PROF. DR. MED. C. JACKISCH

PROF. DR. MED. C. JACKISCH Introduction of subcutaneous formulation: optimization of medcial unmet needs and hospital adminstration challenges from a physicians perspective Department of Obstetrics & Gynecology - Certified Breast and Gynecologic Cancer Center International Clinical Trail Unit in Cooperation with AGO-Breast, AGO-OVAR, BIG, GBG, WSG

As times are changing unmasking the target L o c a l S y s t e m i c Basal-like Luminal A Luminal A HER- 2+/ER- Halsted Fisher, Veronesi Molecular profiler tumor burden Lymph node Single cells

Her2neu overexpression: How everything got started... Impact on DFS: Negative Impact on OS: Negative Prognosis: Negative Prediction: Positive Slamon SD et al., Science 1989;244:707-712

Role of HER2 in Breast Cancer 20% of breast cancer patients present with HER2-positive disease 1,2 HER2-positive status is associated with poor prognosis, including reduced relapse-free and overall survival (OS) 3 Suggests key role for HER2 in carcinogenesis HER2 status is also an important predictor of response to chemotherapy and endocrine therapy 5,6 HER2 is an important target for treatment 1 Owens MA, et al. Clin Breast Cancer 2004;5:63 9; 2 Ross JS, et al. Mol Cell Proteomics 2004;3:379 98; 3 Hynes NE, Stern DF. Biochim Biophys Acta 1994;1198:165 84 5 Lohrisch C, et al. Clin Breast Cancer 2001;2:129 35; 6 Piccart M, et al. Oncol 2001; 61(Suppl. 2)73 82

Testing the target Bilous M, et al. Mod Pathol 2003;16:173 82

Her2neu overexpressing EBC Frequency of relapse after 12 bis 24 months without trastuzumab years: 1986-1992 Cossetti et al., JCO 2015 6

Tratuzumab upfront in EBC Perfect schedule CHT CHT Trastuzumab NSABP-B31 3 CHT NCCTG-N9831 2 CHT Trastuzumab CHT Trastuzumab CHT HERA Trial 1 CHT Trastuzumab CHT Trastuzumab 1 Piccart-Gebhart et al., NEJM 2005; 2 Slamon et al., NEJM 2011; 3 Romond et al., NEJM 2005 C. JACKISCH 2018

Four pivotal trials in over 12,000 patients established trastuzumab as the standard of care for HER2-positive early BC HERA (ex-usa) 1 BCIRG 006 (global) 2 IHC/FISH N = 5102 Observation 1 year 2 years FISH N = 3222 1 year 1 year NCCTG N9831 (USA) 3 NSABP B-31 (USA) 3 IHC/FISH N = 1944 1 year IHC/FISH N = 2101 1 year 1 year Chemotherapy ± radiotherapy Doxorubicin + cyclophosphamide Docetaxel Docetaxel + carboplatin Trastuzumab Paclitaxel 1 Piccart-Gebhart et al., NEJM 2005; 2 Slamon et al., NEJM 2011; 3 Romond et al., NEJM 2005 C. JACKISCH 2018

41. Annual Meeting ASCO Orlando/FL May 14-17, 2005 ASCO, Scientific Session, May 16, 2005 FIRST RESULTS OF THE HERA TRIAL A randomized three-arm multi-centre comparison of: 1 year Herceptin 2 years Herceptin or no Herceptin in women with HER-2 positive primary breast cancer who have completed adjuvant chemotherapy Martine J. Piccart-Gebhart, MD, PhD on behalf of: The Breast International Group (BIG), NON-BIG participating groups, Independent sites, F. Hoffmann La Roche Ltd. Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab as Adjuvant Therapy for Patients with HER-2 Positive Operable Breast Cancer Combined Analysis of NSABP-B31/NCCTG-N9831 Romond EH, Perez EA, Bryant J, Suman V, Geyer CE, Davidson N, Tan-Chiu E, Martino S, Swain SM, Kaufman P, Fehrenbacher L, Pisansky T, Vogel V, Kutteh LA, Yothers G, Visscher D, Brown AM, Jenkins R, Seay TE, Mamounas E, Abrams J, Wolmark N NCCTG N9831 May 2005 Update N9831 Perez EA, Suman VJ, Davidson N, Martino S, Kaufman P, on Behalf of NCCTG, ECOG, SWOG, CALGB C. JACKISCH 2018

