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1 AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP What the pharmacist needs to know when selecting biosimilar monoclonal antibodies in oncology: the case of trastuzumab biosimilars Thursday 23 March 2017 Ask a question Download Meetoo from your app store and enter meeting ID: Or on your mobile browser visit: web.meetoo.io/

2 To ask a question in Meetoo Once you ve joined the Meetoo meeting: Click the message icon Click the + symbol Type your message and press send icon web.meetoo.io/ Post-meeting content Selected content from this symposium will be available after the congress via: The password to access the website will be provided at the end of the meeting Please submit your address now via the ask a question function on the Meetoo app to receive notification when this content is available 2

3 AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP What the pharmacist needs to know when selecting biosimilar monoclonal antibodies in oncology: the case of trastuzumab biosimilars Thursday 23 March 2017 AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP What the pharmacist needs to know when selecting biosimilar monoclonal antibodies in oncology: the case of trastuzumab biosimilars Thursday 23 March

4 AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP Welcome and introduction Arnold Vulto The Netherlands Welcome and introduction Arnold G. Vulto PharmD, FCP, PhD Professor of Hospital Pharmacy & Practical Therapeutics Hospital Pharmacy Erasmus University Medical Center Rotterdam, The Netherlands 4

5 Conflict of interest statement I declare no personal financial interest in any pharmaceutical business My hospital receives financial compensation for the time I consult/lecture for third parties, such as speaking bureaus and pharmaceutical companies I entertain friendly relationships with all innovative and generic/biosimilar companies, and I help them all where I can. I do not personally receive any payment for this Companies/organisations involved are: a.o. AbbVie, Amgen, Biogen, Medicines for Europe (formerly EGA), Mundipharma, Pfizer/Hospira, Roche and Sandoz Agenda Selecting a biosimilar: current recommendations and future challenges Arnold Vulto, The Netherlands Preparing to assess biosimilar mabs in oncology: understanding the clinical role of trastuzumab Marc Thill, Germany Clinical studies for biosimilar trastuzumab in the treatment of breast cancer: similarities and differences Liese Barbier, Belgium Call to action: panel discussion All 5

6 Symposium evaluation Please complete the evaluation form provided and return it to the support staff at the end of the symposium Who is Arnold Vulto? A hospital pharmacist, not a lawyer or regulator Member of ErasmusMC Medical Ethical Review Board We see and run all drug trials Got involved in biosimilars as early as 2004 via European Journal of Hospital Pharmacy How to guide hospital pharmacists in this difficult area 2008: Founder of GaBI, together with Huub Schellekens and Lasia Tang To provide transparency to cost-effective medicines 2013: Co-founder of the Dutch Biosimilar Initiative Independent platform to promote efficient use of biological medicines 6

7 My personal motto as a hospital pharmacist My drive is optimal treatment for all patients at an affordable cost Science gives us the best possible description of the world. It is emotion that distorts this view The urgent need for biosimilars 7

8 FDA new drug admissions FDA, Food and Drug Administration Mullard A. Nat Rev Drug Discov 2016;15:73 6 Blockbusters forecast billion dollars extra cost each year Mullard A. Nat Rev Drug Discov 2015;14:

9 2015 top 10 worldwide sales of biologicals (US$ billion) Product Sales 2015 (vs 2014) Company Patent expiration EU US 1. Adalimumab 14.3 (+12%) AbbVie/Eisai Etanercept 9.0 (+2%) Amgen/Pfizer Infliximab 8.9 (-9%) J&J/MSD Insulin glargine 7.2 (+6%) Sanofi Rituximab 7.1 (+4%) Roche Bevacizumab 6.8 (+6%) Roche Trastuzumab 6.6 (+6%) Roche Pegfilgrastim 4.8 (+5%) Amgen Aflibercept 4.1 (+47%) Regeneron/Bayer Ranibizumab 3.6 (-13%) Roche/Novartis 2022? 2020? Blockbuster Biologics 2015: Sales of Recombinant Therapeutic Antibodies & Proteins. La Merie Publishing, March 2016 Global sales in 2015 of recombinant therapeutic proteins and antibodies: US$ 154 billion (+ 9.2 % versus 2014) Budget increase due to blockbusters by : + US$ 65 billion Biosimilars might offer some solace in this budget pressure: potential for ~US$55 to ~US$110 billion in savings IMS. Delivering on the Potential of Biosimilar Medicines. March Available at: Documents/IMS_Institute_Biosimilar_Brief_March_2016.pdf. Accessed March

10 Top 25 pharma companies in biosimilars? (11 no and 14 yes) Company Involved in biosimilars? 1 Pfizer Yes 2 Novartis Yes 3 Roche No 4 Merck US Yes 5 Sanofi Yes 6 Gilead No 7 J&J No 8 GSK No 9 AstraZeneca Yes 10 AbbVie No 11 Amgen Yes 12 Allergan Yes 13 Teva Yes Company Involved in biosimilars? 14 Novo Nordisk No 15 Eli Lilly Yes 16 Bayer No 17 BMS No 18 Takeda No 19 Boehringer Ingelheim Yes 20 Astellas No 21 Mylan Yes 22 Biogen Yes 23 Celgene No 24 Merck KGaA Yes 25 Daichi Sankyo Yes Moorkens et al (submitted) Summary of where are we now The total drug bill will grow exponentially due to the many blockbuster breakthrough drugs The savings potential of biosimilars is underused in most countries The questions are: why is this so and what can we do about it? 10

11 Three classes of therapeutic proteins (biologicals) Class 1: substitution products Hormones like growth factors or insulin Effect visible/measurable in hours or days Class 2: proteins with a specific pharmacological effect Like TNF-α inhibitors Effect only visible after some time, but not in all patients Class 3: proteins with a less concrete clinical effect Targeted therapies in oncology The effect is a statistical chance some time in the future (survival) Schellekens H, et al. Lancet Oncol 2016;17:e502 9 Molecule Company Approval date Brandname Somatropin Sandoz Apr 2006 Omnitrope Epoetin alfa Medice Aug 2007 Abseamed Epoetin alfa Sandoz Aug 2007 Binocrit Epoetin alfa Hexal Aug 2007 Epoetin Alfa Hexal Epoetin zeta Hospira Dec 2007 Retacrit Epoetin zeta Stada Dec 2007 Silapo Filgrastim AbZ-Pharma Sep 2008 Biograstim Filgrastim Ratiopharm Sep 2008 Ratiograstim Filgrastim Teva Sep 2008 Tevagrastim Filgrastim Hexal Feb 2009 Filgrastim Hexal Filgrastim Sandoz Feb 2009 Zarzio Filgrastim Hospira/Pfizer Jun 2010 Nivestim Infliximab Hospira/Pfizer Sep 2013 Inflectra Infliximab Celltrion Sep 2013 Remsima Follitropin alfa Teva Sep 2013 Ovaleap Filgrastim Apotex Oct 2013 Grastofil Follitropin alfa Finox Mar 2014 Bemfola Filgrastim Accord Healthcare Sep 2014 Accofil Insulin glargine Eli Lilly Sep 2014 Abasaglar Etanercept Samsung Bioepis Jan 2016 Benepali Infliximab Samsung Bioepis May 2016 Flixabi Enoxaparin-Na Techdow Sep 2016 Inhixa Enoxaparin-Na Pharmathen Sep 2016 Thorinane Insulin glargine MSD Jan 2017 Lusduna Rituximab Celltrion Mar 2017 Truxima Positive Opinion Teriparatide Stada Nov 2016 Movymia Teriparatide Gedeon Richter Nov 2016 Terrosa Adalimumab Amgen Jan 2017 Amgevita/Solymbic March 2017: 25 biosimilars licensed by the EMA (not available in all countries) 11

