1. A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs. Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA) J Baselga, J Cortés, S-B Kim, S-A Im, R Hegg, Y-H Im, L Roman, J L Pedrini, T Pienkowski, A Knott, E Clark, M C. Benyunes, G Ross, and S M Swain 1. Baselga et al. N Engl J Med 2011

2. 2 HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer 1. Slamon et al. N Engl J Med 2001; 2. Nahta & Esteva Oncogene 2007; 3. Franklin et al. Cancer Cell 2004; 4. Baselga et al. J Clin Oncol 2010; 5. Gianni et al. Cancer Res 2010 Suppl 2; 6. Baselga & Swain Clin Breast Cancer 2010 Introduction and study objective Trastuzumab-based therapy is the current standard of care in HER2-positive MBC 1 –However, progression of breast cancer still occurs in a majority of patients 2 Pertuzumab is a humanized monoclonal antibody and HER2 dimerization inhibitor that binds HER2 at a different epitope than trastuzumab 3 Phase II trials in patients with HER2-positive breast cancer have shown improved activity, and a good safety profile with pertuzumab- trastuzumab-based therapy 4,5 CLEOPATRA assessed efficacy and safety of a pertuzumab- trastuzumab-based regimen in first-line treatment of patients with HER2-positive MBC 6

3. 3 Study design MBC, metastatic breast cancer; PD, progressive disease Patients with HER2-positive MBC centrally confirmed (N=808) Placebo + trastuzumab 1:1 Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Study dosing q3w: - Pertuzumab/Placebo:840 mg loading dose, 420 mg maintenance - Trastuzumab:8 mg/kg loading dose, 6 mg/kg maintenance - Docetaxel:75 mg/m 2, escalating to 100 mg/m 2 if tolerated Docetaxel* ≥6 cycles recommended n=406 n=402 Pertuzumab + trastuzumab Docetaxel* ≥6 cycles recommended * 6 cycles allowed at investigator discretion PD

4. 4 Key patient eligibility criteria Centrally confirmed HER2-positive (IHC 3+ and/or FISH-positive; ratio ≥2.0) locally recurrent, unresectable, or metastatic breast cancer Measurable and/or non-measurable disease LVEF ≥50% at baseline No more than one hormonal regimen for MBC prior to randomization (Neo)adjuvant systemic breast cancer chemotherapy including trastuzumab and/or taxanes allowed if followed by a disease-free interval of ≥12 months No history of CHF or LVEF decline to <50% during or after prior trastuzumab therapy CHF, congestive heart failure; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction; MBC, metastatic breast cancer

5. 5 Study endpoints Primary endpoint –Independently assessed progression-free survival (PFS) Secondary endpoints –Overall survival –Objective response rate –Safety –PFS by investigator assessment –Duration of response –Evaluation of biomarkers and correlation with clinical outcomes –Time to symptom progression Baselga et al. Clin Breast Cancer 2010.

6. 6 Statistics Progression-free survival –800 patients and ~381 PFS events were required to provide 80% power to detect a 33% improvement in independently assessed PFS (HR = 0.75) at the two-sided significance level of 5% Overall survival –800 patients and 385 OS events were required to provide 80% power to detect a 33% improvement in OS (HR = 0.75) at the two- sided significance level of 5% –The interim OS analysis (estimated at 50% of events for final analysis) was planned at the time of the primary independently assessed PFS analysis OS, overall survival; PFS, progression-free survival

7. 7 Baseline characteristics (I) ECOG PS, Eastern Cooperative Oncology Group performance status Placebo + trastuzumab + docetaxel (n = 406) Pertuzumab + trastuzumab + docetaxel (n = 402) Median age, years (range) 54.0 (27–89) 54.0 (22–82) Region, n (%) Asia Europe North America South America 128 (31.5) 152 (37.4) 68 (16.7) 58 (14.3) 125 (31.1) 154 (38.3) 67 (16.7) 56 (13.9) ECOG PS, n (%) 0 1 ≥2 248 (61.1) 157 (38.7) 1 (0.2) 274 (68.2) 125 (31.1) 3 (0.7)

8. 8 Baseline characteristics (II) ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; PgR, progesterone receptor Placebo + trastuzumab + docetaxel (n = 406) Pertuzumab + trastuzumab + docetaxel (n = 402) HER2 status IHC, n (%) 0 and 1+ 2+ 3+ No data 2 (0.5) 32 (7.9) 371 (91.4) 1 (0.2) 4 (1.0) 47 (11.7) 350 (87.1) 1 (0.2) HER2 status FISH, n (%) Positive Negative No data 383 (94.3) 4 (1.0) 19 (4.7) 384 (95.5) 1 (0.2) 17 (4.2) Hormone receptor status, n (%) ER- and/or PgR-positive ER- and PgR-negative Unknown 199 (49.0) 196 (48.3) 11 (2.7) 189 (47.0) 212 (52.7) 1 (0.2) Disease type at screening, n (%) Non-visceral Visceral 90 (22.2) 316 (77.8) 88 (21.9) 314 (78.1)

9. 9 Prior therapy for breast cancer Placebo + trastuzumab + docetaxel (n = 406) Pertuzumab + trastuzumab + docetaxel (n = 402) Prior (neo)adjuvant chemotherapy, n (%) Yes No 192 (47.3) 214 (52.7) 184 (45.8) 218 (54.2) Prior (neo)adjuvant chemotherapy received, n (%) Components of (neo)adjuvant therapy*, n (%) Anthracycline Hormones Taxane Trastuzumab 192 (100) 164 (85.4) 97 (50.5) 94 (49.0) 41 (21.4) 184 (100) 150 (81.5) 106 (57.6) 91 (49.5) 47 (25.5) * Numbers add up to more than 100% because patients could have received more than one therapy

