prior therapy
`(comparison is considered statistically significant if the one-sided p-value is <0.023).
`d Risk ratio is used for ORR. A risk ratio >1 indicated a higher likelihood of responding in the axitinib arm; a risk
`ratio <1 indicated a higher likelihood of responding in the sorafenib arm.
`e P-value not included since it was not adjusted for multiple testing.
`
`Figure 1: Kaplan-Meier Curve for Progression Free Survival (ITT Population)
`(from Package Insert)
`
`NS
`e
`
`
`
`
`e
`
`
`
`e
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`Deputy Division Director Review
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`7. Safety
`The safety of axitinib has been evaluated in 715 patients in monotherapy studies, which
`included 537 patients with advanced RCC. Per Dr McKee, “The safety profile of axitinib is
`comparable to that of other drugs in the same class of small molecule inhibitors of the VEGF
`pathway in terms of the types of adverse events observed. Common adverse events include
`diarrhea, nausea, fatigue, asthenia, hypertension, dysphonia and dermatologic adverse events.
`Less common serious adverse events include arterial and venous thrombotic events,
`gastrointestinal perforation, bleeding events, hypothyroidism, proteinuria and reversible
`posterior leukoencephalopathy syndrome. There were no new signals for serious adverse
`events with axitinib that had not been previously identified for this class of drugs.”
`
`Per John Johnson M.D. (CDTL), “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 less common, but serious adverse reactions stated above have been included in the
`Warning and Precautions section. There is no Boxed Warning, REMS, PMRs or clinical
`PMCs.
`
`
`8. Advisory Committee Meeting
`Because axitinib is an NME, this NDA was presented to Oncology drug Advisory Committee
`(ODAC). In response to the question “Is the benefit:risk evaluation favorable for axitinib
`treatment in patients with advanced RCC after failure of a first-line systemic therapy?” All 13
`members responded with a unanimous “yes” and there were no abstentions.
`
`It was noted by the ODAC that the toxicity profile of axitinib is different from but manageable
`compared to other products currently on market and it was generally agreed that axitinib offers
`an alternative treatment for patients with renal cancer, that it is an active agent that is modestly
`more effective compared to sorafenib, an approved therapy.
`9. Pediatrics
`
` pediatric waiver was granted because the disease does not exist in children.
`
`10.
`
`Other Relevant Regulatory Issues
`
`• DSI Audits: Four sites (2 in Europe and 2 in US) were inspected. One foreign site had
`a “major objectionable finding related to the documentation of updated consent and not
`to data integrity.” Per MO Dr McKee, she did not believe it affected the findings of the
`Phase 3 trial. Neither is there evidence of widespread issues with Good Clinical
`Practices. It is stated in the DSI review by Robert Young MD that there were no
`
` A
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`Deputy Division Director Review
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`significant regulatory findings relating to data integrity from any of the four sites
`inspected. The data may be used in the evaluation of this application.
`
` Financial Disclosure: Per Dr Johnson, and Dr McKee, investigators who conducted the
`clinical trials supporting this NDA and who had no financial interests to disclose were
`submitted in the FDA form 3454. The disclosure was certified by D. Stuart Sowder,
`Vice President-External Medical Communication for the applicant. Disclosure of
`financial interests of the investigators who conducted the clinical trials supporting this
`NDA was submitted in the FDA form 3455. Thirty-three investigators in the key study
`supporting this NDA were found to have financial conflict of interest, either a
`proprietary interest or significant payments from or equity interest in the applicant.
`These investigators received payments as honoraria for speaking events, professional
`fees and consulting fees ranging from totals of $27,325 to $510,650. These
`investigators enrolled a total of 81 patients onto the Phase 3 trial, ranging from one to
`15 patients at each site. While this represents slightly over 10% of the total patient
`population in the Phase 3 trial, it is unlikely that any single investigator could have
`influenced the efficacy results of the trial.
`
`It is also noted that the primary endpoint of PFS was based on a blinded, independent
`review that would not be expected to be influenced by financial conflicts of these
`investigators.
`
`
`
` •
`
` •
`
` Other consults- All consultants comments were incorporated during labeling meetings.
`
`
`There are no other unresolved relevant regulatory issues
`
`
`
`11.
`
`Labeling
`
`
`Includes:
`• Proprietary name: The name “INLYTA” was ultimately chosen as the proprietary
`name.
`• Physician labeling: All major issues were discussed and resolved. The indication was
`modified to reflect the patient population studied.
`• Carton and immediate container labels: All major issues were discussed and resolved.
`• Patient labeling/Medication guide: All major issues were discussed and resolved.
`
`
`
`12.
`
`Decision/Action/Risk Benefit Assessment
`
`
`
`• Regulatory Action
`I agree with the Medical Officer’s and CDTL’s recommendation as well as those from
`other disciplines as noted earlier. I recommend approval for the following indication:
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`Deputy Division Director Review
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`“INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after
`failure of one prior systemic therapy.”
`• Risk Benefit Assessment
`A modest improvement in PFS was demonstrated with the use of axitinib compared to
`sorafenib. Sorafenib is commonly used to treat renal cell cancer; however, its treatment
`effect as a second-line treatment is not known. The treatment effect of sorafenib should be
`added to the axitinib PFS benefit to give the total treatment effect of axitinib. In addition,
`axitinib has a different but generally manageable toxicity profile when compared to other
`recently approved agents for renal cell cancer. This approval will provide an option for the
`treatment of patients with renal cell cancer who have received one prior systemic therapy.
`
`• Recommendation for Postmarketing Risk Evaluation and Mitigation Strategies
`No REMS are proposed by DRISK or the primary team and none are required.
`
`• Recommendation for other Postmarketing Requirements and Commitments
`One CMC-related PMC will be included in the action letter. This PMC is as follows:
`
`“Provide the analytical methods and method validation for testing of
` in the final drug substance”
`
` and
`
`
`The final report submission date agreed to by the sponsor is April 22. 2012. Dr Lostritto
`stated in his ONDQA Division Director’s memo that this is a test the applicant agreed to
`adopt late in the review cycle and for which they did not have a validated method. Because
`this is a well known test with a long and well characterized history, ONDQA is
`comfortable allowing this time to for validation which should be straightforward.
`
`
`
`
`
`
`
`Amna Ibrahim M.D.,
`Deputy Director,
`Division of Oncology Products 1
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`Page 7 of 7
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`Reference ID: 3077799
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMNA IBRAHIM
`01/26/2012
`
`Reference ID: 3077799
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`