12 Therapy classes exposed to biosimilar competition Market share based on MAT sales values Oncology Fertility Anti-TNF G-CSF EPO HGH EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; HGH, human growth hormone Troien P. Biosimilars more for less. Available at: Accessed March biosimilars in registration (EMA, March 2017) Adalimumab (2x, Boehringer Ingelheim, Samsung) Bevacizumab (2x) Etanercept (1x; Sandoz) Insulin glargine (1x) Insulin lispro (1x; Sanofi-Genzyme) Pegfilgrastim (2x) Rituximab (2x) Trastuzumab (4x; Celltrion, Mylan, Samsung, Amgen) Information available from company press releases and EMA, Applications for new human medicines under evaluation by the Committee for Medicinal Products for Human Use, March Available at: 12

13 Selecting a biosimilar: Current recommendations and future challenges Arnold G Vulto PharmD, FCP, PhD Professor of Hospital Pharmacy & Practical Therapeutics Hospital Pharmacy Erasmus University Medical Center Rotterdam, The Netherlands Criteria for product selection in the hospital Pharmaceutical quality Effectiveness Safety Economic aspects More then price alone Usability (eg RTU vs freeze dried) Various strengths and dosage forms Stability, storage conditions, (in)compatibility Barcode, flag label Additional cost in relation with use (eg tests, monitoring) RTU, ready to use 13

14 What is covered by the EMA? Production process/manufacturer (GMP, API origin, info recalls, info changes, manufacturing, batch consistency, EU reference product, quality and validation production, studies performed under GCP) Product specifications (such as isoform pattern) Clinical efficacy (development program vs regulatory requirement, trial design endpoint) Safety and tolerability (AEs/SAEs, CI, immunogenicity, drug interactions, local reactions) Pharmacovigilance requirements Risk minimisation programmes AE, adverse event; API, active pharmaceutical ingredient; CI, confidence interval; EMA, European Medicines Agency; GCP, Good Clinical Practice; GMP, Good Manufacturing Practice; SAE, serious adverse event Krämer I, et al. Eur J Hosp Pharm Pract 2008;14:73 6; Boone N, et al. Eur J Hosp Pharm 2013;20: Boone N, et al. Eur J Hosp Pharm 2013;20:

15 Biosimilar selection criteria European biosimilar expert panel established 31 general selection criteria 10 were judged as relevant for clinical practice Decision matrix: biosimilar versus originator product European collaboration collecting and interchanging data for specific therapeutic groups Content is filled by experts MD and pharmacist can give own weight to criteria Krämer I, et al. Eur J Hosp Pharm Pract 2008;14:73 6; Boone N, et al. Eur J Hosp Pharm 2013;20: Selection criteria Production process/manufacturer 1. Is the manufacturer of the API and the medicinal product experienced in the production of biopharmaceuticals? 2. How long has the biopharmaceutical been on the market? 3. How extensive is the clinical experience with each individual biosimilar? Expressed as the number of patient days worldwide Product specifications 4. Are there any differences in drug formulation and administration in comparison to the reference product of other biosimilars? 5. What is the current number of registered indications for the biopharmaceutical/biosimilar? Boone N, et al. Eur J Hosp Pharm 2013;20:

16 Selection criteria (continued) Clinical efficacy 6. Are there different results in comparison to the reference product? Clinical safety and tolerability 7. Which (serious and mild) AEs and in which frequency were they reported in clinical trials with the biopharmaceutical? 8. Are there any contraindications, precautions, or warnings which are different compared to the reference product? 9. Is immunogenicity, as far as known, caused by a homogenous type of antibody or is there a high intra-individual and inter-individual variability? Is there a difference between biosimilar products regarding drug antibody homogenicity? 10.Are there differences in the incidence and severity of drug interactions? Boone N, et al. Eur J Hosp Pharm 2013;20: Biosimilar selection criteria Pre-qualification criteria (can be knock-out criterion) Reliability of supply 24/7 medical support Financial and insurance criteria Medication safety aspects: labelling Reference product registered in EU Eg Gastrofil; non-clinical part of development was performed using Neukine, a non-eu-product Final criterion: price Krämer I, et al. Eur J Hosp Pharm Pract 2008;14:73 6; Boone N, et al. Eur J Hosp Pharm 2013;20:275 86; EMA. Assessment Report, Grastofil. Available at: _Public_assessment_report/human/002150/WC pdf. Accessed March

17 Challenges Comparison of different products is not easy Requires detailed study of eg EPAR Requires constant update of information Frequent transition of immunogenic biosimilars is not advisable Is a change once a year acceptable? Presence of several biosimilars in a hospital is a logistical nightmare EPAR, European Public Assessment Report Challenges Data can be tainted/biased Scoring and weighting is subjective System requires constant updating and review The originator may continue to have the best data For new biosimilars, patient-specific immunogenicity data will only emerge after some time; when is long enough? That a drug has been licensed does not imply that we will use it 17

18 2008: Closing the information gap ( Umbrella initiative to build trust in cost-effective treatments: One-stop website with comprehensive information on generics and biosimilars Peer-reviewed open-access scientific journal Scientific symposia Educational meetings Patient information Take-home messages The first biosimilar in the market may not be the best Comparison of biosimilars is not easy and is based on a mixture of arguments These arguments can be weighed in a matrix First, the quality and some practical modalities should be evaluated Price comes second Avoid frequent changes 18

19 AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP Questions Please submit your questions via ask a question on the Meetoo app To ask a question in Meetoo Once you ve joined the Meetoo meeting: Click the message icon Click the + symbol Type your message and press send icon web.meetoo.io/

20 AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP Preparing to assess biosimilar mabs in oncology: understanding the clinical role of trastuzumab Marc Thill Germany Preparing to assess biosimilar mabs in oncology: understanding the clinical role of trastuzumab Marc Thill MD, PhD Director of the Department of of Gynaecology and Obstetrics Certified Breast Cancer Centre Certified Gynaecological Cancer Centre Certified Endometriosis Centre Agaplesion Markus Krankenhaus Frankfurt, Germany SC-EU-NP M.Thill 20

