CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`202570Orig1s000
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`OFFICE DIRECTOR MEMO
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`Summary Review for Regulatory Action
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`Electronic stamp date
`Richard Pazdur, MD
`Office Director Decisional Memo
`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)
`Accelerated Approval
`
`Action/Recommended Action for NME:
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Medical Officer Review
`Statistical Review
`Pharmacology Toxicology Review
`CMC Review/OBP Review
`
`
`Names of discipline reviewers
`Shakuntala Malik
`Lijun Zhang, Shenghui Tang, Meiyu Shen
`Brenda Gehrke, Whitney Helms, John Leighton
`Zedong Dong, Debasis Gosh, Donghao Lu, Richard Lostritto, Karen
`Riviere
`Stephen Langille
`Microbiology Review
`Pengfei Song, Anshu Marathe
`Clinical Pharmacology Review
`Marybeth Toscano, Richard Lyght
`DDMAC
`Robert Young
`OSI
`Ellen Maher
`CDTL Review
`Kimberly DeFronzo, Denise Baugh, Kevin Wright
`OSE/DMEPA
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`OSE/DDRE
`Latonia Ford, Amarilys Vega
`OSE/DRISK
`Wiley Chambers, John Senior
`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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`Office Director Decisional Memo
`NDA 202570_Xalkori (crizotinib)
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`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)
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`Page 1 of 5
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`Reference ID: 3006933
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`Office Director Decisional Memo
`NDA 202570_Xalkori (crizotinib)
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`1.
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`Introduction
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`
`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.
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`2. Background
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`Crizotinib is a receptor tyrosine kinase inhibitor with activity against c-MET, RON, ROS, and the active kinase
`formed by ALK gene rearrangement.
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`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 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.
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`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 surrogate endpoint in the randomized trial. The sponsor was advised to discuss their
`proposed companion diagnostic with CDRH.
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`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.
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` general pre-NDA meeting was held on 7/29/10 to discuss technical aspects of the submission. A CMC pre-NDA
`meeting was held on 9/24/10.
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` A
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`3. CMC/Device
`The CMC review team recommends that this application be approved with 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.
`
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`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.
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`There are no outstanding CMC or device issues.
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`Page 2 of 5
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`Reference ID: 3006933
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`Office Director Decisional Memo
`NDA 202570_Xalkori (crizotinib)
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`4. Nonclinical Pharmacology/Toxicology
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`There are no pharmacology/toxicology issues that preclude the approval of crizotinib in this indication.
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`5.
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` Clinical Pharmacology/Biopharmaceutics
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`The Clinical Pharmacology and Biopharmaceuticals team recommended approval, and there are no issues that
`would preclude approval. However, they are recommending several PMRs and PMCs mainly to study drug
`interactions and dose adjustments with crizotinib based on these interactions. See action letter for these PMRs
`and PMCs.
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`6. Clinical Microbiology
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`Not applicable.
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`7. Clinical/Statistical-Efficacy
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`This accelerated approval is based on the results of two single-arm studies, Study A (N = 136 patients) and Study
`B (N = 119 patients). Crizotinib, 250 mg, was administered orally twice daily to a total of 255 patients with locally
`advanced or metastatic ALK-positive NSCLC. Demographic analysis from the combined data of these trials noted
`that the median age was 52 years, 63% of patients were Caucasian, 30% were Asian, 48% were male and 84%
`had an ECOG performance status of 0 or 1. Fewer than 3% of patients were current smokers. Ninety-six percent
`had adenocarcinoma, 95% had metastatic disease, and 94% had received prior systemic treatment for NSCLC.
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`The primary endpoint of both trials was objective response rate (ORR) as assessed by the investigator. In Study
`A, the ORR was 50% (95% CI: 42, 59) with a median response duration of 42 weeks. In Study B, the ORR was
`61% (95% CI: 52, 70) with a median response duration of 48 weeks. Complete responses were observed in 1% of
`patients. No differences in ORR by performance status, the number of prior chemotherapeutic regimens, or the
`percentage of cells found to have the ALK gene rearrangement were noted. Efficacy data from Studies A and B
`are provided in Table 1.
