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Therapeutic options for relapsed / refractory HER2 positive metastatic breast cancer

Therapeutic options for relapsed / refractory HER2 positive metastatic breast cancer. 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

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Therapeutic options for relapsed / refractory HER2 positive metastatic breast cancer

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  1. Therapeutic options forrelapsed / refractory HER2 positive metastatic breast cancer • William J. GradisharMD, 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

  2. Lapatinib added to capecitabine for patients with HER2 MBC progressing on trastuzumab: PFS Patients Free of Disease Progression (%) 100 Lapatinib+ capecitabine (49 events; median time to progression, 8.4 mo) Capecitabine alone ( 72 events; median time to progression, 4.4 mo) 80 60 40 P<0.001 20 0 0 10 20 30 40 50 60 Weeks No. of patients at risk: L + C C 163 161 96 78 52 33 21 14 10 4 4 1 3 0 Geyer et al, N Engl J Med. 2006;355:2733-43.

  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.

  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.

  5. Lapatinib± trastuzumab in patients with trastuzumab refractory MBC: PFS Alive without progression (cumulative %) 100 80 60 p=0.008 40 28 6-month PFS 20 13 0 0 10 20 30 40 50 60 Time from random assignment (weeks) No. of patients at risk: L L + T 148 148 53 73 21 42 13 27 5 8 0 2 Blackwell et al, J ClinOncol. 2010;28:1124-30.

  6. Lapatinib ± trastuzumab for trastuzumab refractory MBC: OS (updated analysis) Overall Survival (%) 100 80% 80 70% 60 56% 6 month OS 40 41% 12-month OS 20 0 0 5 10 15 20 25 30 35 Time since random assignment (months) No. of at risk: L+T L 146 145 120 100 87 64 63 46 42 28 25 13 1 Blackwell et al, J ClinOncol2012;30:2585-92.

  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 trastuzumabemtansine Burris et al, J ClinOncol. 2011;29:398-405. Kropet al, J ClinOncol. 2012;30(26):3234-41.

  9. Results from a randomized phase II trial of trastuzumabemtansine PFS (months) HR: 0.59 (0.36–0.97) p=0.0035 Hurvitzet al, EurJ Cancer. 2011;47(Suppl1):#5001.

  10. EMILIA – Trastuzumab emtansinevslapatinib + capecitabinein 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 Trastuzumab emtansine (3.6 mg/kg q21d) HER2 + MBC Prior T failure (Target n=978) Primary endpoints: OS, PFS and safety R Lapatinib (1250mg/d) + capecitabine(1000 mg/m2 q12 hr x 14/21d) Verma et al, N Engl J Med. 2012; 367: 1783-91.

  11. EMILIA – Trastuzumabemtansinevslapatinib + capecitabine in patients progressing after trastuzumab: PFS Progression-free survival (%) 100 Trastuzumab emtansine (265 events; median time, 9.6 mo) Lapatinib+ capecitabine(304 events; median time, 6.4 mo) 80 60 • Stratified hazard ratio • 0.65 (95% CI, 0.55-0.77) 40 p<0.001 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Months No. at risk: Lapatinib +capecitabine Trastuzumabemtansine 496 495 404 419 310 341 176 236 129 183 73 130 53 101 35 72 25 54 14 44 9 30 8 18 5 9 1 3 0 1 0 0 Verma et al, N Engl J Med. 2012; 367: 1783-91.

  12. EMILIA – Trastuzumab emtansine vslapatinib + capecitabine in patients progressing after trastuzumab: OS Overall survival (%) Trastuzumab emtansine (149 events; median time, 30.9 mo) Lapatinib + capecitabine(182 events; median time, 25.1 mo) 100 85.2% 80 78.2% • Stratified hazard ratio,0.68 (95% CI, 0.55–0.85) p<0.001 64.7% 60 51.8% 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months No. at risk: Lapatinib +capecitabine Trastuzumabemtansine 496 495 471 485 453 474 435 457 403 439 368 418 297 349 240 293 204 242 159 197 133 164 110 136 86 111 63 86 45 62 27 38 17 28 7 13 4 5 Verma et al, N Engl J Med. 2012; 367: 1783-91.

  13. EMILIA – Trastuzumab emtansinevslapatinib + capecitabine in patients progressing after trastuzumab: ORR p<0.001 Patients (%) 43.6 Duration ofresponse (mo): 12.6 6.5 Verma et al, N Engl J Med. 2012; 367: 1783-91.

  14. EMILIA – Trastuzumab emtansinevslapatinib + capecitabine in patients progressing after trastuzumab: Dose reduction Verma et al, N Engl J Med. 2012; 367: 1783-91.

  15. EMILIA – Trastuzumab emtansine vslapatinib + 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.

  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

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