Keytruda, INN - pembrolizumab · PDF file KEYNOTE-021 (cohort G); -label trial of pembrolizumab in combination with a Phase 1/2, open chemotherapy or immunotherapy in patients with

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14 September 2017 EMA/687095/2017 Committee for Medicinal Products for Human Use (CHMP)

Assessment report

Keytruda

International non-proprietary name: pembrolizumab

Procedure No. EMEA/H/C/003820/II/0027

Note Variation assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.

Marketing authorisation holder (MAH): Merck Sharp & Dohme Limited

Assessment report EMA/687095/2017 Page 2/138

Rapporteur(s) and type of application

CHMP Rapporteur:

Daniela Melchiorri

CHMP Co-Rapporteur:

Jan Mueller-Berghaus

PRAC Rapporteur:

Sabine Straus

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Assessment Timetable

Timetable Planned dates Actual dates

Start of procedure 25 March 2017 25 March 2017

CHMP Rapporteur Assessment Report 19 May 2017 22 May 2017

CHMP Co-Rapporteur Assessment Report 19 May 2017 23 May 2017

PRAC Rapporteur Assessment Report 26 May 2017 26 May 2017

PRAC members comments 31 May 2017 n/a

Updated PRAC Rapporteur Assessment Report 1 June 2017 n/a

PRAC Outcome 9 June 2017 9 June 2017

CHMP members comments 12 June 2017 12 June 2017

Updated CHMP Rapporteur(s) (Joint) Assessment Report

15 June 2017 14 June 2017

Request for Supplementary Information (RSI) 22 June 2017 22 June 2017

Submission of responses 14 July 2017 17 July 2017

CHMP Rapporteurs Joint response Assessment Report 21 August 2017 21 August 2017

Comments from CHMP 4 September 2017 4 September 2017

Updated CHMP Rapporteurs Joint response Assessment Report

7 September 2017 7 September 2017

2nd RSI 14 September 2017 14 September 2017

Restart 20 September 2017 20 September 2017

CHMP Rapporteurs Joint response Assessment Report 27 September 2017 29 September 2017

Comments from CHMP 2 October 2017 2 October 2017

Updated CHMP Rapporteurs Joint response Assessment Report

5 October 2017 5 October 2017

Oral Explanation Oct CHMP 2017 10 October 2017

Opinion

12 October 2017 Withdrawn by the Applicant on 11 October 2017

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Table of contents 1. Background information on the procedure .............................................. 7 1.1. Type II variation .................................................................................................. 7

2. Scientific discussion ................................................................................ 7 2.1. Introduction ........................................................................................................ 7 2.2. Non-clinical aspects ............................................................................................ 10 2.2.1. Ecotoxicity/environmental risk assessment ......................................................... 10 2.3. Clinical aspects .................................................................................................. 10 2.3.1. Introduction.................................................................................................... 10 2.3.2. Pharmacokinetics ............................................................................................ 10 2.3.3. Pharmacodynamics .......................................................................................... 11 2.3.4. PK/PD modelling ............................................................................................. 11 2.3.5. Discussion and Conclusions on clinical pharmacology ........................................... 15 2.4. Clinical efficacy .................................................................................................. 16 2.4.1. Dose response study(ies) ................................................................................. 17 2.4.2. Main study(ies) ............................................................................................... 17 2.4.3. Discussion on clinical efficacy ............................................................................ 47 2.4.4. Conclusions on the clinical efficacy .................................................................... 49 2.5. Clinical safety .................................................................................................... 49 2.5.1. Discussion on clinical safety .............................................................................. 76 2.5.2. Conclusions on clinical safety ............................................................................ 78 2.5.3. PSUR cycle ..................................................................................................... 79 2.6. Risk management plan ....................................................................................... 79 2.7. Update of the Product information ........................................................................ 79 2.7.1. User consultation ............................................................................................ 87

3. Benefit-Risk Balance ............................................................................. 87 3.1. Therapeutic Context ........................................................................................... 87 3.1.1. Disease or condition ........................................................................................ 87 3.1.2. Available therapies and unmet medical need ....................................................... 87 3.1.3. Main clinical studies ......................................................................................... 88 3.2. Favourable effects .............................................................................................. 88 3.3. Uncertainty in the knowledge about the beneficial effects ........................................ 88 3.4. Unfavourable effects ........................................................................................... 89 3.5. Uncertainty in the knowledge about the unfavourable effects ................................... 89 3.6. Effects Table ...................................................................................................... 89 3.7. Benefit-risk assessment and discussion ................................................................. 91 3.7.1. Importance of favourable and unfavourable effects .............................................. 91 3.7.2. Balance of benefits and risks ............................................................................ 91 3.7.3. Additional considerations on the benefit-risk balance ........................................... 92

4. Recommendations ................................................................................. 92

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List of abbreviations

AE Adverse Event AEOSI Adverse Event of Special Interest ALB Albumin ADA Anti-drug antibody ALK Anaplastic lymphoma kinase APT All Patients Treated ASaT/APat All Subject as Treated/ All Patient as Treated AUC Area under the concentration-time curve AUCss Area under the concentration-time curve at steady state BICR Blinded independent central review CI Confidence interval CV Coefficient of variation CL Clearance CMAX Peak serum concentration Cmin Trough serum concentration CONC Concentration CR Complete Response CT Computed tomography CTLA-4 Cytotoxic T-Lymphocyte-Associated protein 4 CWRES Conditional weighted residuals ECI Event of Clinical Interest ECOG Eastern Cooperative Oncology Group eDMC external Data Monitoring Committee DOR Duration of Response eGFR Estimated glomerular filtration rate EGFR Epidermal growth factor receptor ePROs electronically collected Patient-Reported Outcomes FAS Full Analysis Set FWER family-wise type I error rate GCP Good Clinical Practice HR Hazard Ratio HL Hodgkin lymphoma HNSCC Head and neck squamous cell carcinoma IA2 Second Interim Analysis IPRED Individual predicted concentration irAE Immune-related Adverse Event ISS Integrated Summary of Safety ITT Intention To Treat IIV Interindividual variability IV intravenous IWRES Individual weighted residual LS least squares

mAb Monoclonal antibody MedDRA Medical Dictionary for Regulatory Activities

MRI Magnetic Resonance Imaging

MSI-H microsatellite instability-high

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Nab Neutralizing antibody NONMEM Nonlinear mixed-effects modeling software NSCLC Non Small Cell Lung Cancer OFV Objective function value ORR Objective Response Rate OS Overall Survival PD Progressive Disease PD-1 Programmed cell death 1 (receptor) PD-L1 Programmed cell death 1 receptor ligand 1 PD-L2 Programmed cell death 1 receptor ligand 2 PFS Progression Free Survival PK Pharmacokinetic Pop PK Population Pharmacokinetic PRED Population predicted concentration PS Performance Status PR Partial Response PRO Patien-Reported Outcome Q Inter-compartmental flow rate Q3W every 3 weeks QoL Quality of Life RECIST 1.1 Response Evaluation Criteria on Solid Tumors Ver