CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202570Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`July 12, 2011
`V. Ellen Maher, M.D.
`Cross-Discipline Team Leader Review
`202570/S0
`Pfizer, Inc.
`March 30, 2011
`September 30, 2011
`Xalkori/crizotinib
`
`Date
`From
`Subject
`NDA/BLA # Supplement#
`Applicant
`Date of Submission
`PDUFA Goal Date
`Proprietary Name / Established
`(USAN) names
`Dosage forms / Strength
`Proposed Indication(s)
`
`200 mg, 250 mg capsules
`Anaplastic lymphoma kinase-positive advanced non-
`small cell lung cancer
`Approval
`
`Recommended:
`1. Introduction
`On March 30, 2011, Pfizer submitted a new drug application for the use of crizotinib in the
`treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer
`(NSCLC). This application is supported by 2 single arm studies (Study A and Study B)
`evaluating the response rate of crizotinib. Issues in the review of this application include:
`
`
`• An incomplete understanding of the safety signals associated with crizotinib;
`• The atypical disease characteristics of the patients with NSCLC entered on these
`trials;
`• The use of response rate as a surrogate endpoint; and
`• The availability of approved drugs and biologics in NSCLC.
`2. Background
`
`
`Crizotinib is a receptor tyrosine kinase inhibitor with activity against c-MET, RON, ROS, and
`the constituitively active kinase formed by ALK gene rearrangement. The half-maximal
`effective concentration (EC50) of crizotinib against each of these targets is shown below.
`
`
`Table 1: EC50 of Crizotinib Against Receptor Tyrosine Kinases
`In Vitro EC50
`0.5 nM (24 nM)IC
`0.62 nM (11 nM)IC
`9.1 nM (80 nM)EC
`60 nM
`
`Target
`EML4-ALK
`WT c-MET
`RON RTK
`ROS RTK
`
`
`ALK inhibition by crizotinib results in reduced downstream signaling in ERK, Akt, STAT3,
`and PLCγ1, pathways known to contribute to cellular growth and development. In animal
`models, expression of the ALK fusion protein in lung alveolar cells, without other genetic
`alterations, leads directly to the development of lung cancer. ALK rearrangements are
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`estimated to occur in 1-7% of NSCLCs (Clin Cancer Res 2009 15:5216). During the Phase 1
`study of crizotinib, 2 patients in the 50 mg cohort with ALK positive NSCLC had 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. This application includes 2 single arm trials, one from
`this Phase 2 extension (Study B) and the other a single arm, Phase 2 trial (Study A). Both have
`shown a response rate and duration of response that is markedly higher than that expected with
`approved therapy.
`
`Approved agents for NSCLC are shown in the table below. The majority have received regular
`approval based on an improvement in overall survival. To grant accelerated approval of any
`drug, the drug must treat a serious or life-threatening illness and must provide “meaningful
`therapeutic benefit to patients over existing treatments” (21 CFR 314.500). While not every
`patient on these 2 single arm studies has received all approved therapy, the majority of patients
`have received standard first and second line therapy for NSCLC. Further, given the presence
`of a specific genetic rearrangement, patients with ALK positive NSCLC represent a unique
`patient population. Finally, accelerated approval can be granted on a “surrogate endpoint that
`is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence,
`to predict clinical benefit” (21 CFR 314.510). Here, the applicant has chosen to submit 2 trials
`in which the primary endpoint is response rate rather than overall surviva (an endpoint thought
`to directly measure clinical benefit). Given the marked improvement, over existing NSCLC
`therapies, in response rate and duration of response of crizotinib, it is likely that these
`responses will translate into clinical benefit for patients harboring the ALK translocation.
