CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202570Orig1s000
`
`MEDICAL REVIEW(S)
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`

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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s)
`202570
`Priority or Standard Priority
`Submit Date(s) March 30th 2011
`Received Date(s) March 30th 2011
`PDUFA Goal Date September 30th 2011
`Division / Office DDOP/OODP/CDER
`Reviewer Name(s) Shakun Malik, MD
`Review Completion Date August 12th 2011
`Established Name Crizotinib
`(Proposed) Trade Name Xalkori
`Therapeutic Class NME
`Applicant Pfizer, Inc
`Formulation(s) Oral(PO)
`Dosing Regimen
`250mg orally twice daily
`Indication(s) Crizotinib is a kinase inhibitor indicated for the
`treatment of patients with locally advanced or
`metastatic anaplastic lymphoma kinase (ALK)-
`positive advanced non-small cell lung cancer.
`Intended Population(s) Adult patients with advanced non-small cell
`lung cancer harboring a translocation or
`inversion event involving the Anaplastic
`Lymphoma Kinase (ALK) gene locus
`Application Type NDA
`Application Number(s)
`202570
`Priority or Standard Priority
`Submit Date(s) March 30th 2011
`Received Date(s) March 30th 2011
`PDUFA Goal Date September 30th 2011
`
`
`Reference ID: 3000346
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`

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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`2
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`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6
`1.1 Recommendation on Regulatory Action ............................................................. 6
`1.2 Risk Benefit Assessment.................................................................................... 7
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 7
`1.4.1 Clinical PMR.................................................................................................... 7
`1.4.2 Clinical PMR.................................................................................................... 7
`1.4.3 Clinical ............................................................................................................ 7
`1.4.4 Clinical PMR:................................................................................................... 8
`1.4.5 Clinical Pharmacology PMRs.......................................................................... 8
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9
`2.1 Product Information .......................................................................................... 10
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 12
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 13
`2.4
`Important Safety Issues with Consideration to Related Drugs.......................... 14
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 14
`2.6 Other Relevant Background Information .......................................................... 15
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 16
`3.1 Submission Quality and Integrity ...................................................................... 17
`3.2 Compliance with Good Clinical Practices ......................................................... 17
`3.3 Financial Disclosures........................................................................................ 18
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 20
`4.1 Chemistry Manufacturing and Controls ............................................................ 20
`4.2 Clinical Microbiology......................................................................................... 20
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 21
`4.4 Clinical Pharmacology...................................................................................... 21
`4.4.1 Mechanism of Action.................................................................................. 22
`4.4.2 Pharmacodynamics.................................................................................... 22
`4.4.3 Pharmacokinetics....................................................................................... 22
`5 SOURCES OF CLINICAL DATA............................................................................ 24
`5.1 Tables of Studies/Clinical Trials ....................................................................... 24
`5.2 Review Strategy ............................................................................................... 26
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 27
`6 REVIEW OF EFFICACY......................................................................................... 38
`Efficacy Summary...................................................................................................... 38
`6.1
`Indication .......................................................................................................... 38
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`6.1.1 Demographics............................................................................................ 39
`6.1.2 Subject Disposition..................................................................................... 41
`6.1.3 Analysis of Primary Endpoint(s) ................................................................. 42
`6.1.4 Subpopulations .......................................................................................... 44
`7 REVIEW OF SAFETY............................................................................................. 46
`Safety Summary ........................................................................................................ 46
`7.1 Methods............................................................................................................ 46
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 46
`7.1.2 Categorization of Adverse Events.............................................................. 47
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 48
`7.2 Adequacy of Safety Assessments .................................................................... 48
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 48
`7.2.3 Explorations for Dose Response................................................................ 49
`7.3 Major Safety Results ........................................................................................ 49
`7.3.1 Deaths........................................................................................................ 49
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 51
`7.3.3 Dropouts and/or Discontinuations .............................................................. 51