Trastuzumab has changed tumor biology C. JACKISCH 2018

Her2neu overexpressing EBC Treatment options in Germany 2017 Neoadjuvant Approach Perjeta + Trastuzumab 1,2 Surgery Trastuzumab + Chemotherapy 3,4 In the neoadjuvant setting duale blockade iwith trastuzumab and pertuzumab is feasible and a standard of care if NACT is indicated in HER2+ ebc. Adjuvante Approach Surgery Chemotherapy + Trastuzumab 1 Year 3,4 If surgery comes first in the adjuvant setting trastuzumab is indicated for 1 year, only. Herceptin might be used iv or sc 1. Gianni L, et al. Lancet Oncol 2012; 13:25 32; 2. Schneeweiss A, et al. Ann Oncol 2013; 24:2278 2284; 3. Cameron D, et al. Lancet 2017; 389:1165 1205; 4. Slamon D, et al. SABCS 2015 (Abstract S5 04). C. JACKISCH 2018 12

Challenges of long-term intravenous administration Central port Cannulation PICC line Takes time for implanting/removing Infection and blockages Some women feel they ve had enough chest surgery PICC, peripherally inserted central catheter C. JACKISCH 2018 Potential for necrosis following extravasation Damage to peripheral veins over time Courtesy of Lesley Fallowfield Expert insertion needed Daily flushing to prevent infection and blockage Very limiting for patients with active lifestyle

Multiple factors affect choice of administration route Advantages and disadvantages exist for all different routes of administration of drugs Factors affecting choice of administration route: Robust evidence of clinical activity (efficacy, safety and pharmacokinetics) Patient preference and satisfaction Medical resource utilisation Choice of administration route Healthcare professional preference and satisfaction Overall context (patients may be receiving multiple different treatments) C. JACKISCH 2018

Rationale for considering subcutaneous instead of IV administration Clinical activity Potential to provide comparable efficacy, PK and safety with SC administration, demonstrated in several clinical trials with other agents Bortezomib SC 1,2 Alemtuzumab SC 3,4 Patient needs Healthcare professional needs IV, intravenous; PK, pharmacokinetics; SC, subcutaneous C. JACKISCH 2018 More rapid and convenient administration Central line not needed Potential for greater patient preference, satisfaction and reduced treatment burden with SC administration 5,6 Potential for better use of medical resources Substantially reduced clinic/chair time 7 Better use of dedicated infusion suites/staff 7 Reduced pharmacist time 7 Reduced risk of dosing errors with a fixed dose 8 1. Moreau P, et al. Lancet Oncol 2011; 2. Moreau P, et al. Haematologica 2008; 3. Faderl S, et al. Cancer 2010; 4. Hale G, et al. Blood 2004; 5. Freemantle N, et al. Osteoporos Int 2012; 6. Kendler DL, et al. Osteoporos Int 2010; 7. De Cock E, et al. St. Gallen 2013 (Abstract 209); 8. Wang DD, et al. J Clin Pharmacol 2009

SC vs. IV administration: technical considerations Advantages Challenges SC IV Decreased clinic time for patients Reduced costs and optimised medical resource utilisation Less invasive than IV administration Appropriate for agents that may cause irritation Appropriate for drugs that must be administered in large volumes Potential volume limitations Retention at injection site may lead to adverse reactions Poor absorption (low bioavailability) Accurate dose administration requires appropriate training Requires trained personnel in dedicated infusion setting Implanted device (e.g. central port) Central line/intravenous catheter (e.g. Hickman line) Peripherally inserted central catheter (PICC) line Peripheral cannulation Increased clinic time vs. SC administration Risk of systemic infection IV, intravenous; PICC, peripherally inserted central catheter; SC, subcutaneous C. JACKISCH 2018 Haller MF. Pharm Tech 2007

How is the Efficacy of Trastuzumab SC? Phase 3 in HER2+ EBC/ HannaH Study (Neo to Adjuvant Setting)