`
`Table 2: Approved Therapies in Non-Small Cell Lung Cancer
`Indication
`Basis of Approval
`Initial treatment, in combination with carboplatin and paclitaxel
`Overall Survival
`
`Overall Survival
`
`Overall Survival
`
`Progression-free Survival1
`
`Overall Survival
`
`Overall Survival
`
`Overall Survival2
`
`Overall Survival
`
`Overall Survival
`
`Overall Survival
`
`Overall Survival
`
`Drug
`Bevacizumab
`Non-squamous
`Docetaxel
`
`
`
`After platinum therapy
`
`Initial treatment, in combination
`
`Erlotinib
`
`Maintenance treatment
`
`
`
`After failure of at least 1 prior regimen
`
`Gemcitabine
`
`Initial treatment, in combination with cisplatin
`
`Paclitaxel
`
`Initial treatment, in combination with cisplatin
`
`Pemetrexed
`Non-squamous
`
`Initial treatment in combination with cisplatin
`
`Maintenance treatment
`
`After prior chemotherapy
`
`Vinorelbine
`
`Initial treatment, single agent or in combination
`
`1The primary endpoint was PFS. The study also demonstrated a statistically significant improvement in OS.
`2The difference in OS was not statistically significant.
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`Regulatory History
`
`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.
`3. CMC/Device
`
`
`Chemistry, Manufacturing, and Control
`The applicant has pursued a quality-by-design approach to the manufacture of crizotinib
`(shown below). The R enantiomer of Form A is proposed to be the active form of crizotinib.
`
`
` and
`steps,
`Crizotinib is synthesized in
` All excipients are compendial. Crizotinib is provided in 200 and 250
`
`
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`(b)
`(4)
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`(b) (4)
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`(b) (4)
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`Cross Discipline Team Leader Review
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`mg capsules and will have a 15 month expiry when stored in the commercial package at 250C.
`While the commercial drug product is supplied in capsule form, crizotinib tablets and
`crizotinib powder in capsules (PIC are different from the commercial product) were used in
`Studies A and B. The applicant does not have information on the patients treated solely with
`crizotinib tablets, solely with PIC or with a combination of the two. During the review period,
`CMC conveyed a substantial number of comments to the applicant concerning their quality-
`by-design approach. These were ultimately addressed and the CMC reviewers recommend
`approval. Establishment inspections were acceptable.
`
`Device
`The Vysis ALK Break Apart FISH Probe 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. The Vysis test was used to select
`patients for entry into Study A. This kit uses formalin-fixed, paraffin-embedded tissue sections
`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. During hybridization, the green
`probe binds to complementary DNA that is centromeric to the breakpoint while the orange probe
`binds to complementary DNA that is telomeric to the breakpoint. 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. 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 of 100 cells contains a split
`signal, a single orange signal, or a single green signal, the tissue contains an ALK gene
`rearrangement. Tests of the reproducibility of specimen interpretation between readers showed a
`kappa score of 0.72, when equivocal results are included, suggesting substantial reproducibility.
`When the equivocal results were resolved, the kappa statistic was 1.00, suggesting almost perfect
`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.
`There was no relationship between the site of analysis and FISH classification.
`4. Nonclinical Pharmacology/Toxicology
`
`
`ALK is in normally expressed in neural cells, pericytes, and the endothelial cells of the adult
`brain. However, in repeat dose toxicology studies in the dog and rat, abnormalities were noted
`in the liver, gastrointestinal tract, heart, lymph nodes, and bone marrow. In animal studies, it
`was also noted that crizotinib concentrated in the eye with a half-life of 576 hours.
`Electroretinograms in the rat showed reduced dark adaption, but there were no treatment
`related ophthalmic findings in the repeat dose toxicology studies. At 1.1 μM, crizotinib
`inhibits hERG and an increase in QTc was seen in dog studies.
`
`Crizotinib is genotoxic, but not mutagenic. In reproductive toxicology studies, maternal
`mortality, post-implantation fetal loss, and decreased fetal weight were seen. Teratogenicity
`was not seen. Crizotinib has been assigned Pregnancy Category D.
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`5. Clinical Pharmacology/Biopharmaceutics
`
`
`Crizotinib is absorbed orally (more soluble in acid pH) and can be taken with or without food.
`Peak concentration is reached 4-6 hours after dosing and the terminal half-life is 42 hours. In
`patients taking crizotinib 250 mg twice a day, steady state is reached in 15 days. Crizotinib is
`metabolized in the liver by CYP3A4/5. Following oral administration, 63% of crizotinib is
`recovered in the feces and 22% in the urine. No dose adjustment is needed for mild or
`moderate renal impairment. The effects of severe renal impairment and hepatic impairment
`are unknown. Crizotinib acts as a moderate CYP3A inducer and inhibitor and drug-drug
`interaction occurs with strong CYP3A inhibitors or inducers.