21 Breast cancer is the most common cancer in women worldwide Incidence of different cancer types and associated mortality in women worldwide (data for 2012) Ferlay J, et al. Int J Cancer 2015;136:E359 E386 HER2: human epidermal growth factor receptor 2 Hudis CA. N Engl J Med 2007;357:

22 Survival (% patients) HER2+ breast cancer: a common sub-type 1 Intrinsic subtype Clinico-pathological surrogate definition ER status PgR status HER2 status Ki-67 Recurrence risk Luminal A Luminal A-like Positive Positive Negative Low Low* Luminal B Luminal B-like (HER2-) Positive Luminal B-like (HER2+) Positive Any HER2 overexpression HER2+ (non luminal) Absent Absent Negative or low Negative High High * Over-expressed or amplified Over-expressed or amplified Any HER2+: 20 30% of breast cancers 2 Basal-like Triple negative (ductal) Absent Absent Negative *Based on multi-gene expression assay ER+, HER2- and at least one of these factors ER, oestrogen receptor; PgR, progesterone receptor 1. Goldhirsch A, et al. Ann Oncol 2013;24: ; 2. Hudis C. N Engl J Med 2007;357:39 51 HER2+ status is associated with aggressive disease and poor patient outcomes Survival based on HER2 status (patients not treated with HER2-targeted therapy) HER2- (IHC 0 or 1; n=85) HER2+ (IHC 3+; n=50) p< Years IHC, immunohistochemistry P-value represents log-rank difference in cumulative survival Witton CJ, et al. J Pathol 2003;200:

23 Probability of Survival, % Trastuzumab: clinical development FDA approval: HER2-positive metastatic BC 1,2 EMA/FDA approval: HER2-positive early BC 2,4,5 EMA approval: Concurrent trastuzumab + chemotherapy in early BC 4,7 HERA 2-year results EMA approval: HER2-positive metastatic BC 2,3 EMA/FDA approval: HER2-positive metastatic gastric cancer 2,4,6 EMA approval: neoadjuvant-adjuvant therapy with trastuzumab 4,8 1. Slamon DJ, et al. N Engl J Med 2001;344:783 92; 2. Genetech. Herceptin development timeline, 2017; 3. Marty M, et al. J Clin Oncol 2005;23: ; 4. EMA. Herceptin assessment history, 2016; 5. Piccart-Gebhart MJ, et al. N Engl J Med 2005;353: ; 6. Bang YG, et al. Lancet 2010;376:687 97; 7. Perez EA, et al. J Clin Oncol 2011;29: ; 8. Gianni L, et al. Lancet 2010;375: Trastuzumab has changed the prognosis for patients with HER2+ breast cancer Overall survival in patients with metastatic breast cancer HER2+, trastuzumab (n=191) HER2 (n=1782) HER2+, no trastuzumab (n=118) Time from diagnosis, months Dawood S, et al. J Clin Oncol 2010;28:

24 Trastuzumab: a targeted treatment for HER2+ breast cancer Induces ADCC Blocks HER2 receptor dimerisation Prevents cleavage/ shedding of HER2 extracellular domain Increases HER2 receptor endocytosis Immune effector cell Dimerisation (HER1, HER2, HER3 or HER4) HER2 receptor Cleavage Trastuzumab Signal transduction Signalling through p95 Recruitment of immune effector cell leads to tumour cell lysis Blocking dimerisation inhibits signal transduction Prevention of HER2 cleavage inhibits signal transduction Promotes destruction of HER2 receptors ADCC, antibody-dependent cell-mediated cytotoxicity Hudis CA. N Engl J Med 2007;357:39 51 Adjuvant neoadjuvant treatment Diagnosis Staging HR+, hormone receptor positive M Thill, Personal communication Chemotherapy Shrinks the tumour Prevents local and distant recurrence Multigene assay NEOADJUVANT THERAPY S U R G E R Y If HER2+ anti-her2 adds to chemotherapy x 1 year; potential increase in cardiac toxicity sequential to anthracycline Radiotherapy prevents local recurrence If HR+ anti-oestrogen therapy x 5 10 years; prevents local and distant recurrence ADJUVANT THERAPY Assists surgery in improving outcomes 24

25 Post-neoadjuvant No pcr R Standard treatment Experimental treatment CI, confidence interval; pcr, pathological complete response; R, randomisation M Thill, Personal communication Overview of the role of trastuzumab in breast cancer: advanced stage disease HER2+ MBC Advanced or metastatic breast cancer (ABC/MBC) ~6% of breast cancers at diagnosis 1 Up to 30% of node-negative and up to 70% of node-positive cases relapse following initial treatment of early BC 1 Treatable but generally incurable (median survival 2 3 years) 2 Treatment aims to achieve as durable a response as possible 2 Trastuzumab use in HER2+ metastatic BC: 2 First-line treatment first treatment for metastatic BC Trastuzumab in combination with other agents until disease progression Second, third (etc)-line subsequent lines of treatment given upon disease progression Trastuzumab given alone or in combination with other agents (depending on prior therapy) until disease progression 1. Cardoso F, Castiglione M. Ann Oncol 2009;20 (Suppl 4):iv15 iv18; 2. Cardoso F, et al. Ann Oncol 2017;28:

26 EFS (%) OS (%) Neoadjuvant use of trastuzumab (NOAH trial) Example of potential benefits in HER2+ early BC Event-free survival Chemotherapy plus trastuzumab (n=117) Chemotherapy (n=118) Overall survival Chemotherapy plus trastuzumab (n=117) Chemotherapy (n=118) 58% 74% 63% 43% Months Months Gianni L, et al. Lancet Oncol 2014;15: Adjuvant use of trastuzumab Example of potential benefits in HER2+ early BC Adjuvant trastuzumab reduces the risk of relapse in early BC by 50% Piccart-Gebhart MJ, et al. N Engl J Med 2005;353: ; Romond EH, et al. N Engl J Med 2005;353:

27 OS (% patients) OS (% patients) DFS (proportion patients) OS (proportion patients) Adjuvant use of trastuzumab (1 year) disease-free survival Example of long-term benefits in HER2+ early BC HERA 10-year analysis 1 BCIRG-006 final analysis (10.3 years) 2 Trastuzumab 2 years HR 0.78; 95% CI, ; p< Trastuzumab 1 year HR 0.77; 95% CI, ; p< Observation Years post-randomisation 10-y-DFS 69.3% 68.5% 62.5% AC TH HR 0.72; 95% CI, ; p< TCH HR 0.77; 95% CI, ; p< AC T Months post-randomisation 10-y-DFS 74.6% 73.0% 67.9% DFS, disease-free survival AC TH, doxorubicin/cyclophosphamide taxane + trastuzumab Joint analysis N9831/NSABP B y-DFS 73.7% 62.2% NCCTG N y-DFS 84.2% 79.8% AC T, doxorubicin/cyclophosphamide taxane TCH, taxane/carboplatin/trastuzumab AC TH AC T HR 0.60; 95% CI, ; p<0.001 AC TH AC T HR 0.75; 95% CI, ; p= Years post-randomisation Years post-randomisation 1. Jackisch C, et al. San Antonio Breast Cancer Symposium 2015, Abstract PD5-01; 2. Slamon D, et al. San Antonio Breast Cancer Symposium 2015, Abstract S5-04; 3. Perez E, et al. J Clin Oncol 2014;32: ; 4. Perez E, et al. J Clin Oncol. 2011;29: Adjuvant use of trastuzumab (1 year) overall survival Example of long-term benefits in HER2+ early BC HERA 1 BCIRG-006 final analysis (10.3 years) 2 10-y-OS 79.5% 79.4% 72.9% 10-y-OS 85.9% 83.3% 78.7% Trastuzumab 2 years HR 0.72; 95% CI, ; p< Trastuzumab 1 year HR 0.74; 95% CI, ; p< Observation AC TH HR 0.63; 95% CI, ; p< TCH HR 0.76; 95% CI, ; p= AC T Years post-randomisation Joint analysis N9831/NSABP B y-OS 84.0% 75.2% Months post-randomisation OS, overall survival AC TH, doxorubicin/cyclophosphamide taxane + trastuzumab AC TH AC T HR 0.63; 95% CI, ; p<0.001 Years post-randomisation AC T, doxorubicin/cyclophosphamide taxane TCH, taxane/carboplatin/trastuzumab 1. Jackisch C, et al. San Antonio Breast Cancer Symposium Abstract PD5-01; 2. Slamon D, et al. San Antonio Breast Cancer Symposium Abstract S5-04; 3. Perez E, et al. J Clin Oncol 2014;32:

28 Survival probability Use of trastuzumab in metastatic BC Example of potential benefits Docetaxel ± trastuzumab as first-line treatment of HER2+ metastatic BC Significant improvement in overall survival Overall survival All patients Trastuzumab + docetaxel (n=92) Docetaxel alone (n=94) p= months Time (months) ORR: T+D 61% vs D 34%; p= Overall survival Crossover analysis Trastuzumab + docetaxel (n=92) Docetaxel alone/crossover (n=53) Docetaxel alone (n=41) p= Time (months) Median values are shown OS, overall survival Marty M, et al. J Clin Oncol 2005;23: Trastuzumab: key safety considerations Associated with cardiac dysfunction Increased risk for developing chronic heart failure or asymptomatic cardiac dysfunction Incidence and severity highest in patients receiving concomitant anthracycline-containing chemotherapy Administration-related reactions Dyspnoea, hypotension, wheezing, hypertension, bronchospasm, supraventricular tachyarrhythmia, reduced oxygen saturation, anaphylaxis, respiratory distress, urticaria and angioedema reported Majority of events occur within 2.5 hours of the start of the first infusion Recommended that patients observed for at least 6 hours after the start of the first infusion and for 2 hours after the start of subsequent infusions for symptoms like fever and chills or other infusion-related symptoms Pulmonary events Severe pulmonary events reported in the post-marketing setting Trastuzumab (Herceptin ) Summary of Product Characteristics. Roche Registration Limited. September

29 Cumulative incidence (%) Trastuzumab: consistent safety profile Approximately 1,000,000 patients Trastuzumab is well tolerated and has a consistent safety and tolerability profile 1 4 Low cumulative incidence of cardiac events after long-term follow-up Cardiac events: confirmed CHF or cardiac death 3.3% 2.8% 0.8% Time (years) B-31 AC TH (n=947) 1 N9831 AC TH (n=570) 2 N9831 AC T H (n=710) 2 BCIRG 006 AC TH (n=1074) 3 HERA CT H (n=1682) 4 BCIRG 006 TCH (n=1075) 3 3.8% 2.0% 0.4% AC TH, doxorubicin/cyclophosphamide taxane + trastuzumab AC T H, doxorubicin/cyclophosphamide taxane trastuzumab CT H, chemotherapy trastuzumab TCH, taxane/carboplatin/trastuzumab CHF, congestive heart failure 1. Romond EH, et al. J Clin Oncol 2012;30:3792 9; 2. Advani PP, et al. J Clin Oncol 2016;34:581 7; 3. Slamon D, et al. N Engl J Med;2011:365: ; 4. de Azambuja E, et al. J Clin Oncol 2014;32: ; 5. Trastuzumab reference product patent expiry provides opportunity for introduction of biosimilars Patent expiry for IV formulation: 1 UK: 28 July 2014 EU other markets: 28 August 2015 US: 18 June 2019 Development of trastuzumab biosimilars ongoing Initial submissions in EMA review Potentially curative monoclonal antibody biosimilar New paradigm versus supportive care for less complex biosimilars used to date (eg G-CSFs, ESAs) What are the key considerations when assessing the clinical efficacy of trastuzumab biosimilars? EMA, European Medicines Agency; ESA, erythropoietin stimulating agent; G-CSF, granulocyte colony-stimulating factor 1. Derbyshire M. GaBI J 2015;4:

30 Fundamentals of biosimilar clinical development Equivalence studies are necessary to demonstrate biosimilarity Superiority study INTENDED TO DEMONSTRATE: 1 Proposed product provides superior efficacy Noninferiority study INTENDED TO DEMONSTRATE: 1 (based on a prespecified margin) Proposed product is not inferior to an unacceptable extent Equivalence study INTENDED TO DEMONSTRATE: (based on a prespecified margin) 1 3 Proposed product is not inferior AND Proposed product is not superior Usually used for novel agents vs standard of care Usually used for biosimilars Non-inferiority study may be appropriate for biosimilars in certain cases 1. Isakov L, et al. Am J Ther 2016;23:e1903 e1910; 2. FDA. Scientific considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. Guidance for Industry, 2015; 3. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 2014 Fundamentals of biosimilar clinical development Equivalence studies are necessary to demonstrate biosimilarity Statistical testing approach Assume there is a difference (H 0 ) Collected data is used to decide if we can reject H 0 and accept H 1 = there is no clinically-meaningful difference Lower margin 1 Hazard ratio (HR) Upper margin Equivalence margins Region of no clinically meaningful difference (pre-specified) Inference: if 95% CI for HR is within the margins, we reject that there is a clinical meaningful difference between biosimilar and RP Equivalence design is the gold standard for establishing biosimilarity Equivalence means the biosimilar is not better and not worse than the reference product CI, confidence interval; H 0, null hypothesis; H 1, alternative hypothesis, HR, hazard ratio; RP, reference product Isakov L, et al. Am J Ther 2016;23:e1903 e