Surgery HannaH: Randomised, Open-label, Phase III, Non-inferiority Study to Compare the PK, efficacy and safety of Trastuzumab SC and IV in HER2+ EBC 1 Trastuzumab SC HER2-positive early breast cancer (N=596) R 1:1 Trastuzumab IV Follow-up: 5 years 2 Trastuzumab SC Fixed dose of 600 mg (5 ml over 5 minutes) Trastuzumab IV 8 mg/kg loading dose; 6 mg/kg maintenance dose Docetaxel 75 mg/m 2 FEC 500/75/500 1 year (18 cycles) Trastuzumab Safety, tumour response pcr Safety, EFS, OS Pharmacokinetics Co-Primary Endpoint Show non-inferiority of SC vs. IV based on co-primary endpoints Efficacy: pcr in the breast Pharmacokinetics: observed Trastuzumab C trough pre-dose Cycle 8 EFS, event-free survival; FEC, 5-fluorouracil+epirubicin+cyclophosphamide; IV, intravenous; pcr, pathological complete response; OS, overall survival; SC, subcutaneous C. JACKISCH 2018 1. Ismael G, et al. Lancet Oncol 2012; 2. http://clinicaltrials.gov/ct2/show/nct00950300

Serum C trough levels Pathological complete response rate (pcr) in the breast HannaH: Co-primary endpoints met Pharmacokinetics Efficacy Geometric mean ratio: 1.33 (90% CI: 1.24-1.44) Difference pcr rate: 4.7 % (95% CI: -4.0-13.4 %) C. JACKISCH 2018 Ismael G, et al. Lancet Oncol 2012;13:869

Estimated probability HannaH: tpcr and EFS rates were positively associated comparing route of administration (ITT population) 2 years of treatment-free follow-up 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 EFS and tpcr associations were independent of Herceptin formulation (p=0.67) 0.2 0.1 0.0 Randomised treatment Herceptin SC/tpCR Herceptin IV/tpCR Herceptin SC/no tpcr Herceptin IV/no tpcr 0 6 12 18 24 30 36 42 48 54 60 Months EFS, event-free survival; ITT, intention-to-treat; IV, intravenous; SC, subcutaneous; tpcr, total pathologic complete response Jackisch C et al. Ann Oncol 2015;26:320-325 C. JACKISCH 2018

HannaH TRIAL: Long-term efficacy@ 6 yrs.: EFS & OS by tpcr status H IV / tpcr H IV / no tpcr H SC / tpcr H SC / no tpcr EFS, event-free survival; ITT, intention-to-treat; IV, intravenous; SC, subcutaneous; tpcr, total pathologic complete response C. JACKISCH 2018 Jackisch C et al. SABCS 2017

pcr, % (n/n) Fixed-Dose H SC Remains Efficacious in High BW Pts 100 90 Trastuzumab IV Trastuzumab SC SC vs. IV at 60 kg and C trough 43 µg/ml 80 SC vs. IV at 60 kg and C trough 62 µg/ml 70 SC vs. IV at 60 kg and C trough 81 µg/ml 60 50 40 30 42 (124/294) 37 (111/297) 36 (28/77) 48 (34/71) 44 39 (31/70) (32/83) 37 (26/70) 41 (29/71) 37 (25/67) 37 (30/82) 38 (11/29) 35 (12/34) SC vs. IV at 68 kg and C trough 43 µg/ml SC vs. IV at 68 kg and C trough 62 µg/ml SC vs. IV at 68 kg and C trough 81 µg/ml SC vs. IV at 80 kg and C trough 43 µg/ml SC vs. IV at 80 kg and C trough 62 µg/ml 20 SC vs. IV at 80 kg and C trough 81 µg/ml 10 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0 Overall patients <59 59 <68 68 <79 79 Weight decile: 2 90 137 Weight subgroup, kg * In favour of IV Odds ratio In favour of SC pcr is comparable for Trastuzumab SC and Trastuzumab IV across weight subgroups, including higher body weight patients 1,2 pcr rate is consistent across body weight and C trough subgroups 2 ITT population * 24 months treatment-free follow-up 20 months follow-up. Data collected at pre-dose Cycle 8, exploratory analyses. Weight and C trough values determined by the upper and lower quartiles (25% of patients) 1. Jackisch C, et al. ECC 2015 (Poster P134); 2. Ismael G, et al. Lancet Oncol 2012;13:867 878; 3. Jackisch C, et al. Ann Oncol 2015;26(2):320 325.