`
`Crizotinib is highly protein bound and at steady state the mean AUCtrough is 3,880 ng·hr/mL
`while the median Ctrough ranged from 242 to 319 ng/mL over cycles 1-4. The applicant
`estimates that these concentrations are capable of inhibiting kinases in which the IC50 < 114
`nM. Despite this, in Study B an exposure-response relationship was seen between steady state
`trough concentration and patient response. The exposure-response relationship was less clear
`in Study A. No exposure-adverse event relationship was seen for crizotinib. Since it may be
`possible to increase the dose of crizotinib (dose limiting toxicity Phase 1 was fatigue), the
`clinical pharmacology group plans to examine the exposure-response relationship further in
`Studies 1007 and 1014.
`6. Clinical Microbiology
`
`
`Not applicable
`7. Clinical/Statistical- Efficacy
`
`
`Table 3 provides criteria for Study A and for the ALK positive NSCLC cohort in Study B.
`Study B also included a dose escalation cohort, an ALK negative NSCLC cohort, and a cohort
`of patients treated at crizotinib 250 mg bid with a variety of malignancies. The applicant has
`termed this cohort “Other”. It included patients with lesions in the c-MET/hepatocyte growth
`factor pathway, ROS, or ALK (e.g., anaplastic large cell lymphoma).
`
`
`
`
`
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`
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`Cross Discipline Team Leader Review
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`Table 3: Study Design
`
`Study B (1001: ALK+ NSCLC Cohort)
`1. Locally advanced or metastatic NSCLC containing
`an ALK translocation or gene amplification by a
`local laboratory developed test
`2. Measurable disease
`3. Performance status 0-2
`4. No gr 1-2 cardiac arrhythmia, uncontrolled atrial
`fibrillation, QTc > 470 msec
`
`Study A (1005)
`1. Locally advanced or metastatic NSCLC containing an
`ALK translocation or inversion event by the Vysis ALK
`Break Apart Assay
`2. Progressive disease on the control arm of a randomized
`study of crizotinib OR ineligible for a randomized study
`3. Measurable disease
`4. Prior chemotherapy for NSCLC; erlotinib, gefitinib not
`considered prior therapy
`5. Performance status 0-3
`6. No grade 1-2 cardiac arrhythmia, uncontrolled atrial
`fibrillation, QTc > 470 msec
`Crizotinib 250 mg po BID; powder in capsules or tablets
`Treatment Crizotinib 250 mg po BID; tablets
`• Cycles defined as 28 d.
`• Cycles defined as 21 d.
`NCI CTCAE v 3.0
`NCI CTCAE v 4.0
`CBC, Chemistries: baseline, C1D15, q cycle
`CBC, Chemistries: baseline, C1D15, q cycle
`
`EKG: baseline, then C1D1, C2D1 prior to dose and at 2 h, 6 h EKG: baseline, then C1D1, C1D15, C2D1 prior to dose
`and 4-6 h post dose; then C1D2 and q cycle prior to dose
`post dose
`Ophthalmology evaluation: baseline, w/ visual disorder;
`Ophthalmology evaluation: baseline, w/ visual disorder
`visual symptom assessment questionnaire
`Imaging: baseline, q 8 wks until INV-determined progression
`Imaging: baseline, q 6 wks until INV-determined
`or start of a new cancer therapy
`progression or start of a new cancer therapy
`Response rate by Investigator using RECIST v1.1
`Response rate by Investigator using RECIST v 1.0
`95% confidence intervals
`95% confidence intervals
`Duration of response
`Overall survival; 6 and 12 mo OS
`Time to response
`Duration of response
`Disease control rate at 6 and 12 wks
`Disease control rate at 8 and 16 wks
`Progression free survival
`Progression free survival; 6 mo PFS
`Time to response
`Overall Survival; 6 and 12 mo OS
`The primary analysis population includes patients who: 1) received crizotinib, 2) had an adequate baseline tumor
`assessment, and 3) had > 1 adequate post-baseline tumor assessment. Patients who died or withdraw due to disease
`progression are included in this population. The post-baseline assessment must be > 6 wks from the 1st dose.