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`Table 1: Locally Advanced or Metastatic ALK-Positive NSCLC Efficacy Results from Studies A and B a
`Efficacy Parameter
`Study A
`Study B
`N=136
`N=119
`50% (42%, 59%)
`61% (52%, 70%)
`68
`71
`41.9 (6.1+, 42.1+)
`48.1 (4.1+, 76.6+)
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`ORR (CR+PR)b [% (95% CI)]
`Number of Responders
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` Duration of Responsec [Median (range) weeks]
`aResponse as assessed by the Investigator.
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`bOne patient was not evaluable for response in Study A; 3 patients were not evaluable for response in Study B.
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`cPreliminary estimate using Kaplan-Meier method.
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` +Censored values
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`Although this approval will not include the ALK negative NSCLC population, based on Dr. Maher’s CDTL review,
`“23 patients with locally advanced or metastatic ALK negative NSCLC have received crizotinib. 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
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`Page 3 of 5
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`Reference ID: 3006933
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`Office Director Decisional Memo
`NDA 202570_Xalkori (crizotinib)
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`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”.
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`8. Safety
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`The most common adverse reactions (≥25%) observed in both studies were vision disorder, nausea, diarrhea,
`vomiting, edema, and constipation. Vision disorders included visual impairment, photopsia, vision blurred, vitreous
`floaters, photophobia, and diplopia. Grade 3-4 adverse reactions in at least 4% of patients included increased
`ALT and neutropenia. Crizotinib has been associated with severe, life-threatening, or fatal treatment-related
`pneumonitis with a frequency of 1.6% in clinical trials. All cases occurred within 2 months after the treatment
`initiation.
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`9. Advisory Committee Meeting
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`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.
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`10. Pediatrics
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`PREA does not apply because of orphan drug exclusivity.
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`11. Other Relevant Regulatory Issues
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`There are no other unresolved relevant regulatory issues.
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`12. Labeling
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`• 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; however, these issues were communicated to the sponsor and resolved.
`• Patient labeling: Agreement has been reached on patient labeling.
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`13. Decision/Action/Risk Benefit Assessment
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`• Regulatory Action: Accelerated Approval
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`• Risk Benefit Assessment
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`Compared to conventional chemotherapy, there was a marked elevation in response rate and duration of
`response observed in two single-arm studies with crizotinib. It is thought that this will translate into an
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`Page 4 of 5
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`Reference ID: 3006933
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`Office Director Decisional Memo
`NDA 202570_Xalkori (crizotinib)
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`improvement in overall survival in this patient population; however, as a condition of accelerated
`approval, two Phase 3, randomized (crizotinib vs. conventional chemotherapy) confirmatory trials are
`required to be conducted by the applicant to verify clinical benefit.
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`Although crizotinib appears to be less toxic than conventional chemotherapy, further follow up and
`examination of the adverse event profile of crizotinib in a randomized trial will be necessary to fully define
`the safety signals associated with crizotinib.
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`The benefits and risks of crizotinib were discussed in the Division Director’s Summary Review, the CDTL
`and Clinical Reviews. The review team found the risk-benefit assessment to be acceptable. In
`conclusion, I concur with the review team’s recommendation for approval.
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`• Recommendation for Postmarketing Risk Evaluation and Mitigation Strategies
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`None
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`• Recommendation for other Postmarketing Requirements and Commitments
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`See action letter for PMRs and PMCs. This NDA is being approved under Accelerated Approval,
`therefore, the sponsor is required to conduct confirmatory trials to be considered for full approval.
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`Page 5 of 5
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`Reference ID: 3006933
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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/
`----------------------------------------------------
`
`TAMY E KIM
`08/26/2011
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`RICHARD PAZDUR
`08/26/2011
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`Reference ID: 3006933
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