27 June 2013 EMA/CHMP/403683/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Stivarga International non-proprietary name: REGORAFENIB Procedure No. EMEA/H/C/002573/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. EMA/CHMP/403683/2013 Page 1/91 Table of contents 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier ...................................................................................... 6 1.2. Manufacturers ...................................................................................................... 7 1.3. Steps taken for the assessment of the product ......................................................... 7 2. Scientific discussion ................................................................................ 8 2.1. Introduction......................................................................................................... 8 2.2. Quality aspects .................................................................................................... 9 2.2.1. Introduction ...................................................................................................... 9 2.2.2. Active Substance ............................................................................................... 9 2.2.3. Finished Medicinal Product ................................................................................ 11 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 14 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 14 2.3. Non-clinical aspects ............................................................................................ 14 2.3.1. Introduction .................................................................................................... 14 2.3.2. Pharmacology ................................................................................................. 14 2.3.3. Pharmacokinetics............................................................................................. 16 2.3.4. Toxicology ...................................................................................................... 18 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 22 2.3.6. Discussion on non-clinical aspects...................................................................... 24 2.3.7. Conclusion on the non-clinical aspects ................................................................ 28 2.4. Clinical aspects .................................................................................................. 28 2.4.1. Introduction .................................................................................................... 28 2.4.2. Pharmacokinetics............................................................................................. 29 2.4.3. Pharmacodynamics .......................................................................................... 35 2.4.4. Discussion on clinical pharmacology ................................................................... 36 2.4.5. Conclusions on clinical pharmacology ................................................................. 40 2.5. Clinical efficacy .................................................................................................. 41 2.5.1. Dose response studies...................................................................................... 41 2.5.2. Main study ...................................................................................................... 42 2.5.3. Discussion on clinical efficacy ............................................................................ 58 2.5.4. Conclusions on the clinical efficacy ..................................................................... 62 2.6. Clinical safety .................................................................................................... 63 2.6.1. Discussion on clinical safety .............................................................................. 76 2.6.2. Conclusions on the clinical safety ....................................................................... 80 2.7. Pharmacovigilance .............................................................................................. 80 2.8. Risk Management Plan ........................................................................................ 80 2.9. User consultation ............................................................................................... 85 Assessment report EMA/CHMP/403683/2013 Page 2/91 3. Benefit-Risk Balance ............................................................................. 85 4. Recommendations ................................................................................. 90 Assessment report EMA/CHMP/403683/2013 Page 3/91 List of abbreviations ADH alcohol dehydrogenase ADR adverse drug reaction AE adverse event AESI adverse event of special interest ALP alkaline phosphatase ALT alanine aminotransferase AST aspartate aminotransferase AUC area under the curve BCRP Breast Cancer Resistant Protein BCS Biopharmaceutical Classification System BRAF virus-induced Rapidly Accelerated Fibrosarcoma (v-raf) B1 homologue BSC best supportive care BUN blood urea nitrogen BW body weight CNS central nervous system CI confidence interval CR complete response CTCAE common terminology criteria for adverse events CAPIRI capecitabine, irinotecan CAPOX capecitabine, oxaliplatin CMH Cochran-Mantel-Haenszel CRC colorectal cancer CYP cytochrome P450 DCE-MRI Dynamic contrast enhanced MRI (magnetic resonance imaging) DILI drug-induced liver injury DPD dihydro-pyrimidine dehydrogenase ECG electrocardiogram ECOG Eastern Cooperative Oncology Group EGFR epidermal growth factor receptor FACS fluorescence activated cell sorter FOLFIRI folinic acid (leucovorin), 5-fluorouracil, irinotecan FOLFOX folinic acid (leucovorin), 5-fluorouracil, oxaliplatin GGT gamma glutamyl transferase HB haemoglobin HCC hepatocellular carcinoma HCT haematocrit HFSR Hand-foot skin reaction HPLC high performance liquid chromatography HR hazard ratio KRAS Kirsten rat sarcoma 2 viral oncogene homologue LDH lactate dehydrogenase LVEF left ventricular ejection fraction MCH mean corpuscular haemoglobin Assessment report EMA/CHMP/403683/2013 Page 4/91 MCHC mean corpuscular haemoglobin concentration mCRC metastatic colorectal cancer MCV mean corpuscular volume MRP multidrug resistance-associated protein MTD maximum tolerated dose NSCLC non-small cell lung cancer NOAEL no observed adverse effect level OATP Organic anion-transporting polypeptide ORR objective response rate OS overall survival OVAT One Variable At a Time PK pharmacokinetics PFS progression free survival PR partial response RECIST response evaluation criteria in solid tumours RPES Posterior reversible encephalopathy syndrome SAE serious adverse event SD stable disease SJS Stevens-Johnson-Syndrome TEN Toxic epidermal necrolysis TG triglycerides TKI tyrosine kinase inhibitor TSH thyroid stimulating hormone UGT Uridine 5'-diphospho-glucuronosyltransferase ULN upper limit of normal VEGF vascular endothelial growth factor VEGFR vascular endothelial growth factor receptor Assessment report EMA/CHMP/403683/2013 Page 5/91 1. Background information on the procedure 1.1. Submission of the dossier The applicant Bayer Pharma AG submitted on 3 May 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Stivarga, through the centralised procedure falling within the Article 3(1) and point 3 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 21 July 2011. The applicant applied for the following indication: Stivarga is indicated for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, in case of KRAS wild type CRC, an anti-EGFR therapy. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC - complete and independent application 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 tests or studies. Information on Paediatric requirements Pursuant to Article 7 (EC) No 1901/2006, the application included an EMA Decision CW/1/2011 on the granting of a class waiver. 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. New active Substance status The applicant requested the active substance regorafenib 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 did not seek Scientific Advice at the CHMP for the colorectal