`
`
`Eligibility
`Criteria
`
`Safety
`Monitoring
`
`Endpoint
`Evaluation
`Primary
`Endpoint
`Secondary
`Endpoints
`
`Statistical
`Plan
`
`The primary endpoint will be confirmed by an assessment of response by an Independent Radiology Committee. The
`primary analysis population is the same.
`
`
`Changes in Study Conduct
`
`Study A (1005) was amended 9 times. Amendment 7 added the Independent Review
`Committee (IRC) and allowed for a treatment delay < 42 days. It also added a visual
`assessment questionnaire. Dose modification and criteria for pneumonitis and for a QTc > 500
`were added in Amendments 7 and 8.
`
`Study B (1001) was amended 15 times. It includes several substudies in which patients
`received a single dose of crizotinib on day -7 and then began daily crizotinib on day 1.
`Amendment 4 provided for an ALK positive NSCLC cohort and Amendment 12 for an ALK
`negative NSCLC cohort. Amendment 12 also substituted crizotinib capsules for tablets and
`provided for a baseline ophthalmology examination in all patients. Amendment 15 provided
`dose modification and monitoring criteria for pneumonitis. The independent radiology review
`committee (IRC) was added as an amendment to the statistical analysis plan.
`
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`Patient Disposition
`
`Study A was conducted at 57 sites while Study B, which began as a Phase 1 trial, was
`conducted at 8 sites. Fifty-six percent of patients were from the US in Study A and 71% in
`Study B. To be eligible for Study A an ALK translocation must have been documented using
`the Vysis ALK Break Apart FISH Assay. A variety of laboratory developed assays were used
`to document the ALK translocation in Study B.
`
`Both studies are ongoing and contain several populations with a variety of cutoff dates. The
`table below outlines these populations and provides information on the disposition of Safety
`Population 1. Note that among the 5 patients in which discontinuation was listed as due to
`Patient Decision/Lost to Follow Up, 1 died due to an adverse event 5 days after
`discontinuation and 1 reported a grade 3 adverse event the day prior to discontinuation.
`Information on all patient deaths and discontinuations in Safety Population 1 is included in the
`Safety section.
`
`
`Table 4: Patient Disposition
`Study A (1005)
`135
`(Data cutoff 2-1-11)
`261
`
`Study B (1001)
`119
`(Data cutoff 9-15-10)
`136
`
`136
`
`119
`
`
`Efficacy Population
`
`Safety Population 1
`(Deaths, Discontinuations, SAEs)
`Safety Population 2
`(Grade 1-4 AEs)
`
`
`Study A
`(Data cutoff 2-1-11)
`261
`205
`56
`9
`31
`13
`1/2
`0
`
`Study B
`(Data cutoff 2-1-11)
`136
`79
`57
`4
`30
`16
`1/1
`51
`
`Patients Treated
` Ongoing
` Discontinued
` Adverse Events
` Progressive Disease
` Death
` Lost to Follow Up/Patient Decision
` Other
`1Clinical progression in 5 pts
`
`Patient Demographics and Baseline Characteristics
`
`Median age was 52 years on Study A and 51 years on Study B. Both studies, unlike most
`studies of NSCLC, contained a nearly equal proportion of males and females. Racial
`distribution was similar on both studies with 63.1% of patients characterized as Caucasian,
`30.2% Asian, 3.1% Black, and 3.5% Other. The majority of patients were non-smokers or
`former smokers. Among former smokers, the median time since discontinuation was 15 years
`and 10 years on Studies A and B, respectively.
`
`The median time from diagnosis on both studies was surprisingly long. It is unclear if patients
`at the edge of this range (e.g., patients diagnosed with NSCLC 13.7 years prior to study entry),
`in fact, had a second primary tumor. The sample date for ALK testing was examined in
`patients diagnosed more than 5 years prior to study entry and the sample collection dates in all
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`patients were within the year prior to study entry. Finally, the majority of patients on both
`trials had an adenocarcinoma. Additional information on tumor histology is provided in the
`footnote below the table. Thirteen patients entered Study A after disease progression on the
`control arm of randomized trials of crizotinib.
