CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
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`202324Orig1s000
`
`OFFICE DIRECTOR MEMO
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`

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`Office Director Decisional Memo
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`NDA 202324_lnlyla (axitinib)
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`Office Director Decisional Memo for Regulatory Action
`
`Sub'ect
`NDNBLA #
`Su ulement #
`A ulicant Name
`
`Date of Submission
`
`27, 2012
`Janua
`Richard Pazdur, MD
`Office Director Decisional Memo
`202324
`
`Pfizer Pharmaceuticals, Inc.
`A 'l 14, 2011
`
`February 14, 2012
`PDUFA Goal Date
`Inlyta
`Proprietary Name I
`
`Established (USAN) Name
`axitinib
`Dosa . e Forms I Stren . th
`Tablet/5 m.
`Pro I osed Indication s
`For the treatment of - tients with advanced renal cell carcinoma
`>
`c .
`Recommended Action for NME:
`
`
`
`Material ReviewedIConsulted
`0ND Action Packa - e, includin . :
`
`Names of discipline reviewers
`
`Somesh Chattoadh a / Shenhui Tan Ra'i Sridhara
`
`CMC Review/
`OBP Review
`
`Amit Mitra and Jean Tang/Sarah Pope Miksinski; Kareen
`RiviereIAngeIica Dorantes
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`Microbiolo . Review
`
`Denise Miller/Steohen Lanoille
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`Clinical Pharmacology Review
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`Sarah Schrieber/Qi Liu
`
`__
`
`_—
`
`0ND=Offioe of New Drugs
`DDMAC=Divnion of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Enor Prevention and Analysis
`DSI=Division of Scientific Investigations
`DDRE= Division of Dmg Risk Evaluation
`DRISK=Divrsion of Risk Management
`CDTL=Cross—Discipline Team Leader
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`Reference ID: 3078307
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`Page 1 of 4
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`Office Director Decisional Memo
`NDA 202324_Inlyta (axitinib)
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`
`Introduction
`1.
`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- 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
`The Chemistry review team recommends an overall acceptability regarding 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.
`
`
`3. Nonclinical Pharmacology/Toxicology
`Based on nonclinical reviews, there are no nonclinical findings that would preclude the approval of axitinib for the
`proposed indication.
`
`
` Clinical Pharmacology/Biopharmaceutics
`4.
`The Clinical Pharmacology review team recommends approval of this NDA and there are no outstanding clinical
`pharmacology issues that preclude approval.
`
`
`5. Clinical Microbiology
`There are no outstanding clinical microbiology or sterility issues that preclude approval.
`
`
`6. Clinical/Statistical-Efficacy
`Efficacy of axitinib was demonstrated in an international, randomized, open-label trial in patients with advanced
`renal cell carcinoma after failure of one prior systemic regimen. The primary efficacy endpoint was PFS.
`
`The trial enrolled 723 patients: 361 patients were assigned to receive axitinib 5 mg orally twice daily, and 362
`patients were assigned to receive sorafenib 400 mg orally twice daily. Treatment continued until disease
`progression, unacceptable toxicity, and/or consent withdrawal. All enrolled patients had an ECOG performance
`status of 0 or 1 and all patients had received one prior systemic therapy that contained one of the following
`treatments: sunitinib, temsirolimus, bevacizumab or cytokine(s). The trial excluded patients who had uncontrolled
`hypertension.
`
`The PFS analysis demonstrated a statistically significant improvement in PFS 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 receiving sorafenib. This improvement in PFS was greater in the cytokine-
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`Page 2 of 4
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`Reference ID: 3078307
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`

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`Office Director Decisional Memo
`NDA 202324_Inlyta (axitinib)
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`pretreated subgroup compared to the sunitinib-pretreated 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.
`
`Table 1: Table 3. Efficacy Results
`HR (95% CI)
`Sorafenib
`Axitinib
`Endpoint/Study Population
`Overall ITT
`
`N = 362
`N= 361
` 0.67 (0.54, 0.81)
`4.7 (4.6, 5.6)
`6.7 (6.3, 8.6)
`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.
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`Figure 1: Kaplan-Meier Curve for Progression Free Survival (ITT Population)
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`P-value
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`<0.0001c
`NS
`e
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`
`
`e
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`
`
`e
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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.
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`Reference ID: 3078307
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`Office Director Decisional Memo
`NDA 202324_Inlyta (axitinib)
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`
`The most common (≥20%) adverse reactions in patients treated with axitinib were diarrhea, hypertension, fatigue,
`decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight
`decreased, vomiting, asthenia, and constipation. Other severe adverse reactions reported in axitinib-treated
`patients included hypertensive crisis, arterial and venous thrombotic events, hemorrhage, gastrointestinal
`perforation and fistula formation, and reversible posterior leukoencephalopathy syndrome.
`
`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
`This NDA was presented to the 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.
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`9. Pediatrics
`A pediatric waiver was granted because the disease does not exist in children.
`
`
`10. Other Relevant Regulatory Issues
`There are no other unresolved relevant regulatory issues.
`
`
`11. Labeling
` Proprietary name: The name “INLYTA” was found to be acceptable by DMEPA, OPDP and OHOP.
` Physician labeling; Carton and immediate container labels; Patient labeling/Medication guide: All major
`issues were discussed and resolved.
`
`12. Decision/Action/Risk Benefit Assessment
` Regulatory Action: Approval.
` 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. The risk:benefit profile has also been assessed by
`the Deputy Division Director, CDTL and clinical reviewer, and I concur with their recommendation, as well as
`other discipline reviewer recommendations to approve this application.
`
` Recommendation for Postmarketing Risk Evaluation and Mitigation Strategies
`None.
`
` Recommendation for other Postmarketing Requirements and Commitments
`See action letter.
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`Reference ID: 3078307
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`Page 4 of 4
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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/
`----------------------------------------------------
`
`TAMY E KIM
`01/27/2012
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`RICHARD PAZDUR
`01/27/2012
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`Reference ID: 3078307
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`