CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`202570Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Division Director Review
`
`
`
`
`Date
`From
`Subject
`NDA/BLA #
`Supplement #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`Proposed Indication(s)
`
`Summary Review for Regulatory Action
`
`August 26, 2011
`Robert L. Justice, M.D., M.S.
`Division Director Summary Review
`202570
`
`Pfizer Inc
`3/30/11
`9/30/11
`XALKORI/
`crizotinib
`Capsules, 200 mg and 250 mg
`treatment of anaplastic lymphoma kinase (ALK)-
`positive advanced non-small cell lung cancer (NSCLC)
`Approval
`
`Action/Recommended Action for
`NME:
`
`
`Material Reviewed/Consulted
`
`Names of discipline reviewers
`OND Action Package, including:
`Shakuntala Malik
`Medical Officer Review
`Lijun Zhang, Shenghui Tang, Meiyu Shen
`Statistical Review
`Pharmacology Toxicology Review Brenda Gehrke, Whitney Helms, John Leighton
`CMC Review/OBP Review
`Zedong Dong, Debasis Gosh, Donghao Lu, Richard
`Lostritto, Karen Riviere
`Stephen Langille
`Pengfei Song, Anshu Marathe
`Marybeth Toscano, Richard Lyght
`Robert Young
`Ellen Maher
`Kimberly DeFronzo, Denise Baugh, Kevin Wright
`
`Latonia Ford, Amarilys Vega
`Wiley Chambers, John Senior, Rosane Charlab Orbach
`
`Microbiology Review
`Clinical Pharmacology Review
`DDMAC
`OSI
`CDTL Review
`OSE/DMEPA
`OSE/DDRE
`OSE/DRISK
`Other: Consults
`OND = Office of New Drugs
`DDMAC = Division of Drug Marketing, Advertising and Communication
`OSE = Office of Surveillance and Epidemiology
`DMEPA = Division of Medication Error Prevention and Analysis
`OSI = Office of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DRISK = Division of Risk Management
`CDTL = Cross-Discipline Team Leader
`
`
`
`
`
`
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`Division Director Review
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`Division Director Summary Review
`
`
`
`1. Introduction
`
`
`This new drug application for XALKORI (crizotinib) Capsules was submitted on 3/30/11 for
`the indication of treatment of patients with anaplastic lymphoma kinase-positive (ALK-
`positive) advanced non-small cell lung cancer (NSCLC). Because of the high objective
`response rates in two single-arm trials in patients with ALK-positive NSCLC, the application
`was given a priority review. This review will briefly discuss the clinical trial efficacy and
`safety results and the recommendations of each review discipline.
`
`
`2. Background
`
`
`The following summary of crizotinib’s mechanism of action is from the Acting Pharmacology
`Team Leader’s Review.
`
`
`The pharmacology studies submitted to this NDA demonstrate that crizotinib is a
`kinase inhibitor. Like other approved kinase inhibitors crizotinib targets a several
`proteins at clinically relevant concentrations including c-Met/hepatocyte growth factor
`receptor (HGFR), anaplastic lymphoma kinase (ALK), and Recepteur d’Origine
`Nantais (RON). Though the drug has its strongest potency against c-Met, the clinical
`development of crizotinib has focused on patients with tumors expressing ALK gene
`translocation products. ALK has an important role during development, particularly in
`neural development, but has limited expression in normal cells. Translocations with
`the ALK gene have led to the expression of oncogenic fusion proteins resulting in
`dysregulated expression of, and increased signaling through this kinase. Crizotinib
`was able to inhibit the growth of tumors derived from various cell types expressing c-
`Met/HGFR, and either EML-ALK4 or NPM-ALK4 translocations both in vitro and in a
`series of xenograft experiments conducted in athymic mice. Treatment of these mice
`with the drug also led to decreased phosphorylation of a number of downstream targets
`in the tumors, decreases in proliferation markers, and increases in apoptotic markers,
`further demonstrating the pharmacologic activity of crizotinib.