How is the Safety of Trastuzumab SC? Phase 3 in HER2 + EBC - SafeHer Study (Adjuvant Setting) - Hannah Safety Data (Neo to Adjuvant) Phase 3 in HER2 + MBC - SAPPHIRE Safety Study (1L H SC+P+Taxanes) - MetaPHER Safety Study (1L H SC+P+Docetaxel)

SafeHer: Largest Study of Trastuzumab SC Global safety study of Trastuzumab SC for 1 year (administered from a vial using a syringe, needle and manual injection or using an SID) in patients with HER2-positive early breast cancer Cohort A: SC Vial (hand-held syringe ) (n = 1867) Patients with HER2-positive EBC N = 2577 Investigator choice of: Cohort* Chemo regimen H SC 18 cycles (1 year) Cohort B: SC SID (n = 710) with supervised self-administration option Follow-up period (5 years after last dose of last patient) Primary objectives: safety and tolerability Secondary objectives: DFS, OS, self-administration: patient satisfaction (SID) * Depending on availability of cohorts. If Herceptin SC was administered in the neoadjuvant phase (Cohort A, n = 20; Cohort B, n = 24), surgery took place after Cycle 8, without interruption of treatment DFS, disease-free survival; HER2, human epidermal growth factor receptor 2; OS, overall survival; SC, subcutaneous; SID, single-use injection device Jung KH, et al. ESMO 2016 (Poster 211P).

SafeHer: Patients, % Primary Safety Endpoints (Both Cohorts) AEs were more common during concurrent chemotherapy periods 100 90 80 70 93.6% 88.7% (n = 1439) (n = 2282) 78.9% (n = 634) Overall (n = 2573)* H SC + concurrent chemotherapy (n = 1537) H SC + sequential chemotherapy (n = 804) 60 50 40 30 20 10 23.2% (n = 596) 30.6% (n = 470) 16.4% 10.9% 12.7% (n = 252) (n = 88) (n = 326) 6.5% (n = 52) 0 Any grade AE NCI-CTCAE grade 3 AE SAE * Includes the no chemo subgroup. AE, adverse event; H, Herceptin; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; SAE, serious adverse event; SC, subcutaneous Gligorov J, et al. EBCC 2016 (Poster 142; Abstract 326); Jung KH, et al. ESMO 2016 (Poster 211P)..

Grade 3 AEs, % patients SafeHer: Grade 3 AEs of Interest (Both Cohorts) No new safety signals were identified 14 12 10 8 7.3% 11.5% Overall (n = 2573)* H SC + concurrent chemotherapy (n = 1537) H SC + sequential chemotherapy (n = 804) 6 4 2 0 1.1% 3.8% 3.0% 2.9% 1.4% 4.4% 0.9% 2.9% 2.1% 1.7% 2.7% 3.2% 1.2% 1.0% 0.9% 1.2% 0.6% 0.6% 0.8% 0.3% 0.1% 0.7% Blood/ lymphatic system Infections/ infestations Gastrointestinal Vascular General/ admin site Respiratory/ thoracic/ mediastinal Cardiac CHF * Includes the no chemo subgroup. AE, adverse event; CHF, congestive heart failure; H, Herceptin; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; SC, subcutaneous; SID, single-use injection device; SOC, system organ class NCI-CTCAE SOC Gligorov J, et al. EBCC 2016 (Poster 142; Abstract 326)

SAPPHIRE MBC : Trastuzumab SC + Pertuzumab + Taxanes in I -line MBC An open-label, multicentre, Phase IIIb study with pertuzumab IV, trastuzumab SC, and a taxane in patients with HER2+ MBC (SAPPHIRE) Treatment phase* Survival follow-up P (IV): 840 mg loading dose D1, C1; then 420 mg D1, q3w H SC: 600 mg/5 ml D2, C1; then 600 mg/5 ml D1, q3w Previously untreated HER2- positive mbc (IHC 3+ or ISH+) N = 50 H SC + P (IV) + taxane PD Investigator s choice of therapy END 3-weekly assessments 3-monthly assessments Baseline assessment * Continue study treatment until PD, unacceptable toxicity or withdrawal of consent; Continue follow-up until withdrawal of consent, lost to follow-up, death or study closure; Docetaxel, paclitaxel or nab-paclitaxel; regimen determined by investigator; administered as per institutional guidelines and the product information. C1, Cycle 1; D1, Day 1; D2, Day 2; IHC, immunohistochemistry; ISH, in situ hybridisation; IV-P, intravenous PERJETA; mbc, metastatic breast cancer; PD, progressive disease; q3w, every 3 weeks; SC-H, subcutaneous Herceptin. Safety follow-up visit: 28 days after last dose of H SC/P (IV) 1. Woodward N, et al. SABCS 2015 (Poster P4-14-12); 2. Woodward N, et al. SABCS 2016 (Poster P4-21-31).

