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K Gelmon, 1 P Fumoleau, S Verma, A Wardley, PF Conte, D Miles, L Gianni, VA McNally, GA Ross, J Baselga 1 British Colu

Results of a Phase II trial of trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy. K Gelmon, 1 P Fumoleau, S Verma, A Wardley, PF Conte, D Miles, L Gianni, VA McNally, GA Ross, J Baselga

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K Gelmon, 1 P Fumoleau, S Verma, A Wardley, PF Conte, D Miles, L Gianni, VA McNally, GA Ross, J Baselga 1 British Colu

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  1. Results of a Phase II trial of trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy K Gelmon,1 P Fumoleau, S Verma, A Wardley, PF Conte, D Miles, L Gianni, VA McNally,GA Ross, J Baselga 1British Columbia Cancer Agency, Vancouver,Canada

  2. Potent inhibitor of HER2-mediatedsignalling pathways Activates antibody-dependent cellular cytotoxicity Inhibits shedding and, thus, formation of p95 Trastuzumab and pertuzumab bind to distinct epitopes on HER2 extracellular domain Trastuzumab Pertuzumab • Prevents receptor dimerisation • Potent inhibitor of HER-mediatedsignalling pathways Hubbard 2005

  3. Simon-type two-stage study design Stage 2 (n=66) YES Main patient eligibility criteria • Up to 3 lines of prior cytotoxic therapies and / or trastuzumab (including adjuvant) • PD during trastuzumab as most recent treatment for metastatic disease • Study treatment initiated within 9 weeks of the last dose of trastuzumab • Baseline LVEF >55% and no decrease of LVEF to <50% during prior trastuzumab >2 R or 1 R + 12 SDor 13 SD Safety evaluationfor IDSMB Stage 1 (n=24)Trastuzumab +pertuzumaba Stop trial NO aTrastuzumab: 4 mg/kg loading dose  2 mg/kg qw or 8 mg/kg loading dose  6 mg/kg q3wpertuzumab: 840 mg loading dose  420 mg q3w IDSMB, International Data and Safety Monitoring Board; LVEF, left ventricular ejection fraction; PD, progressive disease Baselga et al ASCO 2007

  4. Patient characteristics Characteristic No. patients No. patients Age (years), median (range) ECOG performance status 0 / 1 / 2, %a Organ site (target and non-target lesions), n (%) Visceral Lung Liver Adrenal Pleura Lymph Bone Soft tissue Other ER status, % +ve / -ve No. metastatic sites, median (range) 66 54 (25-85) 80 / 19 / 2 52 (72.8) 25 (37.9) 35 (53.0) 1 (1.5) 2 (3.0) 26 (39.4) 19 (28.8) 1 (1.5) 49 (74.2) 50 / 50 4.0 (1-14) an=59; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor

  5. Adverse events were generally grade 1 or 2 Adverse event (>10% patients) Diarrhoea Fatigue Nausea Rash Headache Arthralgia Cough Anorexia Asthenia Dizziness Muscle spasms Myalgia Paraesthesia Pruritis Vomiting Incidenceall grades (%)(n=66) 42 (64) 22 (33) 18 (27) 17 (26) 13 (20) 11 (17) 9 (14) 9 (14) 8 (12) 8 (12) 8 (12) 8 (12) 7 (11) 7 (11) 7 (11) Incidencegrade 3 / 4 (%) 2 (3) 0 (0) 0 (0) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) 0 (0)

  6. Only 4 of the 66 patients had treatment-related adverse events grade >3 Adverse eventa Diarrhoea (n=2; 3%) Central line infection (n=1; 1.5%) Grade 3 3 Outcome Resolved ResolvedReported as SAE Treatmentcontinued Yes Yes a1 patient had a grade 3 rash following injection of contrast prior to receiving pertuzumabSAE, serious adverse event

  7. Summary of LVEF data over time: local ECHO reading Baseline mean: 61% (SD 5.14); median 60.0% (range 51-75) <50% &>10% 1 (2%) Aftercycle 1 2 4 6 8 12 16 20 24 n 50 52 42 36 30 20 10 6 2 Increase, n/c,or change <10% 49 (98%) 51 (98%) 41 (98%) 35 (97%) 29 (96%) 19 (95%) 9 (90%) 5 (83%) 2 (100%) <50% &>15% LVEF >50% & >10% 1 (2%)a 1 (2%)a 1 (3%)a 1 (3%)a 1 (5%)a 1 (10%)a 1 (17%)a aSame patient