`
`
`
`
`Table 5: Baseline and Disease Characteristics
`Study B (1001)
`Study A (1005)
`N = 119
`N = 136
`
`
`Performance Status
`35.1%
`27.2%
` 0
`52.6%
`54.4%
` 1
`11.8%
`18.4%
` 2
`0.8%
`0
` 3
`
`
`Smoking Status
`72.3%
`67.6%
` Non-smoker
`26.9%
`28.7%
` Former Smoker
`0.8%
`3.7%
` Smoker
`1.22 years (0.04-20.7)
`2 years (0.15-13.7)
`Median Time Since Diagnosis
`Not Collected
`0.9 years (0.005-11.3)
`Median Time Since Metastatic/Recurrent Disease
`
`
`Stage
`4.2%
`6.6%
` Locally Advanced
`95.8%
`93.4%
` Metastatic
`
`
`Histological Subtype
`98.3%2
`97.1%1
` Adenocarcinoma
`0.8%
`0
` Squamous Cell Carcinoma
`0
`2.2%
` Adenosquamous Carcinoma
`0.8%
`0.7%
` Non-small Cell Lung Cancer NOS
`
`
`Prior Therapy
`98.3%
`99.3%
` Surgery
`57.1%
`56.6%
` Radiation Therapy
`86.6%
`100.0%
` Chemotherapy for Metastatic Disease
`1Includes adenocarcinoma NOS (93), signet ring (11), acinar (7), bronchoalveolar (7), solid (6), papillary (5),
`mixed acinar and papillary (2), and large cell (1).
`2Includes adenocarcinoma NOS (115), bronchoalveolar (1), and large cell (1).
`
`The following table provides information on the number of prior chemotherapy regimens and
`the percentage of patients receiving FDA-approved agents for NSCLC. While every patient
`has not received all approved chemotherapy, substantial numbers of patients have received
`each of the approved agents. Since data was available, patient response was examined to each
`agent. In general, the response rate of ALK positive patients is consistent with that of NSCLC
`as a whole. Response to erlotinib was 4.7% in the two studies.
`
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` 0 Prior Regimens
` 1 Prior Regimen
` 2 Prior Regimens
` 3 Prior Regimens
` 4-12 Prior Regimens
`Prior Adjuvant/Metastatic Chemotherapy
`
`Bevacizumab
`Erlotinib
`Gemcitabine
`Pemetrexed
`Platinum Compounds
`Taxanes (docetaxel, paclitaxel)
`Vinorelbine
`
`The baseline tumor characteristics of patients on Studies A and B is outlined below. Disease
`burden is assessed by the sum of the longest diameter (SLD) of the target lesions. The SLD in
`both trials is small and subset analyses of the primary endpoint were conducted in patients
`with varying degrees of tumor burden. The metastatic pattern in patients with ALK positive
`NSCLC appears typical of NSCLC as a whole.
`
`
`Study B
`N = 119
`12.6%
`31.1%
`20.2%
`14.3%
`21.8%
`
`N = 111
`34.2%
` 43.2%
`35.1%
`54.1%
`95.5%
` 64.0%
`22.5%
`
`Cross Discipline Team Leader Review
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`Table 6: Prior Chemotherapy
`Number of Prior Chemotherapy Regimens for Metastatic Disease
`
`Study A
`N = 136
`0
`9.6%
`27.2%
`27.2%
`36.0%
`
`N = 136
`40.4%
`47.8%
`44.9%
`88.2%
` 95.6%
`74.3%
`20.6%
`
`Table 7: Baseline Tumor Characteristics
`Study A
`N = 93
`5.2 cm (1.0-19.6)
`N = 135
`6.7 cm (1.1-62.5)
`N = 135
`70.4%
`38.5%
`35.6%
`7.4%
`3.7%
`2.2%
`
`Study B
`N = 103
`5.3 cm (1.0-43.7)
`N = 114
`8.7 cm (1.0-42.5)
`N = 114
`72.8%
`63.2%
`27.2%
`8.8%
`2.6%
`0.9%
`
`
`IRC Sum of the Longest Diameter
` Median (range)
`INV Sum of the Longest Diameter
` Median (range)
`INV Sites of Target Lesions
` Lung
` Lymph Node
` Liver
` Adrenal
` Chest/Chest Wall
` Brain
`
`Primary Endpoint
`
`The table below provides information on the primary endpoint for Studies A and B. The
`primary endpoint was investigator (INV)-determined response rate on the response-evaluable
`population (see Study Design). Despite the ability of ALK gene rearrangements to induce an
`oncogenic phenotype in the absence of other mutations/amplifications, crizotinib induced
`primarily partial rather than complete response. Although the number of patients with brain
`metastases was small, it appears that these lesions do not respond to crizotinib.
