Australian Public Assessment Report for Cabozantinib Proprietary Product Name: Cabometyx Sponsor: Ipsen Pty Ltd October 2018 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. · The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. · The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. · The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. · To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>. About AusPARs · An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. · An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. · A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2018 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>. AusPAR Cabometyx Cabozantinib Ipsen Pty Ltd PM-2016-04459-1-4 Final 18 October 2018 Page 2 of 61 Therapeutic Goods Administration Contents List of common abbreviations _______________________________________________ 5 I. Introduction to product submission _____________________________________ 8 Submission details ____________________________________________________________________ 8 Product background __________________________________________________________________ 8 Regulatory status ____________________________________________________________________ 10 Product Information_________________________________________________________________ 11 II. Registration time line ___________________________________________________ 11 III. Quality findings __________________________________________________________ 12 Drug substance (active ingredient) ________________________________________________ 12 Drug product _________________________________________________________________________ 13 Biopharmaceutics ___________________________________________________________________ 14 Quality summary and conclusions _________________________________________________ 16 IV. Nonclinical findings _____________________________________________________ 17 Introduction __________________________________________________________________________ 17 Pharmacology ________________________________________________________________________ 17 Pharmacokinetics ____________________________________________________________________ 19 Toxicology ____________________________________________________________________________ 22 Nonclinical summary ________________________________________________________________ 30 Nonclinical conclusions and recommendation ____________________________________ 31 V. Clinical findings ___________________________________________________________ 32 Introduction __________________________________________________________________________ 32 Pharmacokinetics ____________________________________________________________________ 33 Pharmacodynamics__________________________________________________________________ 34 Dosage selection for the pivotal studies ___________________________________________ 34 Efficacy _______________________________________________________________________________ 35 Safety _________________________________________________________________________________ 36 First round benefit-risk assessment _______________________________________________ 41 First round assessment of risks ____________________________________________________ 42 First round recommendation regarding authorisation ___________________________ 43 Second round evaluation ____________________________________________________________ 43 Second round benefit-risk assessment ____________________________________________ 43 Second round recommendation regarding authorisation ___________ 44 VI. Pharmacovigilance findings ___________________________________________ 44 Risk management plan ______________________________________________________________ 44 VII. Overall conclusion and risk/benefit assessment _________________ 47 AusPAR Cabometyx Cabozantinib Ipsen Pty Ltd PM-2016-04459-1-4 Final 18 October 2018 Page 3 of 61 Therapeutic Goods Administration Quality ________________________________________________________________________________ 47 Nonclinical ___________________________________________________________________________ 47 Clinical ________________________________________________________________________________ 48 Risk management plan ______________________________________________________________ 58 Risk-benefit analysis ________________________________________________________________ 59 Outcome ______________________________________________________________________________ 60 Attachment 1. Product Information ______________________________________ 60 Attachment 2. Extract from the Clinical Evaluation Report __________ 60 AusPAR Cabometyx Cabozantinib Ipsen Pty Ltd PM-2016-04459-1-4 Final 18 October 2018 Page 4 of 61 Therapeutic Goods Administration List of common abbreviations Abbreviation Meaning AE Adverse event ALT Alanine aminotransferase AST Aspartate aminotransferase AUC0-24 Area under the plasma concentration-time curve from time 0 to 24-hours AUC0-t Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration AUC0-inf Area under the plasma concentration-time curve from time 0 extrapolated to infinity Bid Twice daily BMI Body Mass Index BP Blood Pressure 14C Carbon-14 isotope Cmax Observed maximum plasma concentration Micro Curies CIμCi Confidence Interval CL/F Apparent total body clearance CP Childs-Pugh CRF Case report form CT Computed tomography CV Coefficient of variation CTCAE Common toxicity criteria for adverse events dL Decilitre ECOG Eastern Cooperative Oncology Group g Grams GLS Geometric least square AusPAR Cabometyx Cabozantinib Ipsen Pty Ltd PM-2016-04459-1-4 Final 18 October 2018 Page 5 of 61 Therapeutic Goods Administration Abbreviation Meaning ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group FBE Free Base Equivalent FDA Food and Drug Administration (US) FT4 Free T4 h Hours HGF Hepatocyte growth factor ICF Informed consent form IC50 Concentration require for 50% inhibition IRC Independent Radiology Committee ITT Intent to treat KPS Karnofsky Performance Status kg Kilograms L Litres LLOQ Lower limit of quantitation LSM Least square mean m Metres MedDRA® Medical Dictionary for Regulatory Activities mg Milligrams mL Millilitres MTC Medullary thyroid cancer MTD Maximum tolerated dose MRI Magnetic resonance imaging NCI National Cancer Institute ng Nanograms ONJ Osteonecrosis of the Jaw AusPAR Cabometyx Cabozantinib Ipsen Pty Ltd PM-2016-04459-1-4 Final 18 October 2018 Page 6 of 61 Therapeutic Goods Administration Abbreviation Meaning PD Pharmacodynamic PFS Progression free survival PK Pharmacokinetic PIB Powder in bottle PITT Primary endpoint intent to treat qd Once daily QTcF Fridericia’s correction of QT interval RBC Red blood cell RCC Renal cell carcinoma RECIST Response Evaluation Criteria in Solid Tumours RPLS reversible posterior leukoencephalopathy syndrome SAE Serious adverse event SD Standard deviation SOC System organ class SoD Sum of lesion diameter Tmax Time to reach maximum plasma concentration TEAE Treatment emergent adverse event TKI Tyrosine kinase inhibitor ULN Upper limit of normal UPCR Urine protein creatinine ratio VEGF(R) Vascular endothelial growth factor (receptor) V/F Apparent total volume of distribution WCC White cell count AusPAR Cabometyx Cabozantinib Ipsen Pty Ltd PM-2016-04459-1-4 Final 18 October 2018 Page 7 of 61 Therapeutic Goods Administration I. Introduction to product submission