`7.3.4 Significant Adverse Events ........................................................................ 51
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 53
`7.4 Supportive Safety Results ................................................................................ 53
`7.4.1 Common Adverse Events .......................................................................... 53
`7.4.2 Laboratory Findings ................................................................................... 54
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 55
`7.5 Other Safety Explorations................................................................................. 56
`7.5.1 Dose Dependency for Adverse Events ...................................................... 56
`7.5.2 Drug-Drug Interactions............................................................................... 56
`7.6 Additional Safety Evaluations ........................................................................... 56
`7.6.1 Human Carcinogenicity.............................................................................. 56
`7.6.2 Human Reproduction and Pregnancy Data................................................ 56
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 57
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 57
`8 POSTMARKET EXPERIENCE............................................................................... 57
`9 APPENDICES ........................................................................................................ 58
`9.1 Literature Review/References .......................................................................... 58
`9.2 Labeling Recommendations ............................................................................. 59
`9.3 Advisory Committee Meeting............................................................................ 59
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`Reference ID: 3000346
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`

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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`Table of Tables
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`Table 1 Approved Therapies for advanced/metastatic NSCLC ..................................... 13
`Table 2 Clinical Trials................................................................................................... 24
`Table 3 Demographic and Disease Characteristics in Studies A and B ........................ 39
`Table 4 Prior chemotherapy .......................................................................................... 40
`Table 5 Baseline Tumor Characteristics....................................................................... 41
`Table 6 patient disposition............................................................................................. 41
`Table 7 Efficacy data from Studies A and B .................................................................. 42
`Table 8 Sub group analysis.......................................................................................... 43
`Table 9 Demographics ALK -ive NSCLC....................................................................... 44
`Table 10 Efficacy Results for ALK Negative cohort....................................................... 45
`Table 11 Grade 1-4 Adverse Events in > 25% of Patients ............................................ 52
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`Table of Figures
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`Figure 1 EML4-ALK fusion gene ................................................................................... 10
`Figure 2 Structural formula of Crizotinib ....................................................................... 11
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`1 Recommendations/Risk Benefit Assessment
`
`
`1.1 Recommendation on Regulatory Action
`
`I recommend approval of the drug crizotinib under accelerate approval regulation
`21CFR 314 (Subpart H) for the treatment of patients with locally advanced or metastatic
`anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer.
`
`
`My recommendation is based on evaluation of data from two Phase II single arm trials
`A8081005 (Study A) and A8081001 (Study B);
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`1. Overall Response Rate (ORR) noted in two trials below that is superior to any
`therapy approved for unselected advanced stage NSCLC and is likely to predict
`clinical benefit.
`(cid:131) Study 1005 (Study A): In 136 previously treated patients with advanced
`(locally advanced or metastatic) NSCLC based on the investigator
`assessments, there were 1 complete and 66 partial responses for an ORR
`of 50% (95% CI: 41%, 58%). The ORR by independent review was 42%
`(95% CI: 32%, 52%). Seventy-nine percent of objective tumor responses
`were achieved during the first 8 weeks of treatment. The median response
`duration was 41.9 weeks.
`
`(cid:131) Study 1001 (Study B): One hundred nineteen patients with ALK-positive
`advanced NSCLC were enrolled into Study B at the time of data cutoff.
`The median duration of treatment was 32 weeks. Based on the
`investigator assessments, there were 2 complete and 69 partial responses
`for an ORR of 61% (95% CI: 52%, 70%). The ORR by independent review
`was 52% (95% CI: 42%, 62%). Fifty-five percent of objective tumor
`responses were achieved during the first 8 weeks of treatment. The
`median response duration was 48.1 weeks.
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`Not all, but majority of these patients had received multiple prior therapies
`including platinum. The response rate seen in these single arm trials is much
`superior to any chemotherapeutic regimen even in the first line setting.
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`1.2 Risk Benefit Assessment
`
`The trials supporting this application were both single arm and non-randomized, the
`magnitude of crizotinib benefits i.e. response rates of 50% in study A and 61.2 % in
`Study B was superior to all the drug regimens approved for the treatment of advanced
`metastatic NSCLC.
`
`Safety however could not be adequately assessed due to the single arm trials. The
`adverse events noted seem favorable compared to the chemotherapeutic agents
`approved for NSCLC. The most common adverse reactions (≥25%) are vision disorder,
`nausea, diarrhea, vomiting, constipation, edema, fatigue, and decreased appetite.(
`Taken together, the data submitted in this application demonstrated a favorable benefit:
`risk profile for crizotinib treatment in patients with advanced NSCLC harboring a
`translocation or inversion event involving the ALK gene locus.