`
`The IRC-determined response rate was slightly lower than the INV-determined response rate,
`but does support the findings of the investigators. Note that the number of patients available
`for IRC review is smaller than the number available for INV review. This is due to problems
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`with the transmission of the scans to the IRC and to the lack of target lesions on IRC review of
`some scans. In Study A, 34 of the 67 patients with INV-determined response (CR or PR)
`were found to have a response by the IRC. In Study B, 52 of the 71 patients with INV-
`determined response had a response IRC assessment.
`
`
`
`
`
`Table 8: Primary Endpoint
`Study A
`
`Study B
`
`INV
`N = 116
`71 (61.2%)
`[51.7%, 70.1%]
`2
`69
`
`48.1 weeks (4.1, 76.6)
`
`IRC
`N = 105
`55 (52.4%)
`[42.4%, 62.2%]
`0
`55
`
`58.1 weeks (36.3, NR)
`
`IRC
`INV
`N = 105
`N = 135
`44 (41.9%)
`67 (49.6%)
`Response Rate
`[32.3%, 51.9%]
`[40.9%, 58.4%]
`[95% CI]
`1
`1
` Complete Response
`43
`66
` Partial Response
`
`
`Duration of Response
` Median (range)1
`33.1 weeks (18.7, NR)
`41.9 weeks (6.1, 42.1)
`1Kaplan-Meier method with censored values
`
`In addition to INV-IRC discrepancies, patient progression was also examined. Among the
`patients who did not achieve a response on Study A, a new lesion was the basis of progression
`in slightly more than half the patients. Likewise, among the patients who responded and later
`progressed, slightly more than half the patients progressed with new lesions. Among patients
`on Study B who responded and later progressed, approximately 1/3 progressed due to the
`presence of a new lesion.
`
`Subset Analyses
`
`To further understand the response to crizotinib, a number of subset analyses were carried out
`and selected analyses are shown in the table below. There was no clear difference in response
`by performance status, sex, age, and number of prior chemotherapeutic regimens.
`Further, there was also no difference in response by tumor burden. This was of particular
`concern since the median SLD in both studies is very small. Finally, the percentage of cells
`found to have a rearrangement in the ALK gene was not related to response. In both studies,
`there was a marked difference in response by race. The clinical pharmacology group has
`examined this and found that this difference appears to be related to body size. That is, the
`higher response rate in Asians (who also had a smaller body size) may be explained by their
`higher dose of crizotinib (on a mg/kg basis).
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`Table 9: Subgroup Analyses
`Study A
`N = 135
`
`Study B
`N = 116
`
`Response by Performance Status
`54.1%
` 0
`52.1%
` 1
`36.0%
` > 2
`
`Response by Race
`60.5%
` Asian
`44.6%
` Non-Asian
`
`Response by Region
`44.3%
` US
`55.4%
` Non-US
`Response by Number of Prior Chemotherapy Regimens
` 0 Prior Regimens
`NA
` 1 Prior Regimen
`46.2%
` 2 Prior Regimens
`62.2%
` 3 Prior Regimens
`43.2%
` > 4 Prior Regimens
`45.8%
`Response by Disease Burden
`
` Baseline SLD < Median
`42.7%
` Baseline SLD > Median
`56.7%
`
`Some patients in Studies A and B were reported to have a prolonged period between diagnosis
`and study entry. Among the 19 patients in whom the time between diagnosis and study entry
`was reported to be > 5 years, 6 (31.6%) were responders. That is, the high response rates in
`these studies are not driven by these “atypical” patients. Of more concern are the 48 patients
`on Study A who were reported to have metastatic or recurrent disease > 18 months prior to
`entry. In these patients, 24 (50.0%) were responders. This is consistent with the patient
`population as a whole and, again, did not drive the high response rates in these studies.