`
`
`ALK rearrangements are estimated to occur in 1-7% of patients with NSCLC (Clin Cancer Res
`2009 15:5216). In October 2007, the sponsor’s phase 1 trial was amended to include a phase 2
`ALK-positive cohort based on partial responses in 7/14 previously treated patients with ALK-
`positive NSCLC.
`
`An End-of-Phase 2 meeting was held on 4/23/09. The sponsor asked about accelerated
`approval based on a single-arm study. The FDA expressed concern about the size of the
`database and recommended a randomized trial vs. conventional therapy (docetaxel or
`pemetrexed). Accelerated approval could be considered based on an interim analysis of a
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`surrogate endpoint in the randomized trial. The sponsor was advised to discuss their proposed
`companion diagnostic with CDRH.
`
`At a meeting on 4/14/10, the sponsor asked whether it would be acceptable to submit an NDA
`for accelerated approval based on two single-arm trials in patients with ALK-positive NSCLC,
`if the safety profile remained acceptable and the observed ORR results were maintained. The
`FDA stated that it would be acceptable to submit the data but whether the response rate would
`support accelerated approval would be a review issue and would depend on the final response
`rate, the durations of response, and the risk:benefit ratio. The sponsor also asked whether one
`phase 3 study (A8081014) would be sufficient for full approval. The FDA cautioned about
`relying on a single trial, recommended overall survival as the primary endpoint, and stated that
`whether PFS would support full approval would be a review issue and would likely require an
`ODAC discussion. There was additional discussion about the companion diagnostic.
`
` A
`
` general pre-NDA meeting was held on 7/29/10 to discuss technical aspects of the
`submission and a CMC pre-NDA meeting was held on 9/24/10.
`
`
`3. CMC/Device
`
` I
`
` concur with the conclusions reached by the chemistry reviewers regarding the acceptability
`of the manufacturing of the drug product and drug substance. Manufacturing site inspections
`were acceptable. Stability testing supports an expiry of fifteen months.
`
`
`The companion diagnostic, the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular,
`Inc.), will be approved concurrently with crizotinib. The test is designed to detect
`rearrangements of the anaplastic lymphoma kinase (ALK) gene in NSCLC.
`
`There are no outstanding CMC or device issues.
`
`
`4. Nonclinical Pharmacology/Toxicology
`
` I
`
` concur with the conclusions reached by the pharmacology/toxicology reviewers that there
`are no outstanding pharm/tox issues that preclude approval.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
` I
`
` concur with the conclusions reached by the clinical pharmacology/biopharmaceutics
`reviewers that there are no outstanding clinical pharmacology issues that preclude approval.
`I also concur with the recommended PMR’s and PMC’s. See section 13.
`
`
`
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`6. Clinical Microbiology
`
`
`Not applicable.
`
`
`7. Clinical/Statistical-Efficacy
`
`
`This accelerated approval is based on the results of two single-arm studies. The following
`excerpt from the agreed-upon package insert summarizes the trials and their results.
`
`
`The use of single-agent XALKORI in the treatment of locally advanced or metastatic
`ALK-positive NSCLC was investigated in 2 multi-center, single-arm studies (Studies
`A and B). Patients enrolled into these studies had received prior systemic therapy, with
`the exception of 15 patients in Study B who had no prior systemic treatment for locally
`advanced or metastatic disease. In Study A, ALK-positive NSCLC was identified using
`the Vysis ALK Break-Apart FISH Probe Kit. In Study B, ALK-positive NSCLC was
`identified using a number of local clinical trial assays. The primary efficacy endpoint in
`both studies was Objective Response Rate (ORR) according to Response Evaluation
`Criteria in Solid Tumors (RECIST). Response was evaluated by the investigator and by
`an independent radiology review panel. Duration of Response (DR) was also evaluated.
`Patients received 250 mg of XALKORI orally twice daily. Demographic and disease
`characteristics for Studies A and B are provided in Table 4.
