William J. Gradishar MD, FACP Betsy Bramsen Professor of Breast Oncology Director, Maggie Daley Center For Women's Cancer Care Robert H. Lurie Comprehensive.

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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

Lapatinib added to capecitabine for patients with HER2 MBC progressing on trastuzumab: PFS Geyer et al, N Engl J Med. 2006;355: No. of patients at risk: L + C C Weeks Patients Free of Disease Progression (%) 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

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

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

Lapatinib ± trastuzumab in patients with trastuzumab refractory MBC: PFS Blackwell et al, J Clin Oncol. 2010;28: No. of patients at risk: L L + T Time from random assignment (weeks) Alive without progression (cumulative %) month PFS p=0.008 Lapatinib + trastuzumab (n=146) Lapatinib (n=145) Progressed or died (n) Median (weeks) Hazard ratio (95% CI)0.73 (0.57–0.93)

Lapatinib ± trastuzumab for trastuzumab refractory MBC: OS (updated analysis) Blackwell et al, J Clin Oncol 2012;30: No. of at risk: L+T L Time since random assignment (months) Overall Survival (%) 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 month OS 56% 80% 70%

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

Single arm phase II trials of trastuzumab emtansine Burris et al, J Clin Oncol. 2011;29: Krop et al, J Clin Oncol. 2012;30(26): 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

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= PFS (months)

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: 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)

EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: PFS Verma et al, N Engl J Med. 2012; 367: Months Progression-free survival (%) p< No. at risk: Lapatinib + capecitabine Trastuzumab emtansine 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, )

EMILIA – Trastuzumab emtansine vs lapatinib + capecitabine in patients progressing after trastuzumab: OS Verma et al, N Engl J Med. 2012; 367: Months Overall survival (%) % 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

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

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:

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: 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)

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