10. Efficacy results

11. 11 Stratified by prior treatment status and region Primary endpoint: Independently assessed PFS Median follow-up: 19.3 months D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab 0510152025303540 0 10 20 30 40 50 60 70 80 90 100 n at risk 40234526713983321000Ptz + T + D 406311209934217700 Pla + T + D Time (months) Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months HR = 0.62 95% CI 0.51 ‒ 0.75 p<0.0001 ∆ = 6.1 months Progression-free survival (%)

12. 12 Independently assessed PFS in pre-defined subgroups ER, estrogen receptor; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; PgR, progesterone receptor; PFS, progression-free survival All No Yes Europe North America South America Asia <65 years ≥65 years <75 years ≥75 years White Black Asian Other Visceral disease Non-visceral disease Positive Negative Unknown IHC 3+ FISH-positive Favors placeboFavors pertuzumab 01230.5 ER/PgR status Disease type Race Age group Region Prior (neo)adjuvant chemotherapy HER2 status Unstratified analyses 8080.630.52 ‒ 0.76 4320.630.49 ‒ 0.82 3760.610.46 ‒ 0.81 3060.720.53 ‒ 0.97 1350.510.31 ‒ 0.84 1140.460.27 ‒ 0.78 2530.680.48 ‒ 0.95 6810.650.53 ‒ 0.80 1270.520.31 ‒ 0.86 7890.640.53 ‒ 0.78 190.550.12 ‒ 2.54 4800.620.49 ‒ 0.80 300.640.23 ‒ 1.79 2610.680.49 ‒ 0.95 370.390.13 ‒ 1.18 6300.550.45 ‒ 0.68 1780.960.61 ‒ 1.52 3880.720.55 ‒ 0.95 4080.550.42 ‒ 0.72 12 - - 721 0.60 0.49 ‒ 0.74 767 0.64 0.53 ‒ 0.78 nHR95% CI

13. 13 Overall survival: Pre-defined interim analysis Median follow-up: 19.3 months, n = 165 OS events D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab 051015202530354045 0 10 20 30 40 50 60 70 80 90 100 n at risk Ptz + T + D4023873672511618731400 4063833472281436724200Pla + T + D Time (months) Ptz + T + D: 69 events Pla + T + D: 96 events HR = 0.64* 95% CI 0.47 ‒ 0.88 p = 0.0053* * The interim overall survival analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p≤0.0012) Overall survival (%)

14. 14 Independently reviewed objective response In patients with measurable disease at baseline Placebo + trastuzumab + docetaxel (n = 336) Pertuzumab + trastuzumab + docetaxel (n = 343) Objective response rate, n (%) Complete response rate, n (%) Partial response rate, n (%) 233 (69.3) 14 (4.2) 219 (65.2) 275 (80.2) 19 (5.5) 256 (74.6) p = 0.0011* Stable disease, n (%)70 (20.8)50 (14.6) Progressive disease, n (%)28 (8.3)13 (3.8) Unable to assess or no assessment, n (%)5 (1.5) * The statistical test result is deemed exploratory

15. Exploratory efficacy results By prior trastuzumab therapy

16. 16 PFS, progression-free survival Independently assessed PFS by prior trastuzumab therapy in patients with (neo)adjuvant therapy Placebo + trastuzumab + docetaxel Median PFS, months Pertuzumab + trastuzumab + docetaxel Median PFS, months Hazard ratio (CI) Prior (neo)adjuvant trastuzumab treatment (n = 88) 10.416.9 0.62 (0.35 ‒ 1.07) No prior (neo)adjuvant trastuzumab treatment (n = 288) 12.621.6 0.60 (0.43 ‒ 0.83)

17. Safety results

18. 18 Withdrawals from study treatment in the safety population * Protocol violation, failure to return, or other Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Safety reasons, n (%) Adverse event Death 31 (7.8) 20 11 30 (7.4) 23 7 Non-safety reasons, n (%) Progressive disease Refused treatment Other* 248 (62.5) 227 18 3 203 (49.9) 180 16 7 Total, n (%)279 (70.3)233 (57.2)

19. 19 Exposure to study treatment Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Study treatment Time on any treatment (median), months11.818.1 Docetaxel Dose intensity (median), mg/m 2 /week Number of cycles administered, median (range) 24.8 8 (1 ‒ 41) 24.6 8 (1 ‒ 35)

20. 20 Cardiac tolerability LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction Pertuzumab + trastuzumab + docetaxel (n = 407) Placebo + trastuzumab + docetaxel (n = 397) LVSD (any grade)4.4%8.3% LVSD (grade >3)1.2%2.8% Fall in LVEF to <50% and by ≥10 percentage points from baseline 3.8%6.6%

21. 21 Adverse events (all grades) ≥25% incidence or ≥5% difference between arms Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Diarrhea184 (46.3)272 (66.8) Alopecia240 (60.5)248 (60.9) Neutropenia197 (49.6)215 (52.8) Nausea165 (41.6)172 (42.3) Fatigue146 (36.8)153 (37.6) Rash96 (24.2)137 (33.7) Decreased appetite105 (26.4)119 (29.2) Mucosal inflammation79 (19.9)113 (27.8) Asthenia120 (30.2)106 (26.0) Peripheral edema119 (30.0)94 (23.1) Constipation99 (24.9)61 (15.0) Febrile neutropenia30 (7.6)56 (13.8) Dry skin17 (4.3)43 (10.6)

22. 22 Grade ≥3 adverse events (incidence ≥5%) Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Neutropenia182 (45.8)199 (48.9) Febrile neutropenia30 (7.6)56 (13.8) Leukopenia58 (14.6)50 (12.3) Diarrhea20 (5.0)32 (7.9)

23. 23 Conclusions The combination of pertuzumab with trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects.