Assessment report - Europa

1 30 Churchill Place Canary Wharf London E14 5EU United Kingdom An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. 21 May 2015 EMA/444458/2015 Rev 1 Committee for Medicinal Products for Human Use (CHMP) Assessment report Keytruda International non-proprietary name: pembrolizumab Procedure No. EMEA/H/C/003820/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Page 2/160 Table of contents 1. Background information on the procedure .. 7 Submission of the dossier .. 7 Manufacturers .. 8 Steps taken for the Assessment of the product .. 8 2. Scientific discussion .. 9 9 Quality aspects .. 11 Introduction .. 11 Active Substance .. 11 Finished Medicinal Product .. 13 Discussion on chemical, pharmaceutical and biological aspects.

2 14 Conclusions on the chemical, pharmaceutical and biological aspects .. 15 Recommendations for future quality development .. 15 Non-clinical aspects .. 15 Introduction .. 15 Pharmacology .. 15 21 Toxicology .. 22 Ecotoxicity/environmental risk Assessment .. 29 Discussion on non-clinical 29 Conclusion on the non-clinical aspects .. 31 Clinical aspects .. 31 Introduction .. 31 34 Pharmacodynamics .. 39 Discussion on clinical pharmacology .. 44 Conclusions on clinical pharmacology .. 46 Clinical efficacy .. 46 Dose response study(ies) .. 46 Main study(ies) .. 48 Discussion on clinical efficacy .. 103 Conclusions on the clinical efficacy .. 107 Clinical safety .. 108 Discussion on clinical safety .. 144 Conclusions on the clinical safety .. 146 Pharmacovigilance .. 147 Risk Management Plan .. 147 Product information .. 154 User consultation .. 154 3. Benefit-Risk 155 4. Recommendations.

3 157 Page 3/160 List of abbreviations ADA Anti-Drug Antibodies AE Adverse Event AEOSI Adverse Events of Special Interest ALP Alkaline phosphatase ALT Alanine aminotrasferase APaT All Patients as Treated APS Allred Proportion Score AST Aspartate aminotrasferase AUC Area under the curve CHMP Committee for Medicinal Products for Human User CHO Chinese Hamster Ovary CI Confidence Interval(s) CYP Cytochrome P CL Clearance Cmax Maximum concentration CNS Central Nervous System CR Complete Response CTCAE Common Toxicity Criteria for Adverse Events CTLA4 Cytotoxic T-Lymphocite antigen-4 CV Coefficient of variation CYP Cytochrome P450 DCR Disease Control Rate DLT Dose Limiting Toxicity DMC Data Monitoring Committee DTIC dacarbazine EC50 Half-Maximal Effective Concentration ECG Electrocardiogram ECL Electrochemiluminescence ECOG Eastern cooperative oncology group ELISA Enzyme-Linked Immunosorbent assay EORTC- QLQ European Organisation for Research and Treatment of Care core Quality of Life Page 4/160 questionnaire ERA Environmental Risk Assessment eGFR Estimated glomerular filtration rate FAS Full Analysis Set FU Fluorouracil FcRn Fc Receptor Neonatal GCP Good clinical practice GLP Good Laboratory Practice HIV human immunodeficiency virus hr Hour(s)

4 IA2 Interim Analysis 2 IC50 Half-maximal inhibitory concentration ICH International Conference of Harmonisation IFN Interferon IgG Immunoglobulin gamma IHC immunohistochemistry IL Interleukin IL-2 Interleukin 2 IPI ipilimumab IRO Integrated radiology and oncology Assessment irRC immune-related Response Criteria ITT intention to treat IV intravenous intravenous KD Dissociation constant KM Kaplan-Meier z Terminal rate constant LDH Lactate dehydrogenase LLN lower limit normal mAb monoclonal antibody MA Marketing Authorisation MAA Marketing Authorisation Application Page 5/160 mg Milligram mL Milliliter mk-3475 pembrolizumab, Keytruda mM Millimolar MRI magnetic resonance imaging MSD Meso Scale Discovery N/A Not Applicable NAb Neutralizing antibody(ies) nM Nanomolar NSCLC Non-Small Cell Lung Cancer ORR Overall Response Rate OS Overall Survival PAES Post-authorisation efficacy studies PK pharamcokinetics PBMC Peripheral blood (mononuclear)

