Innovations In The Management Of

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1 Innovations In The Management Of HER2+ Breast Cancer Dr. Sandeep Goyle Consultant Medical Oncologist Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai, India

2 Introduction - Self MBBS, MD General Medicine Mumbai, India DNB General Medicine, FCPS - India MRCP London Royal College Of Physicians, London CCST Medical Oncology United Kingdom MSc Oncology University of Manchester, UK

3 Introduction Kokilaben Dhirubhai Ambani Hospital, Mumbai

4 From bench to bedside: 1985 Coussens L, et al. Science 1985: 230:

5 From bench to bedside: 1987 Slamon DJ, et al. Science 1987; 235:

6 Overall survival (%) HER2 overexpression: a negative prognostic factor in BC 1,2 Diseas e recurr ence Shorte ned surviva l Not amplified (n = 52) Metasta sis Rapid tumour develop ment p = 0.06 Amplified (n = 11) >5 copies Time (months)) 1. Ross JS, et al. Oncologist 2003; 8: ; 2. Wolff AC, et al. Arch Pathol Lab Med 2007; 131:18 43 Figure adapted from: 1. Slamon DJ, et al. Science 1987; 235: ; 2. Dawood S, et al. J Clin Oncol 2010; 28:92 98.

7 Trastuzumab Antigen binding Humanised anti-her2 monoclonal antibody 95% human, 5% murine --> decreased potential for immunogenicity Blocks activity of HER2 gene, which is involved in cell growth control Targets cancerous cells

8 From bench to bedside: 1998 First Phase III trial results presented at the ASCO annual meeting in 1998 Slamon D et al. Proc. Amer. Soc; Clin. Oncol. 1998;17 (abst. 377) Nass SJ, et al. Nat Med 1998; 4: Slamon D, et al. Proc Amer Soc Clin Oncol 1998; 17(abst. 377).

9 H0648g trial design Slamon DJ, et al. N Engl J Med 2001;334:783 92

10 M77001 Study design 11

11 H0648g and M77001: addition of trastuzumab to taxane as first-line therapy increases OS H0648g M77001

12 Overall survival (%) Trastuzumab prolongs overall survival in HER2+ MBC Chemotherapy (n = 234) Chemotherapy + trastuzumab (n = 235) RR = 0.80 (95% CI = 0.64,1.00) p = Median OS: 20.3 months Median OS: 25.1 months Time (months after enrolment) OS was a secondary endpoint in the study Chemotherapy = either doxorubicin or epirubicin + cyclophosphamide or paclitaxel OS, overall survival; RR, relative risk of death Adapted from Slamon DJ, et al. N Engl J Med 2001; 344:

13 Overall survival (%) Trastuzumab: The SoC* for HER2+MBC Following the addition of trastuzumab, HER2+ no longer dictates the probability of survival HER2-negative HER2-positive with trastuzumab HER2-positive without trastuzumab Adapted from Dawood S, et al. J Clin Oncol 2010; 28: Time (months from diagnosis) *SoC: Standard of Care

14 The addition of trastuzumab to chemotherapy is well tolerated Chemotherapy 1 Docetaxel 2 SAE, % Alone (n=230) Trastuzumab (n=234) Diff Alone (n=94) Trastuzumab (n=92) Diff Fever Heart failure Leucopenia Febrile neutropenia Alopecia * All patients who received paclitaxel ± trastuzumab; Based on pretreatment blood counts only; 1 additional patient developed symptomatic heart failure and died after treatment while enrolled on a novel anthracycline trial; Diff, difference; SAE, serious adverse event. 1. Slamon DJ, et al. N Engl J Med 2001; 344: ; 2. Marty M, et al. J Clin Oncol 2005; 23:

15 Trials of Endocrine therapy with and without Anti- HER2 Therapy TAnDEM

16 Trastuzumab in HER2-positive mbc Trastuzumab-based treatments became the backbone of therapy for HER2-positive breast cancers in first-line mbc: In combination with taxanes In combination with endocrine treatment Slamon DJ, et al. N Engl J Med 2001; 344: ; Marty M, et al. J Clin Oncol 2005; 23: ; Valero V, et al. J Clin Oncol 2011; 29: ; Andersson M, et al. J Clin Oncol 2011; 29: ; Kaufman B, et al. J Clin Oncol 2009; 27: ; Johnston S, et al. J Clin Oncol 2009; 27:

17 Trastuzumab is established as the foundation of care for women with HER2+BC across all stages of the disease Goldhirsch A, et al. Ann Oncol 2011; 22: ;2. Aebi S, et al. Ann Oncol 2011; 22 (suppl 6): 12 24; 3. NCCN Clinical Practice Guidelines in Oncology Breast cancer Version Cardoso F, et al. Ann Oncol 2012; 23 (suppl 7): 11 19; 7. Marty M et al. J Clin Oncol 2005; 23:

19 Despite initial therapy, approximately a third of women with primary BC will develop metastatic disease 1 The average survival of patients after diagnosis of MBC is 2 4 years 2 Despite initial response to trastuzumab therapy, approximately 50% of patients with HER2+ MBC experience disease progression within a year, requiring further intervention to prolong life 3 Novel HER2 targeted agents may improve survival benefits in patients with HER2+ BC at all stages 1. O Shaughnessy J, Oncologist 2005; 10 (suppl 3): 20 29; 2. Chung CT & Carlson RW. Oncologist. 2003; 8(6): ; 2. Cardoso F, et al. Ann Oncol 2012; 23 (suppl 7): 11 19; 7. Marty M et al. J Clin Oncol 2005; 23:

20 Pertuzumab is the first in a new class of HER2 dimerisation inhibitors Key HER signalling pathways that mediate cancer cell proliferation and survival are inhibited by pertuzumab blockade of HER2 dimerisation 1 4 In addition, pertuzumab can activate antibody-dependent cellular cytotoxicity 5 HER1, 3, 4 Pertuzumab HER2 1. Agus DB, et al. Cancer Cell 2002; 2: ; 2. Hughes JB, et al. Mol Cancer Ther 2009; 8: ; 3. Baselga J. Cancer Cell 2002; 2:93 95; 4. Franklin MC, et al. Cancer Cell 2004; 5: ; 5. Scheuer W, et al. Cancer Res 2009; 69:

21 CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) Placebo + trastuzumab (n = 406) PD Patients with HER2-positive mbc centrally confirmed (N = 808) R 1:1 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab (n = 402) PD Docetaxel* 6 cycles recommended Randomisation: Stratified by geographic region and prior treatment status ([neo]adjuvant chemotherapy received or not) Dosing: Pertuzumab/placebo: 840 mg loading dose, 420 mg maintenance q3w Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance q3w Docetaxel: 75 mg/m 2, escalating to 100 mg/m 2 if tolerated q3w *<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion PD, progressive disease Baselga J, et al. N Engl J Med 2012; 366:

22 CLEOPATRA: Study endpoints Primary endpoint Independent review facility (IRF)-assessed PFS Secondary endpoints Investigator-assessed PFS OS Objective response rate Safety (monitored by an independent DMC and CRC) CRC, cardiac review committee; DMC, data monitoring committee; PFS, progression free survival; OS, overall survival Baselga J, et al. N Engl J Med 2012; 366:

23 CLEOPATRA: Baseline characteristics (I) Placebo, trastuzumab and docetaxel (n = 406) Pertuzumab, trastuzumab and docetaxel (n = 402) Median age, years (range) 54.0 (46 61) 54.0 (46 60) Region, n (%) Asia Europe North America South America ECOG PS, n (%) (32) 152 (37) 68 (17) 58 (14) 248 (61) 157 (39) 1 (<1) 125 (31) 154 (38) 67 (17) 56 (14) 274 (68) 125 (31) 3 (1) ECOG PS, Eastern Cooperative Oncology Group performance status Swain SM, et al. Lancet Oncol 2013; 14:

24 CLEOPATRA: Baseline characteristics (II) HER2 status IHC, n (%) 0 and No data HER2 status FISH, n (%) Positive Negative No data Hormone receptor status, n (%) ER- and/or PR-positive ER- and PR-negative Unknown Disease type at screening, n (%) Non-visceral Visceral Placebo, trastuzumab and docetaxel (n = 406) 2 (<1) 32 (8) 371 (91) 1 (<1) 383 (94) 4 (1) 19 (5) 199 (49) 196 (48) 11 (3) 90 (22) 316 (78) Pertuzumab, trastuzumab and docetaxel (n = 402) 4 (1) 47 (12) 350 (87) 1 (<1) 384 (96) 1 (<1) 17 (4) 189 (47) 212 (53) 1 (<1) 88 (22) 314 (78) ER, oestrogen receptor; FISH, fluorescent in situ hybridisation; IHC, immunohistochemistry; PR, progesterone receptor Swain SM, et al. Lancet Oncol 2013; 14:

25 CLEOPATRA: Prior therapy for breast cancer Prior (neo)adjuvant chemotherapy, n (%) Yes No Components of (neo)adjuvant therapy, n (%) Anthracycline Hormones Taxane Trastuzumab Placebo, trastuzumab and docetaxel (n = 406) 192 (47) 214 (53) 164 (40) 97 (24) 94 (23) 41 (10) Pertuzumab, trastuzumab and docetaxel (n = 402) 184 (46) 218 (54) 150 (37) 106 (26) 91 (23) 47 (12) Swain SM, et al. Lancet Oncol 2013; 14:

26 CLEOPATRA: Exposure to study treatment Study treatment Number of cycles, median (range) Time on any treatment, months (range) Docetaxel Number of cycles, median (range) Dose intensity, mg/m 2 /week (range) Dose escalation to 100 mg/m 2, n (%) Dose reduction to <75 mg/m 2, n (%) Proportion of cycles delayed, interrupted, discontinued or infusion rate reduced, % Placebo, trastuzumab and docetaxel (n = 396) 15 (9 29) 11.4 ( ) 8 (6 10) 24.8 ( ) 60 (15) 90 (23) 12 Pertuzumab, trastuzumab and docetaxel (n = 408) 24 (11 38) 17.4 ( ) 8 (6 10) 24.6 ( ) 49 (12) 104 (25) 13 Swain SM, et al. Lancet Oncol 2013; 14:

27 Perjeta Final PFS analysis Pertuzumab + trastuzumab + docetaxel significantly extended PFS by 6.1 months vs. trastuzumab + docetaxel alone

28 Perjeta Final OS analysis Patients lived an unprecedented 15.7 months longer when treated with pertuzumab + trastuzumab + docetaxel vs. trastuzumab + docetaxel alone

29 Treatment after Study Discontinuation ITT population Placebo + T + D (n = 369 withdrawn), % Pertuzumab + T + D (n = 335 withdrawn), % Any n = 291 n = 258 Any HER2-targeted treatment Trastuzumab Pertuzumab Lapatinib Trastuzumab emtansine Capecitabine Vinorelbine Doxorubicin Cyclophosphamide Taxanes Hormonal treatments Swain S, et al. ESMO 2014; 350O_PR 30

Patients (%) CLEOPATRA: Significantly higher response rate with pertuzumab and trastuzumab Pertuzumab + trastuzumab + docetaxel (n = 343) Placebo + trastuzumab + docetaxel (n =

30 Patients (%) CLEOPATRA: Significantly higher response rate with pertuzumab and trastuzumab Pertuzumab + trastuzumab + docetaxel (n = 343) Placebo + trastuzumab + docetaxel (n = 336) 10.8% ( ); p = % CR 4.2% CR 74.6% PR 80.2% ORR 69.3% 65.2% PR ORR CR, complete response; PR, partial response Baselga J, et al. N Engl J Med 2012; 366:

31 CLEOPATRA: Adverse events n (%) Placebo, trastuzumab and docetaxel (n = 396) Pertuzumab, trastuzumab and docetaxel (n = 408) Grade 1 2 Grade 3 4 Grade 5 Grade 1 2 Grade 3 4 Grade 5 Diarrhoea 171 (43) 20 (5) (59) 37 (9) 0 Alopecia 236 (60) 1 (<1) (60) 0 0 Neutropenia 15 (4) 182 (46) 0 16 (4) 200 (49) 0 Nausea 166 (42) 2 (1) (43) 5 (1) 0 Fatigue 134 (34) 13 (3) (35) 9 (2) 0 Rash 91 (23) 3 (1) (36) 3 (1) 0 Decreased appetite 99 (25) 6 (2) (28) 7 (2) 0 Mucosal inflammation 75 (19) 4 (1) (26) 6 (1) 0 Asthenia 114 (29) 7 (2) (25) 10 (2) 0 Vomiting 91 (23) 6 (2) 0 98 (24) 6 (1) 0 Peripheral oedema 116 (29) 3 (1) 0 97 (24) 2 (<1) 0 Pruritus 39 (10) (16) 0 0 Constipation 97 (24) 4 (1) 0 63 (15) 0 0 Febrile neutropenia 0 29 (7) 1 (<1) 0 53 (13) 3 (1) Dry skin 18 (5) (11) 0 0 AEs with higher prevalence in the pertuzumab-based regimen (pertuzumab, trastuzumab and docetaxel) arm Swain SM, et al. Lancet Oncol 2013; 14:

32 CLEOPATRA: No episodes of febrile neutropenia after discontinuation of Patients with 1 episode (%) docetaxel 7 Febrile neutropenia (grade 3) by cycle of treatment Patients were to receive a minimum of 6 cycles of docetaxel Pertuzumab, trastuzumab and docetaxel (n = 408) Placebo, trastuzumab and docetaxel (n = 396) Cycle Swain S, et al. SABCS 2012; Poster P ; 2. Swain S, et al. Lancet Oncol 2013; 14:

33 Patients with 1 episode (%) CLEOPATRA: Frequency of diarrhoea and rash fell considerably following discontinuation of docetaxel Patients with 1 episode (%) Diarrhoea (all grades) by cycle of treatment 1 Rash (all grades) by cycle of treatment Pertuzumab, trastuzumab and docetaxel (n = 408)* 35 Placebo, trastuzumab 30 and docetaxel (n = 396) Pertuzumab, trastuzumab and docetaxel (n = 407) Placebo, trastuzumab and docetaxel (n = 397) * Data cut-off May 2012 Cycle Cycle Data cut-off May Swain S, et al. SABCS Poster P ; 2. Baselga J, et al. ASCO 2012; Poster 597.

34 CLEOPATRA: No increase in incidence of LVSD with the addition of pertuzumab LVSD, n (%) Placebo, trastuzumab and docetaxel (n = 397) Pertuzumab, trastuzumab and docetaxel (n = 407) All grades 33 (8.3) 18 (4.4) Grade 2 15 (3.8) 10 (2.5) Grade 3* 11 (2.8) 5 (1.2) Symptomatic LVSD a 7 (1.8) 4 (1.0) * All symptomatic LVSD events (n = 11) were reported as LVSD grade 3. However, there were five patients with grade 3 LVSD (placebo arm, n = 4; pertuzumab arm, n = 1) that was not deemed to be symptomatic by the investigator Assessment of NCI-CTCAE grade was missing for one patient Data cut-off: May 2011 LVSD, left ventricular systolic dysfunction Swain SM, et al. Oncologist 2013; 18: Swain SM, et al. Oncologist 2013; 18:

35 CLEOPATRA: Cardiac Safety updated Safety population Placebo + T + D (n = 396), % Pertuzumab + T + D (n = 408), % slvd LVEF decline to < 50% and by 10% points from baseline* One new slvd event in the pertuzumab group after 40 months (resolved) LVEF declines reversed in 88% of pertuzumab patients * In patients with post-baseline assessment; n = 378 in the placebo group and 394 in the pertuzumab group. slvd, symptomatic left ventricular dysfunction. Swain S, et al. ESMO 2014; Abstract 350O_PR 36

36 CLEOPATRA: Take-home messages Pertuzumab, trastuzumab and docetaxel provides statistically significant and clinically meaningful improvements in PFS and OS in patients with HER2- positive mbc The combination of pertuzumab + trastuzumab + chemotherapy did not increase the rates of symptomatic or asymptomatic cardiac dysfunction The majority of AEs were grade 1/2 and mostly occurred during the period of concomitant docetaxel administration; there was no evidence of cumulative or late cardiac toxicity associated with pertuzumab Pertuzumab has no detrimental impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms

37 NCCN and AGO guidelines recommend a pertuzumab-based regimen for HER2- positive mbc* NCCN Guidelines v AGO Guidelines Update 2016 First-line treatment Pertuzumab with trastuzumab and docetaxel (category 1) 1 Approved by the EMA 2 Therapy in HER2-positive mbc Pertuzumab in combination with trastuzumab plus docetaxel is standard treatment for HER2-positive mbc 3 * Please note: International guidelines may not be in line with current national guidelines. AGO: Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group); NCCN, National Comprehensive Cancer Network 1. NCCN Guidelines Breast Cancer v3.2013; 2. EMA PERJETA SmPC Harbeck N, et al. Breast Care 2013; 8: Not all treatment combinations recommended by guidelines are approved by regulatory authorities

39 still there was concerns Chemo 2 nd line MBC

The first antibody-drug conjugate (ADC) designed specifically for HER2- overexpressing tumours An innovative

retains anti-her2 activities HOME Indicat ion Linker Links DM1 to trastuzumab, limiting systemic exposure of DM1

for Kadcyla, based on preclinical models *Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the

In preclinical models, Kadcyla retains the HER2 suppression and antitumour activities of unconjugated

proliferative downstream signaling Inhibits HER2 shedding Kadcyla provides controlled cytotoxic potency directed

41 The first antibody-drug conjugate (ADC) designed specifically for HER2- overexpressing tumours An innovative design for potent cytotoxicity and antitumour activities 1 Trastuzumab (monoclonal antibody) Binds to HER2 and retains anti-her2 activities HOME Indicat ion Linker Links DM1 to trastuzumab, limiting systemic exposure of DM1 DM1, a cytotoxic maytansinoid* Inhibits tubulin polymerisation to induce cell death Proposed mechanism of action for Kadcyla, based on preclinical models *Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the linker. In preclinical models, Kadcyla retains the HER2 suppression and antitumour activities of unconjugated trastuzumab 1,2 Triggers an antibody-dependent, cell-mediated cytotoxicity (ADCC) immune response Inhibits proliferative downstream signaling Inhibits HER2 shedding Kadcyla provides controlled cytotoxic potency directed to HER2-positive cancer cells 1,3 The cytotoxic component DM1 is too potent for systemic use in an unconjugated form 1 A thioether linker improves stability of Kadcyla to limit systemic exposure compared with first-generation ADCs 3

How Kadcyla works [1] The trastuzumab component of Kadcyla detects and binds to the HER2-positive cancer cell Upon binding, trastuzumab triggers anti-cancer activities inhibiting HER2 signalling

42 How Kadcyla works [1] The trastuzumab component of Kadcyla detects and binds to the HER2-positive cancer cell Upon binding, trastuzumab triggers anti-cancer activities inhibiting HER2 signalling and activating the body's immune system to target and destroy the tumour. The process of activating the immune system to attack the tumour is called antibody-dependent cellular cytotoxicity (ADCC).

43 How Kadcyla works [2] Kadcyla is taken up by the cancer cell

44 How Kadcyla works [3] Once Kadcyla is taken up by the cancer cell, the chemotherapy DM1 is released, causing the cell to stop growing and the death of the cancer cell

45 Trial that brought approval of this unique concept

46 Data cutoff: 14JAN2012 EMILIA: Patient Demographics and Baseline Characteristics (1) Cap + Lap (n=496) Trastuzumab emtansine (n=495) Median age, years (range) 53 (24 83) 53 (25 84) Race, n (%) White Asian Black/African American Other Not available World region, n (%) United States Western Europe Asia Other ECOG PS, n (%) (75) 86 (17) 21 (4) 10 (2) 5 (1) 136 (27) 160 (32) 76 (15) 124 (25) 312 (64) 176 (36) 358 (72) 94 (19) 29 (6) 7 (1) 7 (1) 134 (27) 157 (32) 82 (17) 122 (25) 299 (61) 194 (39)

47 EMILIA: Patient Demographics and Baseline Characteristics (2) Cap + Lap (n=496) Trastuzumab emtansine (n=495) Measurable disease by independent review, n (%) 389 (78) 397 (80) Site of disease involvement, n (%) Visceral Non-visceral 335 (67) 161 (32) Metastatic sites, n (%) <3 3 Unknown ER/PR status, n (%) ER+ and/or PR+ ER and PR Unknown 307 (62) 175 (35) 14 (3) 263 (53) 224 (45) 9 (2) 334 (68) 161 (33) 298 (60) 189 (38) 8 (2) 282 (57) 202 (41) 11 (2) Data cutoff: 14JAN2012