`
`ALK Negative Non-Small Cell Lung Cancer
`
`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.
`
`Other Malignancies
`
`Two patients with NSCLC with unknown ALK status in the “Other” Cohort on Study B had a
`partial response.
`
`53.8%
`62.9%
`73.3%
`
`82.4%
`52.4%
`
`46.9%
`94.3%
`
`85.7%
`54.6%
`60.0%
`76.5%
`50.0%
`
`52.2%
`53.7%
`
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`8. Safety
`
`
`The focus of the safety review will be on the adverse event information from 255 patients with
`ALK positive NSCLC from Studies A and B. The original NDA submission provided this data
`with a cutoff of September 15, 2010. The original NDA submission also provided adverse
`event information for 85 patients on Study B who did not have ALK positive NSCLC. The
`Safety Update, using a later cutoff of February 1, 2011, provided only information on patient
`deaths and SAEs. This was provided for:
`
`
`• 255 patients with ALK positive NSCLC;
`• 85 patients on Study B without ALK positive NSCLC;
`• An additional 142 patients on Studies A and B with ALK positive NSCLC;
`• An additional 32 patients on Studies A and B without ALK positive NSCLC; and
`• 71 patients with ALK positive NSCLC on Study 1007.
`
`
`This review does not provide information on adverse events which occurred between day -7
`(single dose) and day 1 (continuous dosing). These adverse events were supplied in Listing
`6.3.1 and were primarily gastrointestinal events with 1 report of a grade 2 ALT elevation.
`
`Exposure
`
`The table below provides information on patient exposure to crizotinib on Studies A and B.
`Thirty-two patients on Study B have remained on crizotinib for > 1 year. While only 1 patient
`has been treated on Study A for > 1 year, Study A began approximately 4 years after initiation
`of Study B.
` A substantial number of patients on both studies required treatment interruption or dose
`reduction. The median duration of interruption was similar on both studies, 7 days on Study A
`and 6.5 days on Study B. It is, however, unclear why the percentage of patients who
`underwent dose reduction is higher on Study A. .
`
`
`
`
`Table 10: Duration of Exposure in Studies A and B
`Study A
`N = 136
`
`5.1 months (0.2-12.2)
`36.0%
`44.1%
`
`Study B
`N = 119
`
`7.8 months (0.4-23.5)
`45.4%
`29.4%
`
`Duration of Exposure
` Median (range)
`Dose Interruption
`Dose Reduction
`
`Deaths and Discontinuations
`
`In the ALK positive NSCLC cohorts of Studies A and B, 45 patients died within 28 days of
`study drug. This includes 10 patients who died during their first 28 days on study. Among the
`45 patients, 32 deaths were due to progressive disease and 13 due to an adverse event.
`Adverse events that occurred within 28 days of study drug and led to death are included in the
`table below. The table includes information on all patients with ALK positive NSCLC who
`received crizotinib (N = 397) and on the 255 patients in the efficacy population in which all
`
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`adverse event data is available. The table also include information on 5 patients in Study 1007
`(ALK positive NSCLC) who died within 28 days of crizotinib.
`In reviewing this table, respiratory events and septic shock stand out as areas of concern. In a
`single arm study in NSCLC, it is difficult to discern whether respiratory events are related to
`crizotinib or to the underlying disease. Pneumonitis has been identified as an adverse event
`associated with crizotinib and is discussed below. Septic shock or DIC were reported in 4
`patients (1 patient listed as pneumonia had pneumonia resulting in septic shock). In 2 patients,
`septic shock was associated with possible pneumonia. In 2 additional patients, the c