Assistant Professor of Medicine Dana-Farber Cancer Institute First line therapeutic options for HER2 positive metastatic breast cancer Harold Burstein, MD Assistant Professor of Medicine Dana-Farber Cancer Institute Boston, MA

Trastuzumab in advanced/metastatic breast cancer H0468g1 M770012 TRAVIOTA3 Robert et al4 Patients enrolled 469 186 81 (early termination) 196 Treatment arms Doxorubicin or Epirubicin + cyclophosphamide or Paclitaxel vs or Paclitaxel + H Docetaxel vs Docetaxel + H Vinorelbine + H vs Taxane + H H + paclitaxel  H vs H + paclitaxel + carboplatin  H ORR (%) 32 vs 50 (p<0.001) 34 vs 61 (p=0.0002) 51 vs 40 (p=NS) 36 vs 52 (p=0.04) Median OS (mo) 20.3 vs 25.1 (HR 0.80 [0.64–1.00]; p=0.046) 22.7 vs 31.2 (p=0.0325) N/R 32.2 vs 35.7 Median TTP (mo) 4.6 vs 7.4 (HR 0.51 [0.41–0.63]; p<0.001) 6.1 vs 11.71 (p=0.0001) 8.5 vs 6.5 7.1 vs 10.7 (p=0.03) [PFS] 1. Slamon et al, N Engl J Med. 2001;344:783-92. 2. Marty et al, J Clin Oncol. 2005;23:4265-74. 3. Burstein et al, Cancer. 2007;110:965-72. 4. Robert et al, J Clin Oncol. 2006;24:2786-92.

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

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

HER2 mediated signaling HER2–EGFR HER2–HER2 HER2–HER3 HER2–HER3 Ras PI3K 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.

Mechanisms of resistance to HER2 targeted therapy Comments Barriers to antibody binding Increased expression of p95-HER2 Constitutively active tyrosine kinase with no extracellular domain Epitope masking MUC4 overexpression CD44/hyaluron complexes activate PI3K and RAS Upregulation of downstream signaling PTEN loss Constitutive activation of PI3k/Akt PI3K mutations PI3K pathway mutations allow continued signaling Increased Akt kinase activity Crosstalk Increased IGF-IR signaling Results in PI3K activation Signaling from HER2/HER3 heterodimers Upregulation of HER3 EGFR upregulation Allows continued signaling of PI3k pathway Increased c-Met expression Results in sustained Akt activation Upregulation of ER signaling May be particularly important for lapatinib resistance Increased AXL signaling Activates an alternative survival pathway Failure of ADCC Fc receptor polymorphisms Pohlmann, Clin Cancer Res. 2009;15:7479-7491 Liu et al, Cancer Res. 2009;69:6861-78. Garrett and Artega, Cancer Biol Ther. 2011;11:793-800. Gajra and Chandarlapaty, Expert Rev Anticancer Ther. 2011;11:263-75.

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

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 Raf AKT MAPK mTOR Foxo PLC PKC BAD GSK3 Cell cycle progression Proliferation Differentiation p27 HIF-1α Cyclin MDM2 Apoptosis Transcription Angiogenesis

29 patients with progressive MBC after trastuzumab therapy 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 Clin Oncol. 2012;30:1594-600.

CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Study design Pertuzumab 840 mg  420 mg q3w Trastuzumab 8 mg/kg  6 mg/kg q3w Docetaxel 75 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 R Primary endpoint: PFS Trastuzumab 8 mg/kg  6 mg/kg q3w Docetaxel 75 mg/m2  100 mg/m2* q3w (n=406) *Investigators’ discretion Baselga et al, N Engl J Med. 2012;366:109-19.

CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS Progression-free survival (%) 100 80 60 40 20 Pertuzumab + trastuzumab + docetaxel (median, 18.5 months) Trastuzumab + docetaxel (median, 12.4 months) Hazard ratio, 0.62 (95% CI, 051–0.75) p<0.001 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 Baselga et al, N Engl J Med. 2012;366:109-19.

CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: PFS (Sub-group analysis) No of patients Hazard ratio (95% CI) All patients 808 0.63 (0.52-0.76) Previous record or chemotherapy No 432 0.63 (0.49-0.82) Yes 376 0.61 (0.46-0.81) Geographic region Europe 306 0.72 (0.53-0.97) North America 135 0.51 (0.31-0.84) South America 114 0.46 (0.27-0.78) Asia 253 0.68 (0.48-0.95) Age group <65 yrs 681 0.65 (0.53-0.80) >65 yrs 127 0.52 (0.31-0.86) <75 yrs 789 0.64 (0.53-0.78) >75 yrs 19 0.55 (0.12-2.54) Race ethnic group White 8 0.62 (0.49-0.80) Black 30 0.64 (0.23-1.79) Asian 261 0.68 (0.49-0.95) Other 37 0.39 (0.13-1.18) Disease type Visceral disease 630 0.55 (0.45-0.68) Nonvisceral disease 178 0.96 (0.61-1.52) Hormone receptor status GR-positive, PgR-postive, or both 388 0.72 (0.55-0.95) GR-negative and PgR-negative 408 0.55 (0.42-0.72) GR and PgR status unknown 12 – HER2 status IHC 3+ 721 0.60 (0.49-0.74) FISH-positive 767 0.0 0.2 0.4 0.6 2.0 2.0 Baselga et al, N Engl J Med. 2012;366:109-19. Pertuzamab better Placebo better

Pertuzumab + trastuzumab + docetaxel (n=402) Trastuzumab + docetaxel CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Key secondary endpoints Pertuzumab + trastuzumab + docetaxel (n=402) Trastuzumab + docetaxel (n=406) Deaths 69 (17.2%) 96 (23.6%) Hazard ratio 0.64 (0.47 – 0.88); p=0.005 Objective response rate 80.2% 69.32% Difference 10.8% (4.2–17.5); p=0.001 Cycles (median) 18 15 Duration of treatment (median) 18.1 months 11.8 months Baselga et al, N Engl J Med. 2012;366:109-19.

CLEOPATRA – Pertuzumab + trastuzumab + docetaxel: Tolerability Pertuzumab + trastuzumab + docetaxel (n=407) Trastuzumab + docetaxel (n=397) Any grade* (%) Grade 3 or higher** (%) Diarrhea 66.8 7.9 46.3 5.0 Alopecia 60.9 60.5 Neutropenia 52.8 48.9 49.6 45.8 Febrile neutropenia 13.8 7.6 Nausea 42.3 41.6 Fatigue 37.6 2.2 36.8 3.3 Rash 33.7 24.2 Decreased appetite 29.2 26.4 Mucosal inflammation 27.8 19.9 Asthenia 26.0 2.5 30.2 1.5 Peripheral edema 23.1 30.0 Constipation 15.0 24.9 Dry skin 10.6 4.3 Leukopenia 12.3 14.6 Peripheral neuropathy 2.7 1.8 Anemia 3.5 Granulocytopenia 2.3 Left ventricular systolic dysfunction 1.2 2.8 Dyspnea 1.0 2.0 *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.

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.

MARIANNE – Pertuzumab + trastuzumab emtansine for MBC HER2 + MBC First line (Target n=1,092) R Primary endpoints: PFS and safety Trastuzumab emtansine + pertuzumab Trastuzumab + taxane (open label) Ellis et al, J Clin Oncol. 2011;29 (suppl); abstr TPS102.

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