CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`202570Orig1s000
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`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
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`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
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`Date:
`To:
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`Through:
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`From:
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`Subject:
`Drug Name
`(Established Name):
`Therapeutic Class:
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`August 11, 2011
`Robert Justice, M.D., Director
`Division of Drug Oncology Products
`
`Claudia Karwoski, Pharm.D., Director
`Division of Risk Management (DRISK)
`
`Amarilys Vega, M.D., M.P.H.
`Risk Management Analyst, DRISK
`
`
`Cynthia LaCivita, Pharm.D.
`Risk Management Analyst Team Leader, DRISK
`
`Review of the risks associated to NME Crizotinib
`
`Crizotinib
`Anaplastic lymphoma kinase (ALK) receptor tyrosine
`kinase (RTK) and a hepatocyte growth factor receptor
`(HGFR, c-Met) RTK inhibitor
`
`Dosage and Route:
`
`
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`200 mg and 250 mg capsules, oral
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`Application Type/Number: NDA 20-2570
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`
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`Pfizer Inc.
`
`2011-1135
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`Applicant:
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`OSE RCM #:
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`Reference ID: 2999154
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`1
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`

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`1. INTRODUCTION
`This review provides DRISK’s recommendations based on the safety data submitted by
`the sponsor in support of NDA 20-2570, crizotinib.
`On September 13, 2010, crizotinib received an orphan-drug designation and was reviewed
`under the provisions of 21 CFR 314 Subpart H – Accelerated Approval of New Drugs for
`Serious or Life-Threatening Illnesses.
`Crizotinib is a selective small-molecule inhibitor of the anaplastic lymphoma kinase
`(ALK) receptor tyrosine kinase (RTK) and its oncogenic variants and an inhibitor of the
`hepatocyte growth factor receptor (HGFR, c-Met) RTK. Crizotinib is indicated for the
`treatment of ALK-positive non-small cell lung cancer (NSCLC). Crizotinib is not
`authorized or licensed in any country.
`The sponsor proposed to manage all identified risks through labeling; a Risk Evaluation
`and Mitigation Strategy (REMS) was not included in the submission.
`
`2. MATERIALS REVIEWED
`The following documents were reviewed:
`• Pfizer, Crizotinib, Clinical Safety Summary, March 2, 2011, submitted March 30,
`2011.
`• Pfizer, Crizotinib, proposed Prescribing Information (PI), submitted March 30, 2011
`and FDA revised label from August 3, 2011.
`
`
`3. RESULTS OF REVIEW
`
`3.1 Overview of the Clinical Program
`The clinical development program for crizotinib included a total of 8 studies:
`• Study A8081001 – an ongoing multicenter, multinational, open-label, single-arm study
`evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of
`crizotinib in patients with advanced cancer, including a cohort of patients with ALK-
`positive advanced NSCLC.
`• Study A8081005 – multicenter, multinational, open-label, single-arm, Phase 2 study
`evaluating the safety and efficacy of crizotinib in patients with ALK-positive advanced
`NSCLC.
`• Six, phase 1 clinical pharmacology studies – total of 6 biopharmaceutics and
`clinical pharmacology studies conducted in healthy volunteers (study details provided
`in the Clinical Safety Summary, section 2.7.4, Table 1, page 15).
`
` A
`
` total of 450 subjects were included in these 8 studies. Two hundred fifty five patients
`with ALK-positive NSCLC were treated with crizotinib. Data from ALK-positive
`subjects included in studies A8081001 and A8081005 were pooled to allow composite
`analysis. However, the primary analyses of safety were performed in studies A8081001
`and A8081005 individually since studies used different common toxicity criteria
`
`
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`Reference ID: 2999154
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`2
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`versions.1 The pooled data analyses did not adjust for these differences. In addition,
`Serious Adverse Event (SAE) reports obtained from an ongoing study (A80811007, a
`multicenter, multinational, open-label, randomized Phase 3 study comparing crizotinib to
`pemetrexed or docetaxel in patients with previously treated ALK-positive advanced
`NSCLC) were described by the sponsor.