48 EMILIA: PFS benefit seen with Trastuzumab emtansine

49 EMILIA: OS benefit seen with Trastuzumab emtansine

50 EMILIA: Higher ORR and DOR with Trastuzumab emtansine

51 EMILIA: Patient-reported outcomes Time to symptom progression The FACT-B TOI 1 evaluates Physical well-being Functional well-being Breast cancer-specific symptoms Symptom progression defined as 5-point decrease from baseline Trastuzumab Time to symptom progression 2 = 445) (n = 450) Cap + lap (n emtansine Median, mo HR (95% CI) p value 0.80 ( ) CI, confidence interval; FACT-B, Functional Assessment of Cancer Therapy-Breast; HR, hazard ratio; TOI, Trial Outcome Index. 1. Brady MJ, et al. J Clin Oncol 1997; 15: ; 2. Blackwell KL, et al. ASCO 2012 (Abstract LBA1; oral presentation).

52 EMILIA - Toxicity Lapatinib + capecitabine (n=488) Trastuzumab emtansine (n=490) AE All grades, % Grade 3, % All grades, % Grade 3, % Diarrhoea Hand foot syndrome Vomiting Neutropenia Hypokalaemia Fatigue Nausea Mucosal inflammation Thrombocytopenia Increased AST Increased ALT Anaemia * Listed are grade 3 AEs with an incidence of 2% or higher in either group. Verma, S et al. N Engl J Med 2012; 367:

53 EMILIA: Fewer patients treated with Trastuzumab emtansine required a dose reduction vs lapatinib + capecitabine Cap (n=487) Lap (n=488) Trastuzumab emtansine (n=490) Median dose intensity, % Pts with dose reduction, n (%) 260 (53.4) 133 (27.3) 80 (16.3) Trastuzumab emtansine decreased to 3.0 mg/kg, n (%) 58 (11.8) Trastuzumab emtansine decreased to 2.4 mg/kg, n (%) 22 (4.5) Verma S, et al. N Engl J Med 2012; 367: and Erratum in N Engl J Med 2013; 368:2442. Verma S, et al. ESMO 2012; Abstract LBA12: oral presentation.

54 EMILIA: Cardiac Dysfunction Cardiac dysfunction AEs, a n (%) All grades Grade 3 Cap + Lap (n=488) 16 (3.3) 2 (0.4) Trastuzumab emtansine (n=490) 10 (2.0) 1 (0.2) Lowest post-baseline LVEF value, n (%) 45% 40 to <45% <40% (n=462) 455 (98.5) 4 (0.9) 3 (0.6) (n=482) 476 (98.8) 3 (0.6) 3 (0.6) LVEF <50% and 15-point decrease from baseline, n (%) (n=446) 8 (1.8) (n=481) 8 (1.7) a Includes preferred terms decreased ejection fraction and left ventricular dysfunction ; Does not include cardiac AEs (e.g. myocardial infarction, atrial fibrillation). Data cutoff: 31JUL2012

55 How to administer Trastuzumab emtansine Dosing for Trastuzumab emtansine is weight-based Trastuzumab emtansine is given as a single IV infusion every 3 weeks Administer at a dose of 3.6 mg/kg via IV infusion To be either diluted in 250 ml of sodium chloride 4.5 mg/ml (0.45%) or sodium chloride 9 mg/ml (0.9%) solution for infusion An in-line PES filter (0.22 micron) is required for the 0.9% dilution No loading dose IV, intravenous; PES, polyethersulfone Kadcyla (Trastuzumab Emtansine) Prescribing information, India 2015

56 Dose modifications and reductions Despite the favourable safety profile for Trastuzumab emtansine, management of adverse reactions may require temporary interruption, dose reduction or treatment discontinuation Dose reduction guidelines for Trastuzumab emtansine: Dose reductions should be made in decrements of 0.6 mg/kg A maximum of two dose reductions are allowed to occur before discontinuation Trastuzumab emtansine dose should not be re-escalated after a dose reduction has been made Kadcyla (Trastuzumab Emtansine) Prescribing information, India 2015