SAPPHIRE: 1 AE of Any Grade AE occurring in 25% patients, n (%) Docetaxel n = 13 Nab-paclitaxel n = 36* Paclitaxel n = 1 Total N = 50 Diarrhoea 9 (69.2) 27 (75.0) 36 (72.0) Fatigue 8 (61.5) 25 (69.4) 33 (66.0) Peripheral neuropathy 4 (30.8) 23 (63.9) 1 (100.0) 28 (56.0) Alopecia 7 (53.8) 20 (55.6) 27 (54.0) Rash 7 (53.8) 17 (47.2) 1 (100.0) 25 (50.0) Nausea 4 (30.8) 18 (50.0) 1 (100.0) 23 (46.0) Upper respiratory tract 7 (53.8) 11 (30.6) 18 (36.0) infection Vomiting 3 (23.1) 14 (38.9) 17 (34.0) Myalgia 3 (23.1) 14 (38.9) 17 (34.0) Headache 5 (38.5) 11 (30.6) 16 (32.0) GERD 6 (46.2) 7 (19.4) 13 (26.0) Muscle spasms Observed safety 4 profile (30.8) is consistent 9 (25.0) with CLEOPATRA 13 (26.0) Clinical cut-off: 4 March 2016 * Nab-paclitaxel was the most commonly used taxane; likely due to the fact that in Australian clinical practice, prior to the availability of PERJETA, nab-paclitaxel in combination with Herceptin was the first-line treatment of choice. AE, adverse event; GERD, gastro-oesophageal reflux disease; Woodward N, et al. SABCS 2015 (Poster P4-14-12); Woodward N, et al. SABCS 2016 (Poster P4-21-31).

MetaPHER: Phase 3 Safety Study of 1L H SC+P IV+Docetaxel in HER2+ MBC (ongoing) Treatment period End of treatment Post-treatment follow-up a Patients with HER2-positive advanced BC No previous treatment with systemic non-hormonal therapy in the metastatic or locally advanced setting (N = 400) Trastuzumab SC (600 mg D1, q3w) + PERJETA IV (840 mg loading dose D1 cycle 1, then 420 mg D1, q3w) + docetaxel ( 6 cycles, 75 mg/m 2, D1, q3w) PD, unacceptable toxicity, withdrawal of consent or death (whichever occurs first) Death, loss to follow-up, withdrawal of consent or pre-defined study end (whichever occurs first) Primary endpoint: safety and tolerability Results are consistent with the safety profile from CLEOPATRA Trastuzumab SC + P + Taxane is safe and tolerable and could be a viable treatment option in 1L HER2+ MBC. a Patients will be followed post-treatment for safety, disease progression and survival Kümmel S, et al. SABCS 2016 (Abstract P4-21-42).

FOR INTERNAL USE ONLY Preference of Trastuzumab SC or IV Phase 2 in HER2+ EBC/ PrefHer Study (Adjuvant Setting) Phase 3 in HER2+ MBC/ METASPHER Study (1L mbc)