  8. 20 16 12 8 4 0 -4 -8 -12 -16 Summary of the mean change in LVEF from baseline over time: local ECHO reading Baseline mean: 61% (SD 5.14); median 60.0% (range 51-75) Meanabsolutechange inLVEF (%) AfterCycle 1(n=50) AfterCycle 2(n=52) AfterCycle 4(n=42) AfterCycle 6(n=36) AfterCycle 8(n=30) AfterCycle 12(n=20) AfterCycle 16(n=10) AfterCycle 20(n=6) AfterCycle 24(n=2)

  9. Patients with falling LVEF (1) • Only 3 patients had a falling LVEF (<50% and >10%), 1 solely by local reading (not meeting protocol definition of AE of special significance), 2 solely by central reading (both LVEFs recovered and patients continued treatment) Cycle Patient 1c Screening 4 6 8 Patient 2 Screening 1 2 4 LVEFLocal 60 60 60 60 56 60 55 LVEFCentral 63 49 66 64 72 53 46 70 Changefrom baselinea 0% 0% -4% 0% -5% Changefrom baselineb -14% 3% 1% -18% -25% -1% aLocal reading (patients managed according to local reading); bCentral readingcCycle 1 and 2 change from baseline -3% and 5%, by central reading

  10. Patients with falling LVEF (2) Cycle Patient 3 Screening 1 2 Final visit LVEFLocal 56 50 42 42 LVEFCentral 63 56 56 54 Changefrom baselinea -6% -14% -14% Changefrom baselineb -6% -7% -8% • This patient withdrew from study due to progressive disease at cycle 2 aLocal reading (patients managed according to local reading); bCentral reading

  11. Encouraging efficacy results n (%)(n=66) Response 5 (7.6) 11 (16.7) 17 (25.8) 16 (24.2) 33 (50.0) Complete responsea Partial responsea Stable disease for >8 cycles (approx. 6 months) Objective response rate Clinical benefit rateb aMedian duration of response was 25.1 weeks (12.4-66.6)bAt data cut-off 21 (31.8%) patients have not yet progressed

  12. Characteristics of patients with a complete response Age (years) ER / PR status Performance status Previous chemotherapy regimens Duration of previous trastuzumab (months) Site of target lesions Sum of lesions at BL (mm) Site of non-target lesions Response observed at cycle 34 +/+ 0 3 28 Lymph 46 - 10 55 +/+ 0 1 19 Lymph 28 Lymph 6 76 -/- 1 3 8 Lymph 27 Lymph 12 44 -/- 0 1 54 Lung 11 - 6 74 +/- 0 1? 76 Lymph 22 - 8 • At data cut-off, no patients with complete response had progressed BL, baseline; PR, progesterone receptor

  13. Progression-free survival Patients at risk (%) 100 90 Median PFS:24 weeks 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 Week No. at risk(T and P) 66 66 56 54 48 46 38 37 28 27 25 23 13 9 9 9 6 6 6 5 5 4 4 4 3 0 Patients at data cut-off who had not yet progressed = 21 (31.8%) PFS, progression-free survival; P, pertuzumab; T, trastuzumab

  14. Conclusions • The combination of trastuzumab and pertuzumab is active in patients with HER2-positive breast cancer with documented progression on trastuzumab as last therapy • Adverse events were generally grade 1 or 2 • No significant cardiac events have been observed in 66 patients in this study • Efficacy is highly promising • 24% of patients responded (16% PR and 8% CR), and 50% of patients experienced clinical benefit • median PFS is approximately 6 months at present • a single-agent pertuzumab extension study is ongoing • A Phase III study CLEOPATRA is underway in HER2-positive metastatic breast cancer CR, complete response; PR, partial response

  15. CLEOPATRA: Phase III study of Herceptin + pertuzumab in HER2+ MBC Herceptin + docetaxel + placebo 1:1 randomisation HER2+ MBC n=800 Herceptin + docetaxel + pertuzumab An international Phase III randomised, double-blind, placebo-controlled study (approximately 250 sites worldwide) • End points: • Progression-free survival • Overall survival • Quality of life • Biomarker analysis

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