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`Table 4: Demographic and Disease Characteristics in Studies A and B
`Characteristics
`Study A
`Study B
`N=136
`N=119
`
`
`Sex, n (%)
`59 (50)
`64 (47)
`
`Male
`60 (50)
`72 (53)
`
`Female
`
`
`Age (years)
`52 (29-82)
`51 (21-79)
`
`Median (range)
`
`
`Race, n (%)
`74 (62)
`87 (64)
`
`White
`3 (3)
`5 (4)
`
`Black
`34 (29)
`43 (32)
`
`Asian
`8 (7)
`1 (1)
`
`Other
`
`
`ECOG PS at baseline, n (%)
`37 (27)
`41 (35)
`
`0
`74 (54)
`63 (53)
`
`1
`2 – 3a
`25 (18)
`15 (13)
`
`Smoking status, n (%)
`
`
`
`Never smoked
`92 (68)
`86 (72)
`
`Former smoker
`39 (29)
`32 (27)
`
`Current smoker
`5 (4)
`1 (1)
`
`
`Disease stage, n (%)
`5 (4)
`9 (7)
`
`Locally advanced
`114 (96)
`127 (93)
`
`Metastatic
`Histological classification, n (%)
`
`
`
`Adenocarcinoma
`130 (96)
`116 (98)
`
`Large cell carcinoma
`1 (1)
`1 (1)
`
`Squamous cell carcinoma
`0
`1 (1)
`
`Adenosquamous carcinoma
`3 (2)
`0
`
`Other
`2 (2)
`1 (1)
`Prior systemic therapy for locally advanced or
`
`
`metastatic disease -- number of regimens, n (%)
`
`
`0
`
`15 (13)
`
`1
`13 (10)
`34 (29)
`
`2
`37 (27)
`20 (17)
`
`3
`37 (27)
`17 (14)
` ≥4
`49 (36)
`33 (28)
`a Includes 1 patient with an ECOG PS of 1 at screening but was 3 at baseline.
`
` 0
`
`
`
`
`
`
`One hundred thirty-six patients with locally advanced or metastatic ALK-positive
`NSCLC from Study A were analyzed at the time of data cutoff. The median duration of
`treatment was 22 weeks. Based on investigator assessments, there was 1 complete and
`67 partial responses for an ORR of 50% (95% CI: 42%, 59%). Seventy-nine percent of
`objective tumor responses were achieved during the first 8 weeks of treatment. The
`median response duration was 41.9 weeks.
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`One hundred nineteen patients with locally advanced or metastatic ALK-positive
`NSCLC were enrolled into Study B at the time of data cutoff. The median duration of
`treatment was 32 weeks. Based on investigator assessments, there were 2 complete and
`69 partial responses for an ORR of 61% (95% CI: 52%, 70%). Fifty-five percent of
`objective tumor responses were achieved during the first 8 weeks of treatment. The
`median response duration was 48.1 weeks.
`
`Efficacy data from Studies A and B are provided in Table 5.
`
`Table 5: Locally Advanced or Metastatic ALK-Positive NSCLC
`Efficacy Results from Studies A and B a
`Study A
`N=136
`50% (42%, 59%)
`
`Study B
`N=119
`61% (52%, 70%)
`
`
`
` Duration of Responsec [Median (range)
`weeks]
`
` aResponse as assessed by the Investigator.
` bOne patient was not evaluable for response in Study A; 3 patients were not evaluable for response in Study B.
` cPreliminary estimate using Kaplan-Meier method.
` +Censored values
`
`Since the investigator’s determination of response was the primary endpoint, the results of the
`independent radiology review (IRR) panel’s assessment are not shown above. The following
`excerpt from the Statistical Review and Evaluation summarizes the initial IRR response rates
`and the updated IRR response rates that were submitted on 8/17/11. Study A is Study 1005
`and Study B is Study 1001.
`
`
`Efficacy Parameter
`
`ORR (CR+PR)b [% (95% CI)]
`
`
`Number of Responders
`
`68
`
`71
`
`41.9 (6.1+, 42.1+)
`
`48.1 (4.1+, 76.6+)
`
`In Study 1005, IRR response rate was 41.9% (95% CI: 32.3%, 51.9%) in IRR response
`evaluable patient population (n=105), and was 32.3% (95% CI: 24.6%, 40.9%) in
`safety-analysis population (n=136).
