First line therapeutic options for HER2 positive metastatic breast cancer

1. First line therapeutic options forHER2 positive metastatic breast cancer • Harold Burstein, MD • Assistant Professor of Medicine • Dana-Farber Cancer Institute • Boston, MA

2. Trastuzumab in advanced/metastatic breast cancer • 1. Slamon et al, N Engl J Med. 2001;344:783-92. • 2. Marty et al, J ClinOncol. 2005;23:4265-74. 3. Burstein et al, Cancer. 2007;110:965-72. 4. Robert et al, J ClinOncol. 2006;24:2786-92.

3. Effect of trastuzumab added tocytotoxic chemotherapy: PFS Progression-free survival (%) 100 Chemotherapy + trastuzumab Chemotherapy alone 80 60 40 p<0.001 20 0 0 5 10 15 20 25 Months after enrollment No. at risk: Chemotherapy+trastuzumab Chemotherapy alone 226 224 122 183 60 25 15 0 Slamon et al, N Engl J Med. 2001;344:783-92.

4. Effect of trastuzumab added tocytotoxic chemotherapy: OS Survival (%) 100 Chemotherapy + trastuzumab Chemotherapy alone 80 60 40 p<0.001 20 0 30 0 5 10 15 20 25 35 40 45 50 Months after enrollment No. at risk: Chemotherapy+trastuzumab Chemotherapy alone 11 13 236 234 214 205 102 160 105 136 134 116 114 97 96 76 47 27 Slamon et al, N Engl J Med. 2001;344:783-92.

5. HER2 mediated signaling HER2–EGFR HER2–HER2 HER2–HER3 HER2–HER3 Ras PI3K P P P P P P P P P Raf AKT MAPK mTOR Foxo PLC PKC BAD GSK3 p27 HIF-1α Cell cycle progression Proliferation Differentiation Cyclin MDM2 Apoptosis Transcription Angiogenesis Rosen et al, The Oncologist. 2010;15:216-35.

6. Mechanisms of resistance toHER2 targeted therapy • Pohlmann, Clin Cancer Res. 2009;15:7479-7491 • Liu et al, Cancer Res. 2009;69:6861-78. Garrett and Artega, Cancer BiolTher. 2011;11:793-800. Gajraand Chandarlapaty, Expert Rev Anticancer Ther. 2011;11:263-75.

7. HER2 mediated signaling: Effect of trastuzumab HER2–EGFR HER2–HER2 HER2–HER3 HER2–HER3 Y Y Y Y  Ras PI3K P P P P P P P P P Raf AKT MAPK mTOR Foxo PLC PKC BAD GSK3 p27 HIF-1α Cell cycle progression Proliferation Differentiation Cyclin MDM2 Apoptosis Transcription Angiogenesis

8. HER2 mediated signaling: Effect of trastuzumab and pertuzumab HER2–EGFR HER2–HER2 HER2–HER3 HER2–HER3 Y Y Y Y Y Y     Ras PI3K P P P P P P P P P Raf AKT MAPK mTOR Foxo PLC PKC BAD GSK3 p27 HIF-1α Cell cycle progression Proliferation Differentiation Cyclin MDM2 Apoptosis Transcription Angiogenesis

9. Pertuzumab monotherapy and the effect of addition of trastuzumab in trastuzumab refractory MBC • 29 patients with progressive MBC after trastuzumab therapy • Pertuzumab 840 mg then 420 mg q3w • ORR: 3.4% (1 PR lasting 24 weeks) • CBR: 10.3% (+ 2 SD lasting ≥8 weeks) • Disease progression: 29/29 (median 3 cycles) • PFS: 7.2 weeks • 17 patients received add-on trastuzumab • ORR: 17.6% (3 PR) • CBR: 41.2% (+ 4 SD lasting ≥8 weeks) • PFS: 17.4 weeks Cortes et al, J ClinOncol. 2012;30:1594-600.

10. CLEOPATRA – Pertuzumab + trastuzumab+ docetaxel: Study design • Pertuzumab840 mg  420 mg q3w • Trastuzumab 8 mg/kg  6 mg/kg q3w • Docetaxel75 mg/m2  100 mg/m2*q3w • (n=402) Patients with HER2+ metastatic treatment-naïve MBC (n=808) Recommended minimum of 6 cycles docetaxel Antibody therapy continued to disease progression Primary endpoint: PFS R Trastuzumab 8 mg/kg  6 mg/kg q3w Docetaxel75 mg/m2  100 mg/m2*q3w (n=406) *Investigators’ discretion Baselgaet al, N Engl J Med. 2012;366:109-19.

11. CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS 100 Progression-free survival (%) 80 Pertuzumab + trastuzumab + docetaxel(median, 18.5 months) Trastuzumab + docetaxel(median, 12.4 months) 60 40 20 Hazard ratio, 0.62 (95% CI, 051–0.75) p<0.001 0 0 5 10 15 20 25 30 35 40 Months No. at risk: Pertuzumab Control 402 406 345 311 267 209 139 93 83 42 32 17 10 7 0 0 0 0 Baselga et al, N Engl J Med. 2012;366:109-19.

12. CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS (Sub-group analysis) 0.0 0.2 0.4 0.6 2.0 2.0 Pertuzamab better Placebo better Baselga et al, N Engl J Med. 2012;366:109-19.

13. CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Key secondary endpoints Baselga et al, N Engl J Med. 2012;366:109-19.

14. CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Tolerability *Reported in 25% or more in either group, or at least 5% difference between groups **Reported in 2% or more in either group Baselga et al, N Engl J Med. 2012;366:109-19.

15. Current standards of care for HER2 positive MBC: First line therapy (NCCN) • ‘The NCCN Panel recommends pertuzumab plus trastuzumab in combination with a taxane as a preferred option for first-line treatment of patients with HER2-positive metastatic breast cancer’ NCCN Category 1 (with docetaxel) NCCN Category 2A (with paclitaxel) • ‘First-line trastuzumab in combination with selected chemotherapeutics or as a single agent is another option for HER2 positive metastatic breast cancer…’ • Acceptable combinations with T include paclitaxel ± carboplatin, docetaxel, vinorelbine NCCN 2012; Breast cancer V3.2012.

16. MARIANNE – Pertuzumab + trastuzumab emtansine for MBC Trastuzumabemtansine HER2 + MBC First line (Target n=1,092) Primary endpoints: PFS and safety R Trastuzumabemtansine+ pertuzumab Trastuzumab + taxane (open label) Ellis et al, J ClinOncol. 2011;29 (suppl); abstrTPS102.

17. Summary • First line therapy with trastuzumab for metastatic / advanced HER2 positive breast cancer has had a dramatic effect on clinical outcomes • However, relapse is usual • Resistance mechanisms include HER2 heterodimers and activation of both alternate signaling cascades and changes to downstream pathways • Pertuzumab is a dimerization inhibitor which results in a more profound blockade of HER2 signaling than trastuzumab alone • Pertuzumab is now FDA approved for use in combination with trastuzumab and a taxane • Based on the CLEOPATRA study which demonstrated improved PFS and OS • Recommended in the most recent NCCN Guidelines as a first line option