`
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`None
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`To confirm the clinical benefits of crizotinib treatment and to fulfill the requirement for
`the recommended accelerated approval, the following post-marketed requirements are
`recommended:
`
`1.4.1 Clinical PMR: Study report and datasets from ongoing Study A8081007, “Phase
`3, Randomized, Open-Label Study of the Efficacy and Safety of PF-02341066 versus
`Standard of Care Chemotherapy (Pemetrexed or Docetaxel) in Patients with Advanced
`Non- Small Cell Lung Cancer Harboring a Translocation or Inversion Event Involving the
`Anaplastic Lymphoma Kinase Gene Locus. (Study is ongoing)
`
`1.4.2 Clinical PMR Study report and datasets from A8081014: Study A8081014,
`“Phase 3, Randomized, Open-Label Study of the Efficacy and Safety of crizotinib versus
`pemetrexed/cisplatin or pemetrexed/carboplatin in previously untreated patients with
`non-squamous carcinoma of lung harboring a translocation or Inversion Event Involving
`the Anaplastic Lymphoma Kinase Gene Locus. (Study is ongoing)
`
`1.4.3 Clinical PMR: A clinical trial to explore response to and activity of crizotinib in
`ALK-negative patients based on current assay cut-off, in comparison to standard
`therapy and response in ALK-positive patients, additional biomarkers, and adequacy of
`current cut-off
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`1.4.4 Clinical PMR: Clinical trial (existing trial or new clinical trial) in which at least 30
`patients are studied for the following examinations performed in these patients at
`baseline, 2 and 6 weeks after drug administration and 2-8 weeks after discontinuation of
`the therapy (single visit post therapy)
`
`
`(cid:131) Best corrected distance visual acuity
`(cid:131) Refractive error associated with best corrected distance visual acuity
`(cid:131) Pupil size under standardized lighting conditions
`(cid:131) Slit lamp biomicroscopy of the anterior segment
`(cid:131)
`Intraocular pressure
`(cid:131) Ocular coherence tomography of the macula
`(cid:131) Dilated fundus photography of the retina
`
`
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`1.4.5 Clinical Pharmacology PMRs
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`(cid:131) Complete the ECG sub-study in trial A8081007 and submit the final study
`report, along with a thorough review of cardiac safety data to address any
`potential impact of crizotinib on QTc interval prolongation in patients.
`(cid:131) Conduct a multiple dose trial in humans to determine how to adjust the
`crizotinib dose when it is co-administered with a strong CYP3A inhibitor
`(e.g., ketoconazole).
`(cid:131) Conduct a multiple dose trial to determine the appropriate crizotinib dose
`in patients with various degrees of hepatic impairment.
`(cid:131) Conduct a multiple dose trial to determine the appropriate crizotinib dose
`in patients with severe renal impairment.
`(cid:131) Conduct a multiple dose trial in humans to determine how to dose
`crizotinib with regard to gastric pH elevating agents (i.e., a proton-pump
`inhibitor, an H2-receptor antagonist, and an antacid).
`(cid:131) Submit the study report on the ongoing in vitro evaluations induction
`potential of crizotinib on CYP2B and CYP2C enzymes
`(cid:131) PMC: To conduct exposure-response analysis for progression free
`survival, response rate, overall survival and safety endpoints utilizing data
`from confirmatory trials A8081007 and A8081014.
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`2 Introduction and Regulatory Background
`Lung Cancer remains the number one cause of cancer deaths in United States (1) and
`the World (2). The 5 year survival rate for patients with lung cancer remains dismal
`around 15% (3). Tobacco smoke exposure is a known cause of this cancer in most of
`the cases, however 10% -15 % of the patients are never/light smokers defined as less
`than 100 cigarettes in their lifetime. NSCLC histology comprises about 85% of the lung
`cancer cases and although surgery remains the only curative modality for this disease,
`most of these patients (70%) present at advanced stage and thus are not surgical
`candidates.
`Despite multiple subtypes of NSCLC per WHO Criteria (4) until recently
`
`first-line treatment for advanced disease was platinum-based doublet chemotherapy.
`With the discovery of molecular targets and targeted therapies, new treatment options
`for these patients are evolving.