PrefHer: Randomised, Two-Cohort Crossover Preference Study SID Cohort Crossover period Arm A SID every 3 weeks x 4 IV every 3 weeks x 4 HER2-positive primary invasive breast adenocarcinoma (N = 243) the proportion of patients Cross-over with pre-study period Trastuzumab IV SC Vial Cohort HER2-positive primary invasive breast adenocarcinoma (N = 240) SC Vial via HHS every 3 weeks x 4 Arm B IV SC Vial via HHS Patient Interview 1 every 3 weeks x 4 every 3 weeks x 4 Patient Interview 2 Includes optional TaM sub-study in both cohorts * Remaining Herceptin administered by IV infusion unless patients participated in SID self-administration HHS, hand-held syringe; IV, intravenous; PINT, Patient Interview; R, randomised; SC, subcutaneous; SID, single-use injection device; TaM, time-and-motion R 1:1 R 1:1 Trastuzumab Arm B Randomisation was IV stratified SID by de novo vs PINT1 every 3 weeks x 4 every 3 weeks x 4 PINT2 Arm A Trastuzumab IV every 3 weeks x 4 Remaining Trastuzumab to complete 18 cycles in total* non-de novo Trastuzumab, to balance the sequence groups for treatment Remaining Trastuzumab SC to complete 18 cycles in total Pivot X, et al. Lancet Oncol 2013

Percentage of patients PrefHer: Patients Overwhelmingly Preferred Trastuzumab SC over IV IV SC No preference 100 90 n = 99 83.9% n = 100 88.5% n = 199 86.1% 80 70 60 50 40 30 20 10 0 n = 16 13.6% n = 3 2.5% Arm A Hand-held syringe IV n = 118 n = 13 11.5% n = 0 0.0% Arm B IV hand-held syringe n = 113 n = 29 12.6% Overall N = 231 n = 3 1.3% SC preferred (exact binomial): Overall = 86.1% (95% CI 81.0% to 90.3%) IV, intravenous; SC, subcutaneous Pivot X, et al. SABCS 2013 (Abstract P4-12-11)

PrefHer: High Preference for Trastuzumab SC Irrespective of Received Trastuzumab IV prior to Study Enrolment Percentage of patients Overall (N = 231) Stratification factor: De novo Trastuzumab (n = 40) Stratification factor: Non-de novo Trastuzumab (n = 191) 100 90 80 70 60 50 40 30 20 10 0 n = 29 12.6% n = 3 7.5% n = 26 13.6% * Exploratory analysis SC preferred (exact binomial): overall = 86.1% (95% CI 81.0% to 90.3%); de novo Herceptin = 92.5% (95% CI 79.6% to 98.4%); non-de novo Herceptin = 84.8% (95% CI 78.9% to 89.6%) IV, intravenous; SC, subcutaneous n = 199 86.1% n = 37 92.5% n = 162 84.8% n = 3 1.3% n = 0 0.0% n = 3 1.6% IV SC No preference Pivot X, et al. SABCS 2013 (Abstract P4-12-11)

PrefHer: Main Reasons for SC Preference Category n (%) Example Time saving 179 (77.5) Less pain/ discomfort/side effects Problems with IV Ease of administration Convenience to patient Less stress/anxiety 71 (30.7) 26 (11.3) 23 (10.0) 21 (9.1) 20 (8.7) It does affect me being there so many hours. With this it was Hello and Bye without having to spend hours with patients The SC method was a lot less painful to me and my bruises faded faster than in the case of the intravenous method No veins to be found as my veins are collapsing Nurses can take care of many patients at the same time Busy mum with four young children want to get on with life IV reminds one of chemo and isn t very pleasant for the head Other 14 (6.1) Safer less risk of infections * Exploratory analysis Some patients gave only one reason, or no reason. Percentages calculated on a per-patient basis (N = 231) Statement based on patient preference and not reflective of clinical data IV, intravenous; SC, subcutaneous Pivot X, et al. SABCS 2013 (Abstract P4-12-11)

PrefHer: Healthcare Professional Satisfaction Preferred SC Preferred IV No preference 81% indicated a preference for Trastuzumab SC All things considered with which method of administration were you most satisfied? Healthcare professional questionnaires completed, N 117 Preferred method of administration, n (%) IV SC No preference 5 (4.3) 95 (81.2)* 17 (14.5) IV, intravenous; SC, subcutaneous Pivot X, et al. SABCS 2013 (Abstract P4-12-11)

METASPHER (ML28589): Preference of Long Responders 1 3 cycles 3 cycles HER2-positive mbc (disease-free after 3-yr of 1L Trastuzumab IV) N = 113 enrolled (France study) R 1:1 Trastuzumab SC Trastuzumab IV Trastuzumab IV Trastuzumab SC 12 cycles Trastuzumab SC PPQ and QoL questionnaires 2 QoL PPQ and QoL questionnaire 2 questionnaires HCPQ 2 An open-label, randomised, multicentre phase III study in patients with HER2+ MBC responding to 1L trastuzumab IV for at least 3 years disease-free and investigating pts preference for SC HCPQ, healthcare professional questionnaire; IV, intravenous; MBC, metastatic breast cancer; PPQ, patient preference questionnaire; QoL, quality of life; R, randomisation; SC, subcutaneous 1. http://clinicaltrials.gov/ct2/show/nct01810393; 2. Pivot X, et al. ESMO 2016 (Poster 274).