31 Fundamentals of biosimilar clinical development Study conditions should be selected so that differences between the biosimilar and reference product can be detected Sensitive patient population 1-3 Sensitive endpoints 1-3 Immunocompetent population Consider comorbidities, concomitant medications and medication history, and severity of disease Clinically relevant, readily assessable, and able to detect differences Length of study should be sufficient to allow for adequate immunogenicity assessment 1. FDA. Scientific considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. Guidance for Industry, 2015; 2. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 2014;. 3. Cortes J, et al. Breast Cancer Res Treat 2014;144: ESMO position To appropriately capture clinical efficacy and immunogenic reactions, a biosimilar product should be tested in the most sensitive populations and its data are reported clearly. This will contribute to the robustness of its safety and efficacy and therefore build confidence in the physician and patient alike. Tabernero J, et al. ESMO Open 2016;1:e doi: / esmoopen

32 Potential study populations for biosimilar trastuzumab clinical trials Goal: identify population in which differences with respect to safety, efficacy and immunogenicity between biosimilar and reference product can be attributed to product characteristics rather than patient and disease-related factors HER2+ early breast cancer HER2+ metastatic breast cancer HER2+ metastatic gastric cancer Neoadjuvant First line Adjuvant Later lines Cortes J, et al. Breast Cancer Res Treat 2014;144: ; Jackisch C, et al. Future Oncol 2015;11:61 71 Fundamentals of biosimilar development The biosimilar regulatory pathway includes guidance for extrapolation of indications Biosimilar development Demonstrate biosimilarity to the reference product Knowledge of the reference product Scientific justification Mechanism of Action Totality of evidence PK Immunogenicity Extrapolation Efficacy and Safety Toxicity Indication 1 Extrapolated indications Indication 2 Indication 3 Indication 4 Indication 5 Indication 6 PK, pharmacokinetics 1. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 2014; 2. FDA. Scientific considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. Guidance for industry,

33 ESMO position As biosimilars are complex products that undergo new clinical studies in line with those of their reference products, extrapolation of the indications should be permitted if verified scientifically. Analytical, preclinical, pharmacokinetics, pharmacodynamics and clinical data, along with immunogenicity, should be collected if the biosimilar is to be correctly extrapolated to all indications of its reference product. Tabernero J, et al. ESMO Open 2016;1:e doi: / esmoopen Selected study population may influence confidence in extrapolation to other requested indications HER2+ early BC HER2+ metastatic BC HER2+ MGC MGC, metastatic gastric cancer Cortes J, et al. Breast Cancer Res Treat 2014;144:

34 Proportion surviving Proportion event-free ESMO position physicians should be suitably informed regarding (1) the patient population it was tested on (ie, a sensitive patient population) and (2) the sensitivity of endpoints used in the trial to demonstrate the efficacy of the biosimilar for the specific indication. Tabernero J, et al. ESMO Open 2016;1:e doi: / esmoopen Pathological complete response (pcr) a sensitive endpoint in early BC that correlates with long-term survival tpcr (n) No tpcr (n) Meta-analysis of 12 neoadjuvant breast cancer trials (CTneoBC) Year Overall survival tpcr No tpcr HR 0.36 (95% CI ) Event-free survival tpcr No tpcr 0.2 HR 0.48 (95% CI ) Year tpcr (n) No tpcr (n) Eradication of tumour from both breast and lymph nodes (ypt0 ypn0 or ypt0/is ypn0) was better associated with improved EFS and OS than tumour eradication from the breast alone tpcr, total pathological complete response (response in breast and lymph nodes) CTneoBC, Collaborative Trials in Neoadjuvant Breast Cancer working group Cortazar et al. Lancet 2014;384:

35 Pathological complete response (pcr) a sensitive endpoint in early BC that correlates with long-term survival HR+ G3 HR 0.27 HR- HER2+ HR 0.25 HR- HER2- (TN) HR 0.24 Cortazar et al. Lancet 2014;384: Current use of trastuzumab Adjuvant treatment of HER2+ early BC Treatment of HER2+ metastatic BC Treatment of HER2+ MGC Up to 1 year Until disease progression Until disease progression HCP may consider switching between reference product and biosimilar, or between biosimilars MGC, metastatic gastric cancer Herceptin (trastuzumab) Summary of Product Characteristics. Roche registration ltd,

36 ESMO position Interchangeability and switching should only be permitted if: (1) the physician is wellinformed about the products; (2) the patient is fully briefed by the physician and (3) a nurse is closely monitoring the changes and tracking any adverse events. Tabernero J, et al. ESMO Open 2016;1:e doi: / esmoopen Biosimilar studies may be designed to address considerations for switching treatments Reference drug Transition Study Biosimilar Single Switch Reference drug Biosimilar Reference drug Multiple Switches Biosimilar Modified from Dörner T, et al. Nat Rev Rheumatol 2015;11:

37 In clinical practice, multiple switches involving several products could theoretically occur Switch 1 Switch 2 Switch 3 Switch 4 Reference drug Biosimilar 1 Biosimilar 2 Reference drug Biosimilar 2 Time Can we confidently ensure accurate tracking of product use for pharmacovigilance purposes? Summary HER2+ breast cancer historically associated with poor prognosis and increased risk of recurrent disease Anti-HER2 antibody trastuzumab significantly impacts survival of patients with HER2+ breast cancer, particularly in early BC Patent expiry of trastuzumab originator provides opportunity for introduction of biosimilars Clinical evaluation of trastuzumab biosimilars requires careful selection of sensitive study populations and endpoints To ensure any differences identified can be correctly attributed to differences between the biosimilar and reference product Due to the duration of administration, switching between a biosimilar and reference product or biosimilar and biosimilar may be a consideration Need to ensure pharmacovigilance concerns can be addressed 37

38 Thank you! AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP Questions Please submit your questions via ask a question on the Meetoo app 38

39 To ask a question in Meetoo Once you ve joined the Meetoo meeting: Click the message icon Click the + symbol Type your message and press send icon web.meetoo.io/ AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP Clinical studies for biosimilar trastuzumab in the treatment of breast cancer: similarities and differences Liese Barbier Belgium 39

40 23 th March 2017 EAHP Satellite Symposium, Cannes Clinical studies for biosimilar trastuzumab in the treatment of breast cancer: similarities and differences Pharm D. Liese Barbier PhD Researcher SC-EU-NP Disclosure of speaker s interests No conflict of interest to declare 40

41 Outline of this presentation Introduction Development of a biosimilar Clinical trials of trastuzumab biosimilars - Clinical pharmacology studies: guidelines and results - Efficacy and safety in Phase III trials: guidelines, results and summary Extrapolation of indications The role of the hospital pharmacist Final considerations Research team MABEL Fund Market Analysis of Biologics & Biosimilars following Loss of Exclusivity KU Leuven, Belgium - Clinical Pharmacology and Pharmacotherapy Prof. I. Huys, Prof. S. Simoens - Therapeutic and Diagnostic Antibodies Prof. P. Declerck Erasmus University Medical Center, the Netherlands - Hospital pharmacy Prof. A. G. Vulto 41