`
`Bevacizumab a monoclonal antibody directed against vascular endothelial
`growth factor-A (VEGF-A) is approved, with carboplatin and paclitaxel, for first line
`treatment of unresectable, locally advanced, recurrent or metastatic non-squamous
`non-small cell lung cancer. Erlotinib, an Epidermal Growth Factor Receptor (EGFR)
`tyrosine kinase inhibitor, has been approved for treatment of locally advanced or
`metastatic NSCLC after failure of at least one prior chemotherapy regimen and for
`maintenance treatment of patients with locally advanced or metastatic NSCLC whose
`disease has not progressed after four cycles of platinum-based first-line chemotherapy.
`Although both these targeted agents approved for NSCLC do not require demonstration
`of specific molecular abnormalities in patient’s tumor tissue, there is an increasing
`awareness of the importance of identifying specific NSCLC molecular drivers to
`appropriately direct targeted agents to patient populations. The literature review
`demonstrates that in clinical trials, when compared to chemotherapy, EGFR tyrosine
`kinase inhibitors are associated with a high response rate (70-80%) in NSCLC patients
`whose tumor harbor’s EGFR favorable mutations (either del19 or exon 21 L858R) that
`is associated with improved PFS (5,6), however; no over all survival advantage has
`been demonstrated so far.
`
`Soda et al recently discovered an inversion within chromosome 2p resulting in
`
`the formation of a fusion gene product associated protein-like 4 (EML4) gene and the
`ALK gene in NSCLC cell lines and archived clinical specimens (7). EML4–ALK fusion
`gene has been identified as a key driver of oncogenesis in a subset of NSCLC
`patients. ALK fusion gene results in formation of cytoplasmic chimeric proteins with
`constitutive kinase activity. Since then a number of variants of the EML4-ALK fusion
`gene have been discovered rarer fusion partners for ALK such as KIF5B and TFG have
`also been reported (8).
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`
`
`
`Figure 1 EML4-ALK fusion gene
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`
`
`
`In unselected population of patients with NSCLC the frequency of EML4-ALK has
`ranged from 1.5% to 6.7% (8-14), however in small series of selected population of
`never/light smokers the frequency noted has been significantly higher (15). The majority
`of ALK gene rearrangements have been observed in younger patients with
`adenocarcinoma histology with never or light smoking history (7, 12-16). ALK gene
`rearrangements have been rarely noted to be coincident with EGFR, human epidermal
`growth factor receptor 2 (HER2), or Kirsten rat sarcoma (KRAS) mutations (17).
`
`
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`During the Phase 1 study of crizotinib, 2 patients in the 50 mg cohort with ALK
`positive NSCLC were found to have stable disease at 1.5 and 7 months. This led to the
`inclusion of a Phase 2 extension cohort enrolling patients with ALK positive NSCLC.
`
`
`2.1 Product Information
`
`Crizotinib is an oral receptor tyrosine kinase inhibitor. The molecular formula for
`crizotinib is C21H22Cl2FN5O. The molecular weight is 450.34 Daltons. Crizotinib is
`described chemically as (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-
`yl)-1H-pyrazol-4-yl]pyridin-2-amine.
`
`It is a selective adenosine triphosphatase (ATP)-competitive small-molecule inhibitor of
`ALK and c-Met/hepatocyte growth factor receptor (HGFR) tyrosine kinases and their
`oncogenic variants (i.e., ALK fusion proteins or c-Met/HGFR mutant variants). The drug
`demonstrated potent and selective growth inhibitory activity and induced apoptosis in
`tumor cell lines exhibiting ALK fusion events or exhibiting amplification of the ALK or
`MET gene locus and inhibited ALK and c-Met phosphorylation and anti-tumor efficacy in
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`models dependent on ALK and c-Met signaling. Antitumor efficacy was dose-dependent
`and correlated to inhibition of ALK fusion proteins (including EML4-ALK and NPM-ALK)
`in tumors in vivo.
`
`
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`Figure 2 Structural formula of Crizotinib
`
`
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`
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`
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`Molecular Formula Molecular Weight
`C21H22Cl2FN5O 450.34 Daltons
`
`The commercial crizotinib drug product is a hard gelatin capsule formulation in two
`strengths (200 mg and 250 mg), with a
`being used for capsule filling.