METASPHER: Patient Preference (%) Patient preference overall (N = 92) Patient preference SC IV (n = 47) Patient preference IV SC (n = 45) 14.1 12.8 15.6 85.9 87.2 84.4 p < 0.001 SC IV Pivot X, et al. ESMO 2016 (Poster 274).

Evidence and Practical Experience of Herceptin SC formulation in 7 German Centers 08/2013 Trastuzumab SC is available in Germany (NACT, EBC, MBC) 7 German sites participated in the SafeHER and Time & Motion Study Motivation arised from trial participation and the convincing evidence of the HannaH Trial In 1 center the pharmacist was the motivator for the introduction of SC to save resources in his unit for preparing chemotherapy In 2 centers the optimization of available chair time during peak times was the driver for SC Patients communication and advice from advocats groups on the benefit of SC Jackisch C et al. Geburtsh Frauenheilk 2015;75:566-573

Evidence and Practical Experience of Herceptin SC formulation in 7 German Centers Patients with Her2neu overexpression preferred to remove their permanent IV-lines at the end of chemotherapy as SC adminstration was available High conversion rate from long time IV trastuzumab monotherapy users to SC because of the convenience of the SC administration in ebc and mbc Even patients from other facilities asked in these 7 centers for SC administration of trastuzumab Optimization of travel and vaccation as SC is easy to handle elsewhere Nurses took fully care of the SC admistration Jackisch C et al. Geburtsh Frauenheilk 2015;75:566-573

Evidence and Practical Experience of Herceptin SC formulation in 7 German Centers T Jackisch C et al. Geburtsh Frauenheilk 2015;75:566-573

Time spent by patients in the treatment chair SC vs IV Jde Cock E et al. St. Gallen 2013; abstract F209

Active HCP-Time for administration of Trastuzumab per patient SC vs IV HCP: Health Care Professional Jde Cock E et al. St. Gallen 2013; abstract F209

Now available in SC injection: Herceptin continues to provide strong benefits in HER2-positive BC Herceptin SC is a ready-to-use formulation, irrespective of body weight (fixed dose), with no requirement of loading dose Herceptin SC has demonstrated in a strong clinical program involving nearly 5,000 EBC and MBC patients; Comparable efficacy and safety to Herceptin IV Preferred formulation by patients and HCPs over Herceptin IV Frees up clinic resources, creating admission capacity and cost-savings for hospitals compared to Herceptin IV UMBRELLA Program MetaPHER Pivotal Ph III SC vs. IV; efficacy, PK, safety, ADAs in EBC 1 Ph III safety study in EBC 2 Patient & HCP preference in ebc; Global Time and Motion Study 3,4 Safety studies in EBC and MBC 5 Safety study in MBC 6

Administration Time (min) Patient Chair Time (min) Herceptin SC formulation delivers the benefits of Herceptin in just 2-5 minutes Herceptin SC provides a faster overall treatment experience for patients due to less administration time and reduced overall time in the clinic as shown in HannaH and Time & Motion studies. Other published studies conducted across several countries reported consistent findings The duration of Herceptin IV administration (excluding loading dose) was on average 13- fold greater than the injection time of Herceptin SC 1 Global Time & Motion Study The mean reduction in patient chair time with Herceptin SC was 71.0% (pooled analysis*) 2 12.5 44.1 90.5 42.9 3.3 1 IV Loading Dose IV Subsequent Dose SC * Across Germany, France, Italy, Spain, UK, Switzerland, Turkey, Canada 21.2 22.6 IV IV post-infusion IV infusion IV pre-infusion SC 44

