CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`' APPLICATION NUMBER:
`22-334
`22-334
`
`OFFICE DIRECTOR MEMO
`OFFICE DIRECTOR MEMO
`
`

`

`Summary Review for Regulatory Action
`
`Date
`From
`Subject
`NDAlLA#
`Supplement #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosa2e Forms / Stren2th
`Proposed Indication(s)
`
`(electronic stamp)
`Richard Pazdur, MD
`Office Director Review
`22-334
`
`Novartis Pharmaceuticals Corporation
`June 30, 2008
`March 30, 2008
`Afinitor/everolimus
`
`Tablets/ 5 mg and 10 mg
`
`AFINITOR(ß is indicated for the treatment of
`
`patients
`
`with advanced renal cell carcinoma after failure of
`treatment with sunitinib or sorafenib.
`ActionlRecommended Action for Approval
`NME:
`
`.
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`Statistical Review
`Pharmacology Toxicology Review
`CMC Review/OBP Review
`Microbiology Review
`Clinical Pharmacology Review
`DDMAC
`DSI
`CDTLReview
`OSEIDMEPA
`OSEIDDRE
`OSEIDRISK
`Other - IRT Review
`OND=Offce of New Drugs
`Drug Marketing, Advertising and Communication
`DDMAC=Division of
`OSE= Offce of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DSI=Division of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DRISK=Division of Risk Management
`CDTL=Cross-Discipline Team Leader
`
`X
`X
`X
`X
`X
`X
`X
`X
`N/A
`X
`N/A
`X
`X
`
`1
`
`

`

`OFFICE DIRECTOR'S REVIEW
`
`INDICATION: The treatment of
`
`patients with advanced renal cell carcinoma after failure of
`treatment with sunitinib or sorafenib.
`
`MECHANISM OF ACTION: Everolimus is an inhibitor ofmTOR (mammalian target of
`rapamycin), a serine-threonine kinase, downstream ofthe PI3K/AKT pathway. The mTOR
`pathway is dysregulated in several human cancers. Everolimus binds to an intracellular
`protein, FKBP-12, resulting in an inhibitory complex formation and inhibition of mTOR
`kinase activity. Everolimus reduced the activity ofS6 ribosomal protein kinase (S6Kl) and
`eukaryotic elongation factor 4E-binding protein (4E-BP), downstream effectors ofmTOR,
`hypoxia-
`vascular endothelial growth factor
`(VEGF). Inhibition ofmTOR by everolimus has been shown to reduce cell proliferation,
`angiogenesis, and glucose uptake in in vitro and/or in vivo studies.
`
`involved in protein synthesis. In addition, everolimus inhibited the expression of
`
`inducible factor (e.g., HIF-l) and reduced the expression of
`
`CLINICAL EVAULUATION: The efficacy and safety of everolimus tablets (AFINITOR(ß,
`Novartis Pharmaceuticals Corporation) were evaluated in an international, multicenter,
`randomized, double-blind trial comparing everolimus to placebo. All patients received best
`supportive care. The trial was conduèted in patients with metastatic renal cell carcinoma after
`failure oftreatment with sunitinib or sorafenib. Prior therapy with bevacizumab, interleukin-2,
`or interferon-a was also permitted. Randomization was stratified according to prognostic
`score and prior anticancer therapy.
`
`A total of 416 patients were randomized (2: 1) to receive everolimus (n=277) or placebo
`(n=139). Demographics were well balanced between the two arms. Progression-free survival
`(PFS) was the trial's primary endpoint. The median PFS was 4.9 and 1.9 months in the
`everolimus and placebo arms, respectively (HR = 0.33, P value": 0.0001). The treatment
`effect was similar across prognostic scores and prior treatment status. The overall survival
`patients had died by the time of data cut-off. The objective
`response rates were 2% and 0% for everolimus and placebo, respectively. After documented
`radiological progression, patients receiving placebo could receive everolimus.
`
`results are not mature; 32% of
`
`The most common adverse reactions (incidence 2:30%) were stomatitis, infections, asthenia,
`fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence 2:3%)
`were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and
`asthenia. Anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia,
`and increased creatinine were the most common laboratory abnormalities (incidence 2:50%).
`The most common grade 3/4 laboratory abnormalities (incidence 2:3%) were lymphopenia,
`hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute
`respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) occurred on the
`everolimus arm but not on the placebo arm.
`
`The recommended dose of everolimus for treatment of advanced renal cell carcinoma is 10 mg
`once daily at the same time either with or without food.
`
`2
`
`

`

`This application was not taken to a meeting of
`
`the Oncologic Drugs Advisory Committee
`(ODAC) because the application is based on a trial demonstrating a clinically and statistically
`significant improvement in progression-free survival with an acceptable benefit/risk ratio.
`Progression-free survival has previously been used as the basis for approval of drugs for the
`treatment of advanced renal cell carcinoma and the safety profie is similar to that of other
`drugs approved for this indication
`
`Approval is recommended. The risk benefit assessment is acceptable for this patient
`population. The improvement in PFS is clinically signifcant, the toxicity profile is similar to
`that of other agents approvedfor the treatment of advanced renal cell cancer, and there are no
`other therapies of proven benefit in patients with failure of prior treatment with sunitinib or
`sorafenib.
`
`Recommendation for Post-marketing Risk Management Activities: Routine postmarketing
`surveillance with special emphasis on non-infectious pneumonitis, infections, and renal
`dysfunction.
`
`Recommendation for other Post-marketing Requirements and Commitments:
`
`Trial A2303 evaluated everolimus in patients with moderate hepatic impairment (Child
`Pugh Class B) and due to increases in everolimus exposure, a dose reduction is needed in
`these patients. No exposure data are available for patients with severe hepatic impairment
`and current labeling recommends that everolimus should not be used in these patients.
`Because of an unexpected serious risk of increased drug exposure when everolimus is
`administered to patients with severe hepatic impairment, the following postmarketing
`clinical trial wil be required:
`
`1. Conduct a trial in patients with severe hepatic impairment (Child Pugh Class C). This
`trial need not be conducted in patients with cancer and a single dose evaluation wil be
`appropriate. The protocol should be submitted prior to initiation for review and
`concurrence.
`
`Final Protocol Submission:
`Trial Start Date:
`Final Report Submission:
`
`May 14,2009
`October 14, 2009
`April 14,2011
`
`The following are the agreed-upon post-marketing study commitments:
`
`2. Submit the final, per-protocol overall survival analysis of
`
`protocol C2240 which was to
`be conducted 2 years after randomization of the last patient.
`
`Protocol Submission: July 27, 2006
`Trial Start Date: December 6, 2006
`Final Report Submission: June 2010
`
`3
`
`

`

`3. Develop a 2.5 mg dosage form (tablet) to allow for proper dose reductions when
`everolimus is co-administered with moderate CYP3A4 inhibitors. The 2.5 mg dosage
`form should be suffciently distinguishable from the 5 mg and 10 mg tablets. Full
`chemistry, manufacturing and controls (CMC) information for the 2.5 mg dosage form
`including batch and stability data, updated labeling, and an updated environmental
`assessment should be submitted as a prior approval supplement.
`
`Protocol Submission Date:
`Final Report Submission:
`
`May 14,2009
`January 14,2010
`
`Appears This Way
`On OrIginal
`
`4
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`/s/
`Christy Cottrell
`3/30/2009 11:49:38 AM
`CSO
`Entered into DFS for Dr. Richard Pazdur.
`
`Richard Pazdur
`3/30/2009 12: 50: 59 PM
`MEDICAL OFFICER
`
`