`The excipients (including the components in gelatin capsule shell and printing ink) used
`for manufacturing the drug product are all compendial grade. Crizotinib capsules 200
`mg will be provided as white opaque/pink opaque hard gelatin capsules with “CRZ
`200” printed on the body and “Pfizer” printed on the cap. The 250 mg strength will be
`provided as pink opaque/pink opaque hard gelatin capsules with “CRZ 250” and “Pfizer”
`printed on body and cap, respectively. The drug product will be packaged in HDPE
`bottles with child-resistant caps (60 counts/bottle).
`
`Three formulations (powder in capsule (PIC), immediate release tablet, and intravenous
`solution) were used in clinical trials prior to the commercial capsule. The PIC
`formulation (10 mg, 50 mg, and 100 mg) was used for early stage Phase I studies. The
`immediate release tablet (50 mg and 100 mg) formulation, with
` drug loading, was
`later developed to meet the increased demand for further clinical trials. However, due to
`the lower drug loading of the tablet, the commercial capsule formulation was developed
`
`for administration convenience. The tablets and capsules use qualitatively similar
`excipients. The IV solution was developed for use in the absolute bioavailability study.
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`Reference ID: 3000346
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`(b) (4)
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`(b) (4)
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`

`

`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`Device
`Study A used the Vysis ALK Break Apart FISH Probe Kit to detect the presence of an
`ALK gene rearrangement and to thus, determine patient eligibility for study entry. The
`Vysis kit will be marketed as a qualitative test to detect rearrangements involving the
`ALK gene via fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-
`embedded NSCLC tissue specimens. Testing will be performed to aid in the
`identification of patients eligible for treatment with crizotinib. The kit uses formalin-fixed,
`paraffin-embedded tissue sections which have been mounted to glass slides. The tissue
`sections are deparaffinized and the DNA within the nuclei denatured to a single-stranded
`form. The DNA is then hybridized to 2 anti-sense ALK probes. During hybridization, the
`green probe binds to DNA within the ALK gene while the orange probe binds to DNA that
`is 3’ to ALK gene. Following hybridization, the specimens are washed and the nuclei
`counterstained with 4,6 diamidino-2-phenylindole, a DNA-specific stain that fluoresces
`blue. Hybridization of the Vysis probes is viewed using a fluorescence microscope
`equipped with appropriate excitation and emission filters, allowing visualization of the
`orange and green fluorescent signals. When the ALK gene is rearranged, the green and
`orange probes are no longer next to each other and a split signal (green and orange
`signals separated by at least 2 signal diameters), single orange, or single green signal is
`seen. If > 15 cells out of 100 contain a split signal, a single orange signal, or a single green
`signal the specimen contains an ALK gene rearrangement. Tests of the reproducibility of
`specimen interpretation between readers showed a kappa score of 0.72, suggesting
`substantial reproducibility. Tests of the reproducibility of specimen interpretation in the
`same reader showed an overall percent agreement of 100% (95% CI; 83.9,100).
`Reproducibility was also tested between laboratories. Here, the kappa score was 0.92,
`suggesting almost perfect reproducibility.
`
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Currently there are no therapies that have been specifically approved for NSCLC
`patients with tumors harboring a translocation or inversion event involving the ALK gene
`locus. Discovery of this genetic alteration in the tumor of patients with NSCLC makes
`this a new subset for NSCLC patients. However, ALK positive patients have been
`traditionally treated with therapies for NSCLC.
`
`All of the approved therapies for unresectable, locally advanced, recurrent or metastatic
`disease NSCLC have been based on improvement in overall survival compared to a
`comparator.
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`Reference ID: 3000346
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`
`Table 1 Approved Therapies for advanced/metastatic NSCLC
`
`Drug
`Bevacizumab
`Non-
`squamous
`NSCLC
`Docetaxel
`
`Erlotinib
`
`
`
`Gemcitabine
`
`Indication
`Initial treatment, in combination with
`carboplatin and paclitaxel
`
`After platinum therapy failure
`
`Initial treatment, in combination with cisplatin
`
`Maintenance treatment for patients whose
`disease has not progressed after four cycles
`of platinum based first-line chemotherapy
`After failure of at least 1 prior chemotherapy
`regimen
`Initial treatment, in combination with cisplatin
`
`Paclitaxel
`
`Initial treatment, in combination with cisplatin
`
`Pemetrexed
`Non-
`squamous
`NSCLC
`
`Vinorelbine
`
`Initial treatment in combination with cisplatin
`Maintenance treatment for patients whose
`disease has not progressed after four cycles
`of platinum based first-line chemotherapy
`
`After prior chemotherapy as a single agent
`
`single agent or in combination with cisplatin
`for the first-line treatment of ambulatory
`patients
`
`
`
`
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`The commercial dosage formulation for crizotinib was developed as an immediate
`release hard gelatin capsule to deliver 200 mg and 250 mg crizotinib, using the
`drug loading. A150 mg strength was also developed, but not
` approach at
`proposed for commercialization. It was used during development and is now included in
`registration stability studies to bracket the 200 mg strength.
`
`
`Please refer to CMC review
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`
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`Reference ID: 3000346
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`2.4 Important Safety Issues with Consideration to Related Drugs
`
`Although several tyrosine kinase inhibitors have been approved, this is the first drug
`which inhibits the ALK gene.
`
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`In October 2007, the applicant’s Phase 1 trial was amended to include a Phase 2, ALK
`positive NSCLC cohort. The applicant, noting a partial response in 7/14 ALK positive
`patients, met with the Agency to discuss their registration strategy. The Agency
`expressed concern about the size of the database and recommended that the applicant
`conduct a randomized trial of crizotinib vs. conventional therapy. The Agency did
`suggest that if the applicant chose to pursue accelerated approval, “that you entertain a
`randomized study with an interim analysis of a surrogate end point in a larger
`population.” In April 2010, the applicant again met with the Agency to discuss their
`registration strategy. They proposed the submission of 2 single arm studies of crizotinib
`in ALK positive NSCLC. The Agency stated that such a strategy may be acceptable for
`accelerated approval and noted that the overall registration strategy included the
`following studies.
`
`
`• A8081007: Phase 3, Randomized, Open-label Study of the Efficacy and Safety of
`Crizotinib vs. Standard of Care (Pemetrexed or Docetaxel) in Patients with
`Advanced NSCLC Harboring a Translocation or Inversion Event Involving the
`Anaplastic Lymphoma Kinase Gene Locus
`o Patients will have received 1 prior platinum-based regimen. There is 1
`interim analysis at 60% of events with α = 0.0038. At the final analysis,
`with 318 patients, the study will have 90% power to detect an
`improvement in PFS from 2.9 to 4.4 months with α = 0.025 and an 80%
`power to detect an improvement in OS from 8 to 11.5 months with α =
`0.025.
`
`• A8081014: Phase 3, Randomized, Open-label Study of the Efficacy and Safety of
`Crizotinib vs. Pemetrexed/Cisplatin or Pemetrexed/Carboplatin in Previously
`Untreated Patients with Non-Squamous Carcinoma of the Lung Harboring a
`Translocation or Inversion Event Involving the Anaplastic Lymphoma Kinase Gene
`Locus.
`o With 334 patients, the study will have 85% power to detect an
`improvement in PFS from 6 to 9 months with α = 0.025.
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`Reference ID: 3000346
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`14
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`Clinical Review
`Shakun Malik, MD
`NDA 202570
`Crizotinib
`
`Key Meetings between the FDA and the Sponsor
`
`23 April 2009: Type B meeting held to discuss the crizotinib registrational strategy and
`the study design for treatment of advanced NSCLC patients with tumors harboring an
`EML4-ALK fusion.
`
`
`24 July 2009: A joint Pfizer and Abbott Molecular Diagnostic meeting with FDA’s Office
`of In Vitro Diagnostics (OIVD) held to discuss the requirements for an investigational
`use only (IUO) assay.
`
`14 April 2010: Type B meeting held to discuss sponsor’s proposal for accelerated
`approval under Subpart H for crizotinib, based on studies A8081001 and A8081005.
`The registration strategy and the study design for previously untreated locally advanced
`or metastatic non-small cell lung cancer (NSCLC) positive for Anaplastic Lymphoma
`Kinase (ALK) fusion was also discussed.
`
`11 May 2010: A joint Pfizer and Abbott Molecular Diagnostic meeting with FDA’s OIVD
`held to respond to questions from the Agency regarding Pfizer's request for accelerated
`approval of crizotinib, discuss the potential for expedited review status and approval of
`the Vysis ALK BAP kit, and clarify the previously disc