EMILIA study findings: conclusions The EMILIA trial demonstrated that when compared to lapatinib plus Xeloda, Kadcyla provided: Significantly improved overall survival Significantly improved

57 EMILIA study findings: conclusions The EMILIA trial demonstrated that when compared to lapatinib plus Xeloda, Kadcyla provided: Significantly improved overall survival Significantly improved progression free survival More tolerable safety profile Improved quality of life To conclude, Kadcyla is the first ADC for the treatment of HER2-positive mbc which has been shown to provide significant benefits for this patient population over and above currently available treatments.

58 Trastuzumab emtansine is recommended by AGO as highest ranked treatment option for second-line HER2-positive mbc Treatment regimen Recommendation Trastuzumab emtansine * Grade A, ++ (A++ highest rank, D-- lowest rank criteria) Lapatinib + capecitabine Grade B, + Trastuzumab + lapatinib Grade B, + TBP: Second-line chemotherapy + trastuzumab Grade D, + Pertuzumab + trastuzumab + taxane Grade D, + Pertuzumab + trastuzumab + other second-line chemotherapy (e.g. vinorelbine; taxane/carboplatin; capecitabine/docetaxel) Grade D,+/- Trastuzumab + AI (ER-positive) Grade B, + Lapatinib + AI (ER-positive) Grade B, + AGO, German Gynaecological Oncology Group; AI, aromatase inhibitor; ER, oestrogen receptor; HR, hormone receptor; TBP, treatment beyond progression * The AGO guidelines highlight that Trastuzumab emtansine is recommended more highly than lapatinib + capecitabine; Trastuzumab emtansine is also recommended (Grade A++) in further lines of therapy. See speaker notes and Appendix for further information on recommendations/gradings; AGO recommendations for second-line therapies apply to patients whose disease has progressed on trastuzumab-based therapy. Not all treatment combinations recommended by the guidelines are approved by the regulatory authorities. Not all treatment combinations recommended by guidelines are approved by regulatory authorities

59 1. Hurvitz S, et al. Eur J Cancer 2011; 47S330Abstract ClinicalTrials.gov NCT ClinicalTrials.gov NCT ClinicalTrials.gov NCT Other key Kadcyla trials - mbc Study Status Design N Primary objective TDM4450g 1 Completed Phase II, international, multicentre, two-arm, open-label study of Kadcyla versus Herceptin plus docetaxel chemotherapy in the first-line treatment of mbc 137 PFS and safety profile MARIANNE 2 TH3RESA 3 Enrolment closed Enrolment closed Phase III international, randomised, three-arm study of Kadcyla with PERJETA (pertuzumab) or Kadcyla with placebo (blinded for PERJETA), versus the combination of Herceptin plus taxane chemotherapy in patients with HER2- positive progressive or recurrent locally advanced or previously untreated mbc Phase III international, randomised, multicentre, two-arm, open-label study of Kadcyla versus physicians choice of therapy in the third-line treatment of mbc KAMILLA 4 Enrolling Phase IIIb, global safety study of Kadcyla in patients with HER2-positive mbc who have previously received treatment for their disease 1092 PFS, safety 600 OS and PFS 1000 Safety and tolerability

60 Summary The options available for HER2-positive mbc have exponentially increased since the advent of trastuzumab Combined HER2 targeting with trastuzumab and pertuzumab prolonged median overall survival (~5 years) in first-line mbc Novel targeted agent T-DM1 improved survival outcomes in patients progressed on trastuzumab and taxane. Baselga J, et al. N Engl J Med 2012; 366: ; Perez et al. Cancer 2012; Hernandez-Aya & Gonzalez-Angulo Oncologist 2011

61 Question To Audience How to increase the availability of these novel agents for our patients?

62 Thank You

The next wave of successful drug therapy strategies in HER2-positive breast cancer. Hans Wildiers University Hospitals Leuven Belgium

The next wave of successful drug therapy strategies in HER2-positive breast cancer Hans Wildiers University Hospitals Leuven Belgium Trastuzumab in 1st Line significantly improved the prognosis of HER2-positive