5 Cell PD pharmacodynamic PD Progressive disease PD-1 Programmed Cell Death Receptor-1 PD-L1 Programmed Cell Death Receptor- Ligand 1 PD-L2 Programmed Cell Death Receptor- Ligand 2 PK Pharmacokinetic PIP Paediatric Investigation Plan PFS Progression Free Survival pM Picomolar PS Performance Status PSUR Periodic Safety Update report PR Partial Response PRAC Pharmacovigilance Risk Assessment Committee PRO patient reported outcome Q Distribution clearance Q2W every 2 weeks Q3W every 3 weeks Page 6/160 QTc QT interval corrected RECIST Response Evaluation Criteria In Solid Tumors RMP Risk Management Plan RR Response Rate RNA Ribonucleic Acid SAE Serious Adverse Event SD Stable disease SEB Staphylococcal Enterotoxin B SmPC Summary of Product Characteristics t1/2 Elimination half-life TK Toxicokinetics Tmax Time to reach maximum concentration TNF Tumor Necrosis Factor TT Tetanus toxoid ULN upper limit normal Vc Volume of distribution central compartment Vp Peripheral volume of distribution Vss Distribution Volume at steady state WBC Whole blood cells g Microgram Page 7/160 1.

6 Background information on the procedure Submission of the dossier The applicant MERCK SHARP & DOHME LIMITED submitted on 4 June 2014 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Keytruda, through the centralised procedure falling within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004. The applicant applied for the following indication: KEYTRUDA is indicated for the treatment of unresectable or metastatic melanoma in adults. The legal basis for this application refers to: Article of Directive 2001/83/EC - complete and independent application. The applicant indicated that pembrolizumab was considered to be a new active substance. The application submitted is composed of administrative information, complete quality data, non-clinical and clinical data based on applicants own tests and studies and/or bibliographic literature substituting/supporting certain test(s) or study(ies).

7 Information on Paediatric requirements Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision P/0059/2014 on the agreement of a paediatric investigation plan (PIP) and the granting of a (product-specific) waiver. At the time of submission of the application, the PIP P/0059/2014 was not yet completed as some measures were deferred. Information relating to orphan market exclusivity Similarity Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised orphan medicinal products because there is no authorised orphan medicinal product for a condition related to the proposed indication. Applicant s request(s) for consideration New active Substance status The applicant requested the active substance pembrolizumab contained in the above medicinal product to be considered as a new active substance in itself, as the applicant claims that it is not a constituent of a product previously authorised within the Union Scientific Advice The applicant received Scientific Advice from the CHMP on 13 December 2012, The Scientific Advice Page 8/160 pertained to non-clinical and clinical aspects of the dossier.

8 Licensing status Keytruda has been given a Marketing Authorisation in the USA on 4 September 2014. Manufacturers Manufacturer of the biological active substance MedImmune, LLC Frederick Manufacturing Center (FMC) 633/636/660 Research Court Frederick MD 21703-8619, USA Manufacturer responsible for batch release Schering-Plough Labo NV Industriepark 30 Heist-op-den-Berg B-2220, Belgium Steps taken for the Assessment of the product The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur: Daniela Melchiorri Co-Rapporteur: Jan Mueller -Berghaus CHMP Peer reviewer: Pieter de Graeff The application was received by the EMA on 4 June 2014. The procedure started on 25 June 2014. The Rapporteur's first Assessment report was circulated to all CHMP members on 12 September 2014. The Co-Rapporteur's first Assessment report was circulated to all CHMP members on 12 September 2014. The PRAC RMP Advice and Assessment overview were adopted by PRAC on 9 October 2014.

9 During the meeting on 20-23 October 2014, the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 24 October 2014. The applicant submitted the responses to the CHMP consolidated List of Questions on 20 February 2015. The Rapporteurs circulated the Joint Assessment report on the applicant s responses to the List of Questions to all CHMP members on 3 April 2015. The PRAC RMP Advice and Assessment overview were adopted by PRAC on 10 April 2015. During the CHMP meeting on 20-23 April 2015, the CHMP agreed on a list of outstanding issues to be addressed in writing by the applicant. Page 9/160 The applicant submitted the responses to the CHMP List of Outstanding Issues on 27 April 2015. The Rapporteurs circulated the Joint Assessment report on the applicant s responses to the CHMP List of Outstanding Issues on 5 May 2015. PRAC RMP Advice and Assessment overview was adopted on 4 May 2015.

10 During the meeting on 21 May 2015, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to Keytruda. 2. Scientific discussion Introduction Melanoma is the most aggressive form of skin cancer. Melanoma is the sixth and seventh most common malignancy in men and women, The median age at diagnosis is 59 years. The incidence of melanoma varies between different European countries but the estimated incidence was about cases men and cases women in 2012. In Europe in 2012, the mortality rate was approximately in males and in The outcome of melanoma depends on the stage at presentation2. Approximately 85% of patients with melanoma present with localised disease, 10% with regional disease and 5% with distant metastatic disease. The 5-year survival rates in patients who present with localised disease and primary tumours or less in thickness are very good, with more than 90% of patients surviving.