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Multi-Discipline Review/Summary, Clinical, Non-Clinical CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210868Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multi-disciplinary Review and Evaluation NDA 210868 Lorlatinib NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NDA Application Number(s) 210868 Priority or Standard Priority Submit Date(s) December 5, 2017 Received Date(s) December 5, 2017 PDUFA Goal Date November 5, 2018 Division/Office OHOP/DOP2 Review Completion Date November 2, 2018 Established Name Lorlatinib (Proposed) Trade Name LORBRENA Pharmacologic Class Kinase inhibitor Code name PF-06463922 Applicant Pfizer, Inc. Formulation(s) 100 mg and 25 mg tablets Dosing Regimen 100 mg orally once daily Applicant Proposed For the treatment of patients with anaplastic lymphoma kinase Indication(s)/Population(s) (ALK)-positive metastatic non-small cell lung cancer (NSCLC) previously treated with one or more ALK tyrosine kinase inhibitors (TKIs). Recommendation on Accelerated Approval Regulatory Action Recommended For the treatment of patients with anaplastic lymphoma kinase Indication(s)/Population(s) (ALK)-positive metastatic non-small celling cancer (NSCLC) (if applicable) whose disease has progressed on: • crizotinib and at least one other ALK inhibitor for metastatic disease; or • alectinib as the first ALK inhibitor therapy for metastatic disease; or • ceritinib as the first ALK inhibitor therapy for metastatic disease 1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4344794 NDA Multi-disciplinary Review and Evaluation NDA 210868 Lorlatinib Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 13 Additional Reviewers of Application ............................................................................................. 13 Glossary ......................................................................................................................................... 14 1 Executive Summary ............................................................................................................... 17 Product Introduction ...................................................................................................... 17 Conclusions on the Substantial Evidence of Effectiveness ............................................ 17 Benefit-Risk Assessment ................................................................................................. 18 Patient Experience Data ................................................................................................. 25 Section 19.6, Additional Clinical Outcome Assessment Analyses ............................................ 25 2 Therapeutic Context .............................................................................................................. 27 Analysis of Condition ...................................................................................................... 27 Analysis of Current Treatment Options .......................................................................... 28 3 Regulatory Background ......................................................................................................... 35 U.S. Regulatory Actions and Marketing History ............................................................. 35 Summary of Presubmission/Submission Regulatory ..................................................... 35 ActivityFollowing the receipt of final written responses for a Type B pre-IND meeting on June 14, 2013, regarding the design of the first-in-patient trial of lorlatinib (PF-06463922) under IND 118296, the original IND was filed on August 15, 2013. A list outlining the pertinent regulatory history for lorlatinib is included in the table below. ............................................... 35 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety................................................................................................................. 38 Office of Scientific Investigations (OSI) .......................................................................... 38 Product Quality ............................................................................................................... 39 Clinical Microbiology ...................................................................................................... 39 Devices and Companion Diagnostic Issues ..................................................................... 39 5 Nonclinical Pharmacology/Toxicology................................................................................... 40 Executive Summary ........................................................................................................ 40 Referenced NDAs, BLAs, DMFs ....................................................................................... 42 Pharmacology ................................................................................................................. 43 2 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4344794 NDA Multi-disciplinary Review and Evaluation NDA 210868 Lorlatinib ADME/PK ........................................................................................................................ 52 Toxicology ....................................................................................................................... 56 General Toxicology .................................................................................................. 56 Genetic Toxicology .................................................................................................. 66 Carcinogenicity ........................................................................................................ 68 Reproductive and Developmental Toxicology ........................................................ 68 Other Toxicology Studies ........................................................................................ 73 6 Clinical Pharmacology ............................................................................................................ 74 Executive Summary ........................................................................................................ 74 Summary of Clinical Pharmacology Assessment ............................................................ 77 Pharmacology and Clinical Pharmacokinetics ........................................................ 77 General Dosing and Therapeutic Individualization ................................................. 78 Comprehensive Clinical Pharmacology Review .............................................................. 80 General Pharmacology and Pharmacokinetic Characteristics ................................ 80 Clinical Pharmacology Questions ............................................................................ 84 7 Sources of Clinical Data and Review Strategy ..................................................................... 105 Table of Clinical Studies ................................................................................................ 105 Review Strategy ............................................................................................................ 107 8 Statistical and Clinical and Evaluation ................................................................................. 108 Review of Relevant Individual Trials Used to Support Efficacy .................................... 108 Study B761001 ...................................................................................................... 108 Study Results ......................................................................................................... 131 Assessment of Efficacy Across Trials ..................................................................... 149 Review of Safety ........................................................................................................... 152 Safety Review Approach ....................................................................................... 152 Review of the Safety Database ............................................................................. 152 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 155 Safety Results ........................................................................................................ 158 Analysis of Submission-Specific Safety Issues ....................................................... 177 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 202 Safety Analyses by Demographic Subgroups ........................................................ 202 3 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews) Reference ID: 4344794 NDA Multi-disciplinary Review and Evaluation NDA 210868 Lorlatinib Specific Safety Studies/Clinical Trials .................................................................... 205 Additional Safety Explorations .............................................................................. 205 Safety in the Postmarket Setting ................................................................... 207 Integrated Assessment of Safety ................................................................... 207 SUMMARY AND CONCLUSIONS .................................................................................................
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