42 Biosimilars in oncology Small molecule biosimilars First EPO biosimilar in 2007 Currently: 5 MA 1 First G-CSF biosimilar in 2008 Currently: 8 MA 1 mab biosimilars in oncology Trastuzumab: 4 MAA 1 Rituximab: 1 MA, 1 MAA 1 From supportive care to treatment From small to complex mab biosimilars Reducing healthcare expenditure 2 Improving patient access to biological therapy 2 MA= Marketing authorization, MAA= Marketing authorization application Figure adapted from: Revers L, et al. (2010) Canadian Pharmacists J (01/2017); 2. IMS (2016). Delivering on the Potential of Biosimilar Medicines Development of a biosimilar Aim: to demonstrate biosimilarity to the reference product based on totality of evidence, not to independently establish safety and efficacy of the proposed biosimilar New drug development PK/P Clinical D trials Preclinica l PK/PD Biosimilar development Preclinical Analytical Figure: McCamish (2011) Mabs EMA: Guideline on similar biological medicinal products (EMA/CHMP/437/04) 42

43 EMA guidelines on biosimilar antibodies Overarching guideline Guideline on similar biological medicinal products 1 General guidelines Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance I. Non clinical and clinical issues 2 II. Quality issues 3 Product class specific data requirements LMWH Insulin Somatropin G-CSF Epoetin INF alpha INF beta FSH mab 1. EMA/CHMP/437/04 2. EMA/CHMP/BMWP/42832/ EMA/CHMP/BWP/247713/ EMA/CHMP/BMWP/403543/2010 Guideline on similar biological medicinal products containing monoclonal antibodies non-clinical and clinical issues 4 Trastuzumab biosimilars in clinical development Trastuzumab biosimilar Company Phase I Phase III Trastuzumab CT-P6 biosimilar Company Celltrion/Hospira Phase I Phase III CT-P6 MYL-1401O MYL-1401O SB3 SB3 ABP 980 ABP BCD BCD-022 PF PF DMB-3111 DMB-3111 Published on Embase or Medline Registered on ClinicalTrials.gov Celltrion/Hospira Mylan Mylan Samsung Bioepis Samsung Amgen Bioepis Amgen Biocad Biocad Pfizer Pfizer Meiji Seika Pharma Meiji Seika Pharma Currently most data only available in abstracts or posterst Phase I completed Phase III completed in registration 43

44 Biosimilar clinical development Clinical pharmacology studies (Phase I) of biosimilar trastuzumab PK/PD Comparative clinical pharmacology studies: guidelines PK study: Primary objective: demonstrate similar exposure over time between biosimilar and RP Study population: Sensitive and homogenous (reduce variability) Recommended: in healthy volunteers (HV) Encouraged: supportive population PK measurements during clinical efficacy trial Trial design: Recommended: single dose cross-over study Parallel design may be necessary for mab: long t 1/2, potential influence of immunogenicity Dose: recommended to investigate a low or lowest therapeutic dose Dosing interval: single dose study recommended EMA (2012) Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010); EMA (2014) Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMA/CHMP/BMWP/42832/2005) 44

45 Comparative clinical pharmacology studies: guidelines PK study: Parameters: Single dose study 1. AUC (0-inf) 2. C max, t max, V d, t 1/2 Anti-drug antibodies in parallel of PK assessment Bioequivalence: CI 90%, margin % PD study: Multiple dose study 1. AUC (0-t), AUC τ 2. C max, and C trough at steady state Primary objective: demonstrate effects on clinically relevant measures related to efficacy or safety concerns, when feasible Lack of appropriately defined PD endpoints for trastuzumab Establish similar clinical efficacy through randomised, comparative clinical trial EMA (2012) Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010); EMA (2014) Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMA/CHMP/BMWP/42832/2005); Thill, M (2015) Expert Review of anticancer therapy, 15:3, Phase 1 PK results for trastuzumab biosimilars Trastuzumab biosimilar BCD (Biocad) CT-P6 2 (Celltrion) ABP (Amgen) DMB (Meiji Seika) MYL1401O 4 (Mylan) PF * 5 (Pfizer) SB3* 7 (Samsung Bioepis) Study population HER2+ MBC (N=46) HER2+ MBC (N=174) HV (N=157) HV (N=70) HV (N=120) HV (N=105) HV (N=109) Comparator Dosing Primary endpoints RP RP EU-RP + US-RP 1 x 8 mg/kg 1 x 8 mg/kg, 8 x 6 mg/kg Bio-equivalence margin AUC % CI, % Yes AUC SS 90% CI, % Yes 1 x 6 mg/kg AUC inf, C max 90% CI, % Yes RP 1 x 6 mg/kg C max, AUC inf, T 1/2 90% CI, % Yes EU-RP + US-RP EU-RP + US-RP EU-RP + US-RP 1 x 8 mg/kg 1 x 6 mg/kg 1 x 6 mg/kg AUC 0-inf, AUC 0-last, C max 90% CI, % Yes AUC T, AUC inf, C max 90% CI, % Yes AUC inf, AUC 0-last, C max 90% CI, % Yes Equivalent to RP? EBC, early breast cancer; HV: healthy volunteer; MBC, metastatic breast cancer; RP: reference product *Comparison between EU-RP and US-RP also conducted 1. Stenina MB, et al. (2014) J Clin Oncol; 2. Im Y, et al. (2013) Breast; 3. Morita J, et al. (2016) Biodrugs; 4. Waller CF, et al. (2016) J Clin Oncol; 5. Jacobs I, et al. (2015) J Clin Oncol; 6. Hanes V, et al. (2016) Eur. J. Cancer; 7. Pivot X, et al. (2016) Clin Ther. 45

46 Safety in PK study for trastuzumab biosimilars Biosimilar AE Cardiotoxicity Anti-drug antibody ABP 980 1,2 (Amgen) BCD (Biocad) CT-P6 4 (Celltrion) DMB (Meiji Seika) MYL-1401O 6 (Mylan) PF (Pfizer) SB3 8 (Samsung Bioepis) TEAE incidence comparable between groups. 1 grade 3 SAE in RP group No significant differences between groups NR NR No significant differences between groups NR 2.6% cardiotoxicity in CT-P6 group, 7.5% in RP group No subjects developed ADA No significant differences between groups NR No subjects developed ADA No significant differences between groups NR No subjects developed ADA Numerically higher incidence of pyrexia in biosimilar arm (but severity generally mild) TEAEs: 36.1%, 44.4%, and 61.1% in the SB3, EU-RP, US-RP No unusual LVEF values ADA, anti-drug antibody; AEs, adverse events; LVEF, left ventricular ejection fraction, NR, not reported, RP, reference product, SAE, serious adverse event; TEAE, treatment emergent serious adverse event 1. Hanes V, et al. San Antonio Breast Cancer Symposium 2015, Abstract P and poster presentation; 2. Hanes V, et al. European Breast Cancer Conference 2016, Abstract 436 and poster presentation; 3. Stenina MB, et al. (2014) J Clin Oncol; 4. Im Y, et al. (2013) Breast; 5. Morita J, et al. (2016) Biodrugs; 6. Waller CF, et al. (2016) J Clin Oncol; 7. Yin D, et al. Br J Clin Pharmacol 2014;78: ; 8. Pivot X, et al. (2016) Clin Ther. NR NR 1 case of ADA (after EU-RP) No subjects developed ADA Biosimilar clinical development Efficacy and safety in Phase III trials of trastuzumab biosimilars Clinical trial 46