`
`In Study 1001, IRR response rate was 52.4% (95% CI: 42.4%, 62.2%) in IRR response
`evaluable patient population (n=105), and was 46.2% (95% CI: 37.0%, 55.6%) in
`safety-analysis population (n=119).
`
`On 17 August 2011, the applicant submitted updated objective response data per IRR
`assessments for both studies. Study 1005 had 1 complete response and 62 partial
`responses, with an IRR response rate of 46.3% (95% CI: 37.7%, 55.1%) in safety-
`analysis population (n=136). Study 1001 had 63 partial responses, with an IRR
`response rate of 52.9% (95% CI: 43.6%, 62.2%) in safety-analysis population (n=119).
`
`The initial IRR response rates were somewhat lower than the investigator response rates,
`particularly in the safety-analysis population. However, not all scans were available for the
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`initial review. The updated IRR response rates were higher for both studies and closer to the
`investigator assessed response rates.
`
`The following summary of the available data on the activity of crizotinib in patients with
`locally advanced or metastatic NSCLC that is ALK-negative is from the CDTL Review.
`
`Twenty-three (23) patients with locally advanced or metastatic ALK negative NSCLC
`have received crizotinib. ALK status was determined using the Vysis kit. Eight of the
`23 (34.8%) had not received prior chemotherapy for metastatic disease. Five of 19
`patients responded for an investigator response rate of 26.3% (95% CI 9.1%, 51.2%).
`Two additional patients have a single assessment of PR. If confirmed, the response rate
`would be 7/20 (35.0%). This is similar to the response rate in patients with ALK
`positive NSCLC in Study A. It is unclear if this finding is related to the assay or to the
`ability of crizotinib to target other genetic abnormalities associated with NSCLC such
`as c-Met or ROS. The applicant is retrospectively testing tumor samples for the
`presence of these genetic abnormalities. The study of additional patients with ALK
`negative NSCLC will be a post-marketing requirement.
`
`Since the activity of crizotinib in patients with ALK-negative NSCLC is not a safety issue, it
`will be a postmarketing commitment.
`
`8. Safety
`
`
`The following summary of safety is from the adverse reactions section of the agreed-upon
`package insert.
`
`
`In Studies A and B, patients with locally advanced or metastatic ALK-positive NSCLC
`received crizotinib 250 mg orally twice daily continuously. Among the 255 patients for
`whom data on Grade 1-4 adverse reactions are available, median exposure to study
`drug was 5.1 months in Study A and 7.8 months in Study B. Dosing interruptions
`occurred in 36% and 45% of patients in Studies A and B, and lasted greater than 2
`weeks in 13% and 19% of patients in Studies A and B, respectively. Dose reductions
`occurred in 44% and 29% of patients in Studies A and B, respectively. The rates of
`treatment-related adverse events resulting in permanent discontinuation were 6% in
`Study A and 3% in Study B. The most common adverse reactions (≥25%) across both
`studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation.
`Grade 3-4 adverse reactions in at least 4% of patients in both studies included ALT
`increased and neutropenia.
`
`Among the 397 patients for whom information on deaths and serious adverse reactions
`are available, deaths within 28 days of the last dose of study drug occurred in 45
`patients. Ten (2.5%) patients died within 28 days of their first dose of study drug.
`Causes of death included disease progression (32 patients), respiratory events (9), and
`other (4). Respiratory causes of death included pneumonia (2), hypoxia (2), ARDS (1),
`dyspnea (1), pneumonitis (1), empyema (1), and pulmonary hemorrhage (1). Other
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`
`
` 0
`
` 0
`
`
`0
`0
`1 (<1%)
`0
`0
`1 (<1%)
`
` 0
`
`
`4 (2%)
`0
`0
`
`
`
` 0
`
`
`14 (5%)
`5 (2%)
`
` 0
`
` 0
`
`Division Director Review
`
`causes of deaths included septic shock, DIC, cardiovascular event, and death due to
`unknown cause (1 each). Serious adverse events in greater than or equal to 2% of
`patients included pneumonia, dyspnea, and pulmonary embolism. Table 3 lists the
`common adverse reactions on Studies A and B in patients receiving XALKORI.