Herceptin SC is strongly preferred by patients and HCPs Patient and HCP preference for Herceptin SC has been demonstrated in PrefHER study and confirmed in ESCAPE 1, BELIS 2, ChangHer 3 and METASPHER 4 Patients Among patients treated with Herceptin, 89% expressed a preference for the SC formulation vs IV 5 The key drivers of patient preference were time saved and the reduction in pain, discomfort and side effects 5 Health Care Professionals Among HCPs, 77% expressed greater satisfaction with Herceptin SC compared to just 3% with IV 5 For HCPs, clinical management and efficiency are improved in care units and drug preparation areas with Herceptin SC 6 In addition, use of the SC formulation contribute to: avoid dosing errors 7 lead to less drug wastage 7 improves working conditions, especially at peak times 8 increase availability for other tasks in the pharmacy 6,7 allows more flexibility in scheduling patient appointments 8,9 allows centers to treat 1-2 additional patients for every Herceptin SC instead of IV 9 45

Active HCP Time (min) Clinical management and efficiency are improved in care units and drug preparation areas with Herceptin SC Multiple studies conducted in the hospital setting across various countries consistently demonstrated similar resource savings related to the switch from Herceptin IV to SC Global Time & Motion Study Active HCP time* was reduced by 54% when Herceptin SC was used instead of Herceptin IV 1 31.8 17.9 5 9.8 IV SC Time in drug preparation area Time in treatment room Reduction in mean active HCP time = 79% 2 Reduction in mean chair time = 92% 2 Reduction in total time spent in day care unit = 71% 2 Preparation time saving = 7.5 min/loading dose & 6.5 min/maintenance dose 3 Nurse time saving = 4.5 min/loading dose & 4.25 min/maintenance dose 3 Time saving = 3.3 hr for 1 st cycle 4 Total time saving for patient preparation = 17.2 hr 4 Total time saving = 1,500 hr for 238 HER2+ EBC patients included 5 Reduction of the total nurse time by 6.12 min 6 Reduction of the total pharmacist time by 20.45 min 6 Time saving = 68 min for HCP time 7 Time saving = 64.2 min for patient time in the unit 7 * Active HCP time was defined as the time actively dedicated by any HCP to SC or IV Herceptin processes. Active time for all pre-specified tasks was measured, irrespective of whether these occurred in parallel or whether tasks were performed by multiple HCPs simultaneously. 46

Herceptin SC is a ready-to-use formulation which frees up clinic resources, creating admission capacity and cost-savings for hospitals compared to Herceptin IV Multiple studies conducted in the hospital setting of various countries have consistently demonstrated cost-savings related to the switch from Herceptin IV to SC Cost saving = 196/administration or 3.536 over 18 cycles 1 Reductions in wastage through the SC administration (93% 100%) with cost savings = 28,399 for 18 cycles 2 Overall estimated saving with Herceptin SC = $76.94 (New Zealand dollars) per patient per cycle 3 Savings of approximately 720/patient over the total course of treatment of 18 cycles 4 The monetary value of time saved for HCP =1,175 rubles and for patient=6,314 rubles for 18 cycles 5 Net variable cost saving = 9.1 million SEK; Capacity gain = 3,219-6,438 additional administrations within the facility; Incremental revenue potential of up to 38 million SEK due to increased capacity gain 6 Savings at 2012.58/patient over a full course of adjuvant treatment (18 cycles); for all UK patients ~ 15,000,000 7 Saving of consumables of 13.31 /injection for monotherapy 8

Summary Trastuzumab SC: ready-to-use vial with fixed-dose 600mg/5mL plus rhuph20 2000 units/ml rhuph20 offers potential for SC administration of large volumes Short administration time of 2-5 minutes No requirement for loading dose Trastuzumab SC has shown non-inferior efficacy and similar PK and safety profile when compared with trastuzumab IV in patients with HER2+ EBC regardless of body weight (HannaH) Safety of trastuzumab SC 600mg fixed dose for HER2+ BC has been confirmed (SafeHer/SAPPHIRE/MetaPHER) Switching between H IV and SC did NOT present any new safety signals (PrefHer) Immunogenicity of trastuzumab SC did NOT affect efficacy or safety (HannaH) Patients (~86%) and HCPs (81%) overwhelmingly preferred trastuzuamb SC over IV due to time saving and less discomfort (PrefHer/MetaSPHER)