47 Comparative clinical safety and efficacy assessments: guidelines Primary objective: demonstrate similar efficacy and safety compared to the RP, not patient benefit per se, which has already been established for the RP Design: adequately powered, randomised, parallel group comparative clinical trial, preferably double-blind, normally equivalence trials Patient population: sensitive and homogenous, to reduce patient and disease-related factors to a minimum Safety: comparable safety (type, frequency, and severity of AEs), other safety parameters (LVEF) and immunogenicity should be demonstrated at all steps of clinical evaluation RP: reference product EMA (2012) Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010) Selection of a sensitive patient population for biosimilar trastuzumab clinical trials In early breast cancer (early BC) as neoadjuvant or adjuvant therapy - Less likely confounded by baseline characteristics, external factors In metastatic breast cancer (metastatic BC) as first-line or later line treatment - Difficult to select homogeneous group - Need to stratify for multiple factors (e.g. prior therapy, performance status) Sensitive and homogenous patient population Potential differences attributed to drug itself rather than patient and disease-related factors Early BC most sensitive patient population for phase III comparative trastuzumab biosimilar trials EMA (2012) Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010); Thill, M (2015) Expert Review of anticancer therapy,15:3, ; Cortes, J et al. (2014) Breast Cancer Res Treat, 144:233-9; Jackisch C, et al. (2015) Future Oncol;11:

48 Selection of sensitive endpoints for biosimilar trastuzumab clinical trials The primary efficacy endpoints may be different to those used for approval reference product Endpoints should be sensitive in nature and enable the detection of clinically meaningful differences between the proposed biosimilar and the reference product Preferred endpoints for demonstrating efficacy A clinical endpoint that measures survival - Overall survival (OS) - Disease-free survival (DFS) - Progression-free survival (PFS) May be not feasible/sensitive enough to demonstrate biosimilarity of a biosimilar mab to the reference product Recommended endpoints for demonstrating biosimilarity A clinical endpoint that measures activity - Overall response rate (ORR) preferred in metastatic setting - Pathologic complete response (pcr) preferred in neoadjuvant setting ORR not established as an appropriate surrogate for survival EMA. Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues; EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: nonclinical and clinical issues Overview of trastuzumab biosimilars in Phase III trial Biosimilar Patient population N Primary endpoint E/NI BCD-022 (Biocad) HER2+ metastatic BC (first line) 126 ORR NI MYL1401O (Mylan) HER2+ metastatic BC (first line) 500 ORR E ABP 980 (Amgen) HER2+ early BC (neoadjuvant + adjuvant) 827 pcr E SB3 (Samsung Bioepis) HER2+ early BC (neoadjuvant) 806 pcr - CT-P6 (Celltrion) HER2+ early BC (neoadjuvant + adjuvant) HER2+ metastatic BC (first line) pcr ORR E E PF (Pfizer) HER2+ early BC (neoadjuvant) HER2+ metastatic BC (first line) PK endpoints ORR NI E E: equivalence, NI: non-inferiority; ORR: overall response rate, pcr: pathological complete response Shustova M, et al. Ann Oncol 2016;27(Suppl 6):vi68 vi99 abstract and poster; Rugo HS, et al. JAMA 2017;317:37 47; Amgen press release. June Available at: Samsung Bioepsis press release. October Available at: Clinical trial NCT Im Y-H, et al. ASCO 2013; Poster 629; Pfizer press release. November Available at: March

49 Phase III: MYL-1401O in HER2+ metastatic BC (Heritage study) Full text Double-blind, randomised, multicentre Phase III equivalence trial of first-line treatment in HER2+ metastatic BC Primary endpoint: overall response rate (ORR: CR or PR), at week 24 Secondary endpoints (exploratory): time to tumor progression (TTP), progression-free survival (PFS), overall survival (OS) HER2+ MBC (n=500) R 1:1 MYL-1401O initial LD 8 mg/kg IV, then MD 6 mg/kg IV Q3W + docetaxel or paclitaxel x 8 cycles Trastuzumab RP initial LD 8 mg/kg IV, then MD 6 mg/kg IV Q3W + docetaxel or paclitaxel x 8 cycles MYL-1401O MD 6 mg/kg IV Q3W until unacceptable toxic effects or disease progression Trastuzumab RP MD 6 mg/kg IV Q3W until unacceptable toxic effects or disease progression 24w CR: complete response, PR: partial response Complete results of part 2 (biosimilar/trastuzumab RP alone) will be presented in a future publication Rugo HS, et al. (2017) JAMA,317:37 47; Identifier: NCT Phase III: MYL-1401O in HER2+ metastatic BC (Heritage study): efficacy results Full text Overall response rate (ORR) similar between groups Ratio of ORR (FDA recommended) and difference in ORR (EMA recommended) within predefined equivalence boundaries No statistically significant differences in secondary endpoints between groups Primary endpoint ORR (ITT) 24w MYL-1401O (n=230) 69.6% (95% CI, ) Trastuzumab RP (n=228) 64% (95% CI, ) Ratio (90% CI) Equivalence margin ( ) Difference (95% CI) Equivalence margin 5.53% ( ) -15% to +15% Secondary endpoints (48w) MYL-1401O 0.81 Favours Trastuzumab RP 1 Favours Difference (95% CI) 1.24 TTP 41.3% trastuzumab RP 43.0% MYL-1401O -1.7 (95% CI, ) PFS 44.3% Ratio 44.7% of ORR -0.4 (95% CI, ) OS 89.1% 85.1% 4.0 (95% CI, ) Rugo HS, et al. (2017) JAMA,317:

50 Phase III: MYL-1401O in HER2+ metastatic BC (Heritage study): safety results Full text Treatment-emergent and serious adverse events similar between groups No difference in median LVEF between groups* ADAs similar between groups and consistent with trastuzumab reference historical data, confirming low immunogenicity n (%) MYL-1401O + taxane (n=247) Trastuzumab RP + taxane (n=246) 1 TEAE 239 (96.8) 233 (94.7) Alopecia 142 (57.5) 135 (54.9) Neutropenia 142 (57.5) 131 (53.3) Peripheral neuropathy 57 (23.1) 61 (24.8) 1 serious AE 94 (38.1) 89 (36.2) Neutropenia 68 (27.5) 62 (25.2) Neutropenia with fever 11 (4.5) 10 (4.1) Leukopenia 4 (1.6) 12 (4.9) Immunogenicity Positive for ADAs 6 (2.4) 7 (2.8) *Left ventricular ejection fraction (LVEF) was measured at baseline, Week 12 and Week 24 TEAE: treatment-emergent adverse event Rugo HS, et al. (2017) JAMA,317:37 47 Phase III: CT-P6 in HER2+ metastatic BC Efficacy and safety results Abstract Double-blind, randomised, multicentre Phase III equivalence trial of first-line treatment in HER2+ metastatic BC CT-P6 + paclitaxel vs trastuzumab RP + paclitaxel Efficacy: - Primary endpoint: overall response rate (CR or PR at 6 months) - Difference in ORR was within predefined equivalence margins Primary endpoint CT-P6 + paclitaxel -5.4 (n=244) RP + paclitaxel (n=231) ORR, % Difference -15 in Favours ORR, % (95% trastuzumab CI) RP Equivalence margin Safety: 0 Favours -5 (-14, 4) +15 CT-P6 Difference in ORR (-15, (%) 15) - AEs comparable between groups - LVEF and immunogenicity data not available Marketed in South Korea since 2014 under the name Herzuma CR: complete response, PR: partial response Im YH, et al. (2013) J Clin Oncol,31;Suppl; Abstr 629; Im YH, et al. ASCO 2013; Poster

51 Phase III: BCD-022 in HER2+ metastatic BC Efficacy and safety results Abstract Multicentre randomised double blind non-inferiority trial of first line treatment in HER2+ metastatic BC BCD paclitaxel vs trastuzumab + paclitaxel Efficacy: - Primary endpoint: difference in ORR (CR or PR at 6 months) - The lower limit of 95% CI for difference in ORR between groups did not exceed the NI margin Primary endpoint BCD paclitaxel (n=54) RP + paclitaxel (n=56) ORR % 53.57% (95% CI ) 53.70% (95% CI ) Difference -20 in ORR, (-19.83, 18.35) % non-inferiority (95% CI) margin Difference in ORR (%) NI boundary -20% Safety: - No statistically significant difference in AEs between groups - ADA in 1 patient in each group: confirms low immunogenic potential of both drugs CR: complete response, PR: partial response Shustova M, et al. Ann Oncol 2016;27(Suppl 6):vi68 vi99; Clinical trial NCT Available at: Phase III: PF , ABP 980 and SB3 Press release Phase III equivalence trial in HER2+ metastatic BC: equivalence in ORR between groups, N=690 Non-inferiority trial in neoadjuvant treatment of HER2+ early BC: similar C trough at SS between groups Phase III equivalence trial in HER2+ early BC: inferiority ruled out, but not superiority based on primary endpoint, pcr (upper end CI: 13.4%, equivalence margin: -13, +13), N=808 Study design includes a switch Available at: _b _study_for_pf_ _a_potential_biosimilar_to_herceptin_1_ trastuzumab; Samsung-Bioepis-Marketing-Authorization-Application-SB3-Trastuzumab 51

52 Summary of primary endpoint results in Phase III trials of trastuzumab biosimilars Trastuzumab biosimilar N patients Patient setting Primary endpoint Primary endpoint results Source BCD Metastatic BC ORR Did not exceed non-inferiority (Biocad) 2 margin PF (Pfizer) Metastatic BC Neoadjuvant early BC ABP Neoadjuvant + (Amgen) 6 adjuvant early BC CT-P6 (Celltrion) Metastatic BC Neoadjuvant + adjuvant early BC ORR C trough at SS tpcr ORR pcr Within equivalence margin Primary endpoint met Results ruled out inferiority, not superiority Within equivalence margin NR Abstract Press release Press release Press release Abstract MYL-1401O 500 Metastatic BC ORR Within equivalence margin Full text Yes (Mylan/Biocon) 4 SB3 (Samsung Bioepis) Neoadjuvant early BC pcr NR NR Yes NR EMA submission 1 No No Yes Yes EBC, early breast cancer; MBC, metastatic breast cancer; NR: not reported; RD: risk difference 1. GaBI online. Biosimilars of trastuzumab. (01/2017) Available at: 2. Shustova M, et al. Ann Oncol 2016;27(Suppl 6):vi68 vi99; 3. Im YH, et al. ASCO 2013; Poster 629; 4. Rugo HS, et al. JAMA. 2017;317:37 47; 5. Pfizer press release. November 2016; 6. Amgen press release. June 2016; 7. ClinicalTrials.gov, identifier: NCT Extrapolation of indication Use of trial data in one indication to justify the use of the drug to other indications of the reference product Complex and decided on a case by case basis Allowed if biosimilarity is confirmed based on totality of evidence and mechanism of action is known to be the same Challenge for trastuzumab biosimilar - Used in different tumour types and disease settings - Precise mechanism of action in each indication unknown - Early breast cancer more sensitive and possibly more appropriate for extrapolating clinical data to metastatic breast cancer than the reverse EMA (2012) Guideline on similar biological medicinal products containing monoclonal antibodies - non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010); Thill, M (2015) Expert Review of anticancer therapy, 15:3, ; Jackisch, C et al. (2014) Future Oncol,28:1-11; Cortes, J et al. (2014) Breast Cancer Res Treat, 144:

53 Integrating biosimilars in clinical practice: the role of the hospital pharmacist Ensuring the safe, effective and cost-effective use of biosimilars in hospitals Informing and educating other HCP and patients about the concept of biosimilarity and the regulatory pathway followed by biosimilars Reducing confusion by clarifying terminology and science of biotechnology processes Setting up monitoring systems and documenting any adverse drug reactions of patients treated with biologicals, including biosimilars (traceability: brand name) Final considerations Several trastuzumab biosimilars currently in development and in registration - Currently limited published efficacy and safety data of these biosimilars - Available clinical data positive for the approval of trastuzumab biosimilar Understanding of concept of totality of evidence and the stepwise approach used to demonstrate biosimilarity and gain regulatory approval pcr as primary endpoint in early breast cancer setting may represent a more sensitive approach for comparability exercise and extrapolation of indications than ORR in metastatic breast cancer population - Several trastuzumab biosimilars in development in metastatic breast cancer - Development of biosimilars in close interaction with EMA Trastuzumab biosimilars can potentially provide a high quality and clinically effective treatment at reduced cost and with improved patient access to biological therapy 53

54 Thank you for your attention Liese Barbier Clinical Pharmacology & Pharmacotherapy KU Leuven, Belgium AMGEN-SPONSORED SATELLITE SYMPOSIUM AT 22nd CONGRESS OF THE EAHP Questions Please submit your questions via ask a question on the Meetoo app 54

55 To ask a question in Meetoo Once you ve joined the Meetoo meeting: Click the message icon Click the + symbol Type your message and press send icon web.meetoo.io/ Call to action: panel discussion Please submit your questions via ask a question on the Meetoo app 55