`
`Table 3: Adverse Reactions in ≥10% of Patients with Locally Advanced or
`Metastatic ALK-Positive NSCLC on Studies A and B1
`Adverse Event
`Treatment Emergent
`N=255
`All Grades
`Grade 3/4
`n (%)
`n (%)
`Eye Disorders
`
` Vision Disorder2
`163 (64%)
`Gastrointestinal Disorders
`
` Nausea
`145 (57%)
` Diarrhea
`124 (49%)
` Vomiting
`116 (45%)
` Constipation
`98 (38%)
` Esophageal Disorder3
`51 (20%)
` Abdominal Pain4
`40 (16%)
` Stomatitis5
`27 (11%)
`General Disorders
`
` Edema6
`97 (38%)
`80 (31%)
` Fatigue
` Chest Pain/Discomfort7
`30 (12%)
`30 (12%)
` Fever
`Infections and Infestations
`
` Upper Respiratory Infection8
`50 (20%)
`Investigations
`
`38 (15%)
` Alanine Aminotransferase Increased
`29 (11%)
` Aspartate Aminotransferase Increased
`Metabolism and Nutrition
`
`69 (27%)
` Decreased Appetite
`Musculoskeletal
`
`29 (11%)
` Arthralgia
` Back Pain
`28 (11%)
`Nervous System Disorders
`
` Dizziness9
`60 (24%)
` Neuropathy10
`58 (23%)
`34 (13%)
` Headache
`33 (13%)
` Dysgeusia
`Psychiatric Disorders
`
` Insomnia
`30 (12%)
`Respiratory Disorders
`
`57 (22%)
` Dyspnea
`54 (21%)
` Cough
`Skin Disorders
`
`
`41 (16%)
` Rash
`1Study A used CTCAE v4.0, and Study B used CTCAE v3.0.
`
`
`
` 0
`
`
`2 (<1%)
`1 (<1%)
`3 (1%)
`2 (<1%)
`3 (1%)
`1 (<1%)
`1 (<1%)
`
`2 (<1%)
`6 (2%)
`1 (<1%)
`1 (<1%)
`
`1 (<1%)
`
`17 (7%)
`7 (3%)
`
`3 (1%)
`
`3 (1%)
`0
`
` 0
`
`
`1 (<1%)
`1 (<1%)
`0
`
`
`
` 0
`
` 0
`
`
`16 (6%)
`3 (1%)
`
`
`
`
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`Treatment Related
`N=255
`All Grades
`Grade 3/4
`n (%)
`n (%)
`
`159 (62%)
`
`136 (53%)
`109 (43%)
`101 (40%)
`69 (27%)
`29 (11%)
`20 (8%)
`15 (6%)
`
`72 (28%)
`51 (20%)
`3 (1%)
`2 (<1%)
`
`4 (2%)
`
`34 (13%)
`24 (9%)
`
`49 (19%)
`
`4 (2%)
`2 (<1%)
`
`42 (16%)
`34 (13%)
`10 (4%)
`30 (12%)
`
`8 (3%)
`
`5 (2%)
`9 (4%)
`
`25 (10%)
`
`
`
`
`0
`
` 0
`
`
`1 (<1%)
`0
`0
`
`
`
` 0
`
`
`
` 0
`
`
`3 (1%)
`0
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`

`Division Director Review
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`
`
`
`
`
`
`
`
`2Includes diplopia, photopsia, photophobia, vision blurred, visual field defect, visual
`impairment, vitreous floaters, visual brightness, and visual acuity reduced.
`3Includes dyspepsia, dysphagia, epigastric discomfort/pain/burning, esophagitis,
`esophageal obstruction/pain/spasm/ulcer, gastroesophageal reflux, odynophagia, and
`reflux esophagitis.
