1. William J. Gradishar MD, FACP Betsy Bramsen Professor of Breast Oncology Director, Maggie Daley Center For Women's Cancer Care Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago, IL Therapeutic options for relapsed / refractory HER2 positive metastatic breast cancer

2. Lapatinib added to capecitabine for patients with HER2 MBC progressing on trastuzumab: PFS Geyer et al, N Engl J Med. 2006;355:2733-43. No. of patients at risk: L + C C 163 161 96 78 52 33 21 14 10 4 4141 Weeks Patients Free of Disease Progression (%) 100 80 60 40 20 0 0102030405060 P<0.001 Lapatinib + capecitabine (49 events; median time to progression, 8.4 mo) Capecitabine alone ( 72 events; median time to progression, 4.4 mo) 3030

3. Lapatinib added to capecitabine for patients with HER2 MBC progressing on trastuzumab: Efficacy Geyer et al, N Engl J Med. 2006;355:2733-43. Lapatinib + capecitabine (n=163) Capecitabine (n=161) HR (95% CI)P Median TTP (months) 8.44.4 0.49 (0.34–0.71) <0.001 Median PFS (months) 8.44.1 0.49 (0.33–0.67) <0.001 Overall response (%) 22140.09 Death (%) 22

4. Lapatinib added to capecitabine for patients with HER2 MBC progressing on trastuzumab: Adverse events Geyer et al, N Engl J Med. 2006;355:2733-43. Lapatinib + capecitabine (n=164) Capecitabine (n=152) P (incidence - any grade) Grade 1234Any1234 Diarrhea (%) 27201216014 11039<0.001 Dyspepsia (%) 8300183<10050.014 Rash (%) 20710279570150.011

5. Lapatinib ± trastuzumab in patients with trastuzumab refractory MBC: PFS Blackwell et al, J Clin Oncol. 2010;28:1124-30. No. of patients at risk: L L + T 148 53 73 21 42 13 27 5858 0202 Time from random assignment (weeks) Alive without progression (cumulative %) 100 80 60 40 20 0 0102030405060 13 28 6-month PFS p=0.008 Lapatinib + trastuzumab (n=146) Lapatinib (n=145) Progressed or died (n)127128 Median (weeks)12.08.1 Hazard ratio (95% CI)0.73 (0.57–0.93)

6. Lapatinib ± trastuzumab for trastuzumab refractory MBC: OS (updated analysis) Blackwell et al, J Clin Oncol 2012;30:2585-92. No. of at risk: L+T L 146 145 120 100 87 64 63 46 42 28 1 Time since random assignment (months) Overall Survival (%) 100 80 60 40 20 0 051015202535 6 month OS 41% Lapatinib + trastuzumab (n=146) Lapatinib (n=145) Died, n (%)105 (72)113 (78) Median (weeks)149.5 Hazard ratio (95% CI) 0.74 (0.57–0.97) Log-rank P.026 12-month OS 56% 80% 70% 30 25 13

7. Current standards of care for HER2 positive MBC: patients progressing on trastuzumab (NCCN)  Agents for trastuzumab-exposed HER2-positive disease Capecitabine + lapatinib Capecitabine + trastuzumab Lapatinib + trastuzumab NCCN Category 2A NCCN 2012; Breast cancer V3.2012

8. Single arm phase II trials of trastuzumab emtansine Burris et al, J Clin Oncol. 2011;29:398-405. Krop et al, J Clin Oncol. 2012;30(26):3234-41. Burris et alKrop et al Patients Patients with MBC progressing after HER2 therapy with chemotherapy (n=112) Patients with MBC previously treated with trastuzumab and lapatinib, anthracylines, capecitabine and taxane (n=110) Treatment Trastuzumab emtansine 3.6 mg/kg q3w Objective response rate (%) 25.9 (all PR) (33.8% in HER2 positive tumors tested centrally) 35 (all PR) PFS N/R6.9 months

9. Results from a randomized phase II trial of trastuzumab emtansine Hurvitz et al, Eur J Cancer. 2011;47(Suppl 1):#5001. HR: 0.59 (0.36–0.97) p=0.0035 PFS (months)

10. EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: Study design  Entry criteria Centrally confirmed HER2+ locally advanced or metastatic, progressive breast cancer Prior taxane and trastuzumab ECOG PS 0–1  Secondary endpoints ORR and clinical benefit, duration of response Time to symptom progression Verma et al, N Engl J Med. 2012; 367: 1783-91. Trastuzumab emtansine (3.6 mg/kg q21d) Primary endpoints: OS, PFS and safety R HER2 + MBC Prior T failure (Target n=978) Lapatinib (1250mg/d) + capecitabine (1000 mg/m 2 q12 hr x 14/21d)

11. EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: PFS Verma et al, N Engl J Med. 2012; 367: 1783-91. Months Progression-free survival (%) p<0.001 0612182430 100 80 60 40 20 0 No. at risk: Lapatinib + capecitabine Trastuzumab emtansine 496 495 176 236 28262220161410842 404 419 310 341 5959 0000 1313 0101 129 183 35 72 73 130 53 101 25 54 8 18 14 44 9 30 Trastuzumab emtansine (265 events; median time, 9.6 mo) Lapatinib + capecitabine (304 events; median time, 6.4 mo) Stratified hazard ratio 0.65 (95% CI, 0.55-0.77)

12. EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: OS Verma et al, N Engl J Med. 2012; 367: 1783-91. Months Overall survival (%) 0 100 80 60 40 20 0 496 495 435 457 471 485 453 474 27 38 4545 17 28 7 13 403 439 240 293 368 418 297 349 110 136 45 62 86 111 63 86 204 242 159 197 133 164 61218243028262220161410842363432 78.2% 51.8% 85.2% 64.7% Trastuzumab emtansine (149 events; median time, 30.9 mo) Lapatinib + capecitabine (182 events; median time, 25.1 mo) Stratified hazard ratio, 0.68 (95% CI, 0.55–0.85) p<0.001 No. at risk: Lapatinib + capecitabine Trastuzumab emtansine

13. EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: ORR Verma et al, N Engl J Med. 2012; 367: 1783-91. Patients (%) 43.6 p<0.001 Duration of response (mo): 12.66.5

14. EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: Dose reduction Trastutumab emtansine (n=495) Lapatinib + capecitabine (n=496) Dose reduction (patients, %) 16.3L: 27.3 C: 53.4 Median daily dose3.5 mg/kg/21dL:1250 mg/d C: 1730 mg/m 2 /d Discontinued due to adverse events (patients, %) 5.9L: 7.6 C: 9.4 Verma et al, N Engl J Med. 2012; 367: 1783-91.

15. EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: Grade 3 or 4 events in ≥2% in either arm Verma et al, N Engl J Med. 2012; 367: 1783-91. Adverse Event Trastuzumab emtansine (n=490) Lapatinib + capecitabine (n=488) Events of any grade (%) Grade 3 or 4 events (%) Events of any grade (%) Grade 3 or 4 events (%) Any event470 (95.9)200 (40.8)477 (97.7)278 (57.0) Specific events † Diarrhea114 (23.3)8 (1.6)389 (79.7)101 (20.7) Palmar-plantar erythrodysesthesia6 (1.2)0283 (58.0)80 (16.4) Vomiting93 (19.0)4 (0.8)143 (29.3)22 (4.5) Neutropenia29 (5.9)10 (2.0)42 (8.6)21 (4.3) Hypokalemia42 (8.6)11 (2.2)42 (8.6)20 (4.1) Fatigue172 (35.1)12 (2.4)136 (27.9)17 (3.5) Nausea192 (39.2)4 (0.8)218 (44.7)12 (2.5) Mucosal inflammation33 (6.7)1 (0.2)93 (19.1)11 (2.3) Anemia51 (10.4)13 (2.7)39 (8.0)8 (1.6) Elevated ALT83 (16.9)14 (2.9)43 (8.8)7 (1.4) Elevated AST110 (22.4)21 (4.3)46 (9.4)4 (0.8) Thrombocytopenia137 (28.0)63 (12.9)12 (2.5)1 (0.2)

16. Summary  For patients with relapsed / refractory metastatic breast cancer lapatinib + capecitabine is the current standard of care Based on a comparison with capecitabine alone improvements in PFS and OS  Studies have shown that dual HER2 inhibition with lapatinib and trastuzumab also has clinical activity in this setting and may be considered  The novel drug-antibody conjugate trastuzumab emtansine is now approved by the FDA in this setting The EMILIA trial demonstrated improved PFS and OS with less dose reduction due to AEs