`
`3.2
`Important Safety Concerns
`Most adverse events (AEs) reported were mild to moderate (Grade 1 or Grade 2). The
`most commonly reported AEs were gastrointestinal, neurological, visual, constitutional,
`and hepatic in nature. Twenty-four percent of the patients reported SAEs, the most
`common Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PT)
`were PT Disease Progression (3.9%) and PT Pneumonia (3.9%). Two of the 22 in-study
`deaths (1 death due to pneumonitis, 1 death of unknown cause) were considered
`crizotinib-related.
`The sponsor identified several safety issues based on their clinical significance or
`frequency of observation in the clinical trials and potential attribution to treatment with
`crizotinib. These included pneumonitis, QT interval prolongation, increases in serum
`transaminases, neutropenia, gastrointestinal disorders, neuropathy, and visual disorders.
`Following is a brief description of the safety concerns.
`• Pneumonitis – Four subjects presented with potentially drug-induced pneumonitis,
`including 1 death. Crizotinib has been associated (frequency <2%) with severe, life-
`threatening pneumonitis in the above mentioned clinical trials. The background
`incidence rate of pneumonitis or interstitial lung disease in retrospective studies and
`clinical studies of advanced NSCLC patients ranges from 3.0% to 47.0% in patients
`receiving chemotherapy or radiation therapy and from 0.2% to 3.0% in patients
`receiving epidermal growth factor receptor (EGFR) and tyrosine kinase inhibitor
`(TKI) or placebo. 2
`• QT Interval Prolongation - Prolongation of the QTcF interval ≥ 500 (Fridericia’s
`correction) was reported in 1.2% of subjects in studies A8081001 and A8081005.
`There were 4 (1.6%) patients with reported AEs coded as “Electrocardiogram QT
`prolonged”. However, there was 1 treatment-related SAE of QTc prolongation in
`study A8081007. A substudy of A8081007, designed to characterize the effects of
`therapy with crizotinib on QTc, is ongoing.
`• Hepatic Enzyme Elevation: AE reports describing increases in ALT were received
`from subjects participating in Studies A8081001 (4.2%) and A8081005 (4.4%). These
`reactions were generally asymptomatic, had a positive dechallenge, and did not recur
`at lower crizotinib doses. However, 2 patients required permanent discontinuation of
`therapy. Increases in ALT >3 X ULN and total bilirubin >2 X ULN without elevated
`
`1 National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0
`was used in Study 1001 and Version 4.0 in Study 1005. NCI CTCAE displays Grades 1 through 5 with
`unique clinical descriptions of severity for each AE based on the following general guideline: Grade 1 Mild
`AE; Grade 2 Moderate AE; Grade 3 Severe AE; Grade 4 Life-threatening or disabling AE; Grade 5 Death
`related to AE
`2 Pfizer, Crizotinib, Clinical Safety Summary, March 2, 2011, submitted March 30, 2011
`
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`Reference ID: 2999154
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`alkaline phosphatase were detected in 1/225 (< 0.5%) of patients with available
`laboratory data across both studies. There was 1 patient in Study A8081001 who
`experienced hepatic dysfunction meeting Hy’s Law criteria.
`• Neutropenia: Severe and life-threatening neutropenia (Grade 3 or 4) was reported in
`studies A8081001 (3.4%) and A8081005 (2.2%). There were no deaths or SAEs
`reported in association to neutropenia. However, there was 1 case of PT Fungal
`infection reported in association with treatment-related Grade 4 Neutropenia in Study
`A8081005.
`• Vision Disorders: Included PT Diplopia, PT Photopsia, PT Vision blurred, PT Visual
`field defect, PT Visual impairment, and PT Vitreous floaters. Although frequent,
`vision disorders were mild in severity and did not required dosing interruption, dose
`reduction, or permanent discontinuation from study treatment. The sponsor
`recommends having an ophthalmological evaluation only if the symptoms persist of
`worsen in severity.
`• Edema: Reports of edema including PT Localized oedema, PT Oedema, PT Oedema
`peripheral, were frequent but mild to moderate in nature. There was a treatment-
`related SAE reported (PT Oedema peripheral) in study A8081005, but there was no
`need to discontinue crizotinib permanently.
`• Neuropathy: Treatment-related mild to moderate neuropathy was reported by 11% of
`patients in both studies. Previous therapy with platinum could be a confounding
`factor.
`• Gastrointestinal Disorders: The most commonly reported gastrointestinal AE were
`PT Nausea, PT Diarrhea, PT Vomiting, PT Constipation, and esophageal disorders
`(PT Dysphagia, PT Epigastric discomfort, PT Gastrooesophageal reflux disease, PT
`Odynophagia, PT Oesophageal obstruction, PT Oesophageal pain, PT Oesophageal
`spasm, PT Oesophageal ulcer, PT Oesphagitis, PT Reflux oesophagitis). These were
`mainly mild in severity and its prevalence decreased after 3-4 weeks of crizotinib
`therapy.
`
`
`4. DISCUSSION
`Lung cancer is the leading cause of cancer death for both men and women; approximately
`85% of lung cancers are NSCLC. 3 Crizotinib’s proposed indication is for a narrowly
`defined patient population; specifically patients who have anaplastic lymphoma kinase
`(ALK)-positive advanced NSCLC. ALK-positive patients are the only ones for whom
`crizotinib demonstrated a benefit. FDA agrees with the sponsor on the inclusion of a
`warning indicating that detection of ALK-positive NSCLC is necessary for selection of
`patients treated with crizotinib.
`Non-clinical studies in rats and rabbits showed that crizotinib was embryotoxic and
`fetotoxic at exposures similar to and above those observed in humans at the
`recommended clinical dose of 250 mg BID. Based on these data, the FDA designated
`
`
`3 American Cancer Society- Lung Cancer http://www.cancer.org/Cancer/LungCancer-Non-
`SmallCell/OverviewGuide/index revised 6/20/2011 accessed August 9, 2011.
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`Reference ID: 2999154
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`crizotinib as Pregnancy Category D. A warning regarding potential fetal harm will be
`added to the Warnings and Precautions section of the label.
`The Food and Drug Administration Amendments Act (FDAAA) of 2007 gives FDA
`authority to require a REMS if a strategy beyond routine labeling is required to ensure the
`benefits of the drug outweigh the risks.
`Most, if not all of the prescribers of crizotinib will be oncologists who are experienced
`and familiar with prescribing as well as monitoring and managing similar serious adverse
`events that are associated with antineoplastic therapy. DRISK concurs with DDOP that
`the serious adverse events of neutropenia, pneumonitis, QT interval prolongation, and
`increases in transaminases are consistent with risks associated with other antineoplastic
`agents and managed by oncologists without a REMS and therefore can be adequately
`addressed by inclusion in the Warnings and Precautions section of the label along with
`guidelines for dosage modifications or interruptions based on the severity of
`hematological, pulmonary, cardiac or liver toxicities.
`
`In clinical trials, crizotinib demonstrated antitumor efficacy for the treatment of ALK-
`positive advanced NSCLC. At this time, the benefits of crizotinib appear to outweigh the
`risks in a defined patient population with advanced disease, the decision to not require a
`REMS is reasonable based on the current risk-benefit profile.
`
`5. RECOMMENDATIONS
`DRISK recommends managing all identified serious safety risks through labeling.
`Additional risk management strategies such as a Medication Guide, Communication Plan,
`and/or Elements to Assure Safe Use do not appear warranted at this time. DRISK will
`provide additional comments and recommendations if the review division has further
`concerns with the risks outlined above, or identifies additional risks associated with
`crizotinib warranting more extensive risk mitigation.
`
`Please notify DRISK if you have any questions.
`
`
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`Reference ID: 2999154
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`5
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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/
`----------------------------------------------------
`
`AMARILYS VEGA
`08/11/2011
`
`CLAUDIA B KARWOSKI
`08/11/2011
`concur
`
`Reference ID: 2999154
`
`