`4Includes abdominal discomfort, abdominal pain, abdominal pain upper, and
`abdominal tenderness.
`5Includes mouth ulceration, glossodynia, glossitis, cheilitis, mucosal inflammation,
`oropharyngeal pain/discomfort, oral pain, and stomatitis.
`6Includes edema, edema localized, and peripheral edema.
`7Includes chest pain, chest discomfort, and musculoskeletal chest pain.
`8Includes nasopharyngitis, rhinitis, pharyngitis, and upper respiratory tract infection.
`9Includes balance disorder, dizziness, and presyncope.
`10Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia,
`paresthesia, peripheral neuropathy, peripheral motor neuropathy, and peripheral
`sensory neuropathy.
`
`Vision disorders including visual impairment, photopsia, vision blurred, vitreous
`floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical
`trials. These events generally started within two weeks of drug administration.
`Ophthalmological evaluation should be considered, particularly if patients experience
`photopsia or experience new or increased vitreous floaters. Severe or worsening
`vitreous floaters and/or photopsia could also be signs of a retinal hole or pending
`retinal detachment. Caution should be exercised when driving or operating machinery
`by patients who experience vision disorder…
`
`Neuropathy as defined in Table 3 and attributed to study drug by the investigator was
`reported in 34 (13%) patients. While most events were Grade 1, Grade 2 motor
`neuropathy and Grade 3 peripheral neuropathy were reported in 1 patient each.
`Dizziness and dysgeusia were also very commonly reported in these studies, but were
`all Grade 1 or 2 in severity.
`
`Bradycardia has been reported in 12 (5%) patients treated with XALKORI. All of these
`cases were Grade 1 or 2 in severity.
`
`Complex renal cysts have been reported in 2 (1%) patients treated with XALKORI.
`There were no reports of abnormal urinalyses or renal impairment in these cases.
`Laboratory Abnormalities
`Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia were seen in 5.2%,
`0.4%, and 11.4% of patients, respectively.
`
`Three reported adverse reactions warrant inclusion in the Warnings and Precautions section.
`Crizotinib has been associated with severe, life-threatening, or fatal treatment-related
`pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients across Studies A and
`B. All of these cases occurred within 2 months after the initiation of treatment. Therefore,
`patients should be monitored for pulmonary symptoms indicative of pneumonitis and should
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`be evaluated for the cause of pneumonitis. In patients diagnosed with treatment-related
`pneumonitis, crizotinib should be permanently discontinued.
`
`Grade 3 or 4 ALT elevation was observed in 7% of patients in Study A and in 4% of patients
`in Study B. They were generally asymptomatic and reversible upon dosing interruption.
`Although patients usually resumed treatment at a lower dose without recurrence, 3 patients
`from Study A (2%) and 1 patient from Study B (less than 1%) required permanent drug
`discontinuation. Concurrent elevations in ALT greater than 3 x ULN and total bilirubin greater
`than 2 x ULN without elevated alkaline phosphatase were detected in 1/255 (less than 0.5%) of
`patients with available laboratory data across both studies. Criteria are provided for monitoring
`liver function tests and for treatment interruption, dose reduction and drug discontinuation.
`
`QTc prolongation has been observed and crizotinb should be avoided in patients with
`congenital long QT syndrome. In patients with congestive heart failure, bradyarrhythmias,
`electrolyte abnormalities, or who are taking medications that are known to prolong the QT
`interval, periodic monitoring with electrocardiograms (ECGs) and electrolytes should be
`considered. Criteria are provided for drug discontinuation, treatment interruption, and dose
`reduction.
`9. Advisory Committee Meeting
`
`
`The application was not referred to an FDA advisory committee because it did not raise
`significant safety or efficacy issues in the intended population. However, the application was
`discussed independently with two SGE’s. Both recommended approval.
`
`
`10.
`
`Pediatrics
`
`
`PREA does not apply because of orphan drug exclusivity.
`
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`There are no other unresolved relevant regulatory issues.
`
`
`12.
`
`Labeling
`
`
`
`• Proprietary name: XALKORI was found to be acceptable by DMEPA.
`• Physician labeling: Agreement has been reached on the physician labeling.
`•
`Immediate container labels: Minor problems in the immediate container label were
`identified by DMEPA and CMC. The FDA agreed that the applicant could launch with
`the originally submitted container labels so that the drug could get to patients quicker.
`However, the applicant is required to make the revisions with the next printing in
`September.
`
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`
`
`
`
`
`
`
`• Patient labeling: Agreement has been reached on patient labeling.
`13.
`Decision/Action/Risk Benefit Assessment
`
`• Regulatory Action
`
`Accelerated approval
`
`The following two postmarketing trials are required to confirm clinical benefit.
`
`
`1789-1
`
`
`
`
`
`Clinical trial report and datasets from A8081007: Phase 3, Randomized, Open-
`label Study of the Efficacy and Safety of PF-02341066 vs. Standard of Care
`(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
`
`
`Final Protocol Submission: 09/2009 (submitted)
`Trial Completion:
`
`12/2013
`Final Report Submission:
`06/2014
`
`
`1789-2
`
`Clinical trial report and datasets from 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
`
`
`Final Protocol Submission: 06/2010 (submitted)
`Trial Completion:
`
`12/2015
`Final Report Submission:
`06/2016
`
`
`
`
`
`• Risk Benefit Assessment
`
`As noted in Table 4 above, these two studies enrolled patients who had received
`multiple prior systemic therapies. Twenty-eight to 36% of patients had received four
`or more treatment regimens. Despite this, the objective response rates in these studies
`(50% and 61%) were higher than would be expected with standard chemotherapy. In
`addition, the median durations of response were 41.9 and 48.1 weeks, respectively. It
`is likely that these responses will translate into an improvement in progression-free
`survival and overall survival in the ongoing confirmatory trials.
`
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`Division Director Review
`
`The most common adverse reactions were vision disorder, nausea, diarrhea, vomiting,
`edema, and constipation. The incidence of Grade 3-4 adverse reactions was low
`compared to other chemotherapy agents. The most common Grade 3-4 adverse
`reactions were ALT increased (5%) and neutropenia (5.2%). The major safety
`concerns are vision disorders and severe, life-threatening, or fatal treatment-related
`pneumonitis which occurred in 1.6% of patients. Almost all of the vision disorders
`were Grade 1 and there is a PMR that will require better characterization of this
`toxicity. Pneumonitis has been seen with other kinase inhibitors and is difficult to
`evaluate in a single arm trial in patients with NSCLC who often have pneumonitis due
`to disease or other treatments. Again, the confirmatory trials will further characterize
`this safety signal.
`
`• Recommendation for Postmarketing Risk Evaluation and Mitigation Strategies
`
`None
`
`• Recommendation for other Postmarketing Requirements and Commitments
`
`Postmarketing Requirements (PMR)
`
`The following PMR recommended by Clinical Pharmacology is intended to identify an
`unexpected serious risk of drug interactions caused by the induction of human CYP2B
`and CYP2C enzymes by crizotinib.
`
`1789-3
`
`
`Submit the final report on the ongoing in vitro evaluations of induction potential of
`crizotinib on CYP2B and CYP2C enzymes.
`
`
`Final Protocol Submission: 12/2011
`Study Completion:
`
`12/2011
`Final Report Submission:
`12/2011
`
`The following PMR recommended by the ophthalmologic consultant is intended to
`assess a known serious risk of visual disorders with crizotinib.
`
`1789-4
`
`Clinical trial (existing trial or new clinical trial) in which at least 30 patients are
`studied. The following examinations should be 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).
`
`
`1. Best corrected distance visual acuity
`2. Refractive error associated with best corrected distance visual acuity
`
`
`
`
`
`
`
`
`
`
`
`
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`Division Director Review
`
`3. Pupil size under standardized lighting conditions
`4. Slit lamp biomicroscopy of the anterior segment
`5. Intraocular pressure
`6. Ocular coherence tomography of the macula
`7. Dilated fundus photography of the retina
`
`
`
`Final Protocol Submission: 10/2011
`Trial Completion:
`
`12/2013
`Final Report Submission:
`06/2014
`
`
`
`The following PMRs recommended by Clinical Pharmacology are intended to assess
`signals of a serious risk of QT prolongation, drug-drug interactions with CYP3A
`inhibitors and inducers and gastric pH elevating drugs, and increased concentrations of
`crizotinib in patients with hepatic impairment or severe renal impairment.
`
`1789-5
`
`Complete the ECG sub-study in trial A8081007 and submit the final report, along with
`a thorough review of cardiac safety data to address any potential impact of crizotinib
`on QTc interval prolongation in patients.
`
`
`
`Final Protocol Submission: 09/2009 (submitted)
`Trial Completion:
`
`12/2013
`Final Report Submission:
`06/2014
`
`
`1789-6
`
`Conduct a multiple dose trial in patients to determine how to adjust the crizotinib dose
`when it is coadministered with a strong CYP3A inhibitor (e.g., ketoconazole).
`
`
`Final Protocol Submission: 03/2012
`Trial Completion:
`
`01/2015
`Final Report Submission:
`07/2015
`
`
`1789-7
`
`Conduct a multiple dose trial in patients to determine how to adjust the crizotinib dose
`when it is coadministered with a strong CYP3A inducer (e.g., rifampin).
`
`
`Final Protocol Submission: 03/2012
`Trial Completion:
`
`01/2015
`Final Report Submission:
`07/2015
`
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`
`
`
`1789-8
`
`Conduct a multiple dose trial to determine the appropriate crizotinib dose in patients
`with various degrees of hepatic impairment.
`
`
`Final Protocol Submission: 09/2011
`Trial Completion:
`
`07/2013
`Final Report Submission:
`01/2014
`
`
`1789-9
`
`Conduct a trial in humans to determine the appropriate crizotinib dose in patients with
`severe renal impairment.
`
`
`Final Protocol Submission: 09/2011
`Trial Completion:
`
`04/2012
`Final Report Submission:
`10/2012
`
`
`
`
`
`
`1789-10
`Conduct a 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).
`
`
`Final Protocol Submission: 01/2012
`Trial Completion:
`
`03/2013
`Final Report Submission:
`09/2013
`
`Postmarketing Commitments
`
`The following PMC recommended by CDRH is intended to further explore the
`observed responses in patients with ALK-negative NSCLC.
`
`1789-11
`
`To assess the adequacy of the current cut-off, conduct a clinical trial to explore
`response to crizotinib in ALK-negative patients based on current assay cut-off. This
`should be compared to historic controls and to the response in ALK-positive patients.
`Additional biomarkers should be assessed in ALK-negative patients.
`
`
`Final Protocol Submission: 10/2011
`Trial Completion:
`
`05/2013
`Final Report Submission:
`11/2013
`
`
`
`
`
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`Division Director Review
`
`
`
`The following PMCs recommended by Clinical Pharmacology are intended to provide
`exposure-response analyses based on the two confirmatory trials.
`
`1789-12
`
`To conduct exposure-response analysis for progression-free survival, response rate,
`overall survival and safety endpoints utilizing data from confirmatory trial A8081007
`and to submit the analysis plan for review.
`
`
`Final Protocol Submission: 09/2009 (submitted)
`Analysis Plan Submission: 05/2012
`Trial Completion:
`
`12/2013
`Final Report Submission:
`06/2014
`
`
`1789-13
`
`To conduct exposure-response analysis for progression free survival, response rate,
`overall survival and safety endpoints utilizing data from confirmatory trial A8081014
`and to submit the analysis plan for review.
`
`
`
`
`Final Protocol Submission: 06/2010 (submitted)
`Analysis Plan Submission: 05/2012
`Trial Completion:
`
`12/2015
`Final Report Submission:
`06/2016
`
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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/
`----------------------------------------------------
`
`ROBERT L JUSTICE
`08/26/2011
`
`Reference ID: 3007072
`
`