Herceptin ® : leading the way in metastatic breast cancer care Steffen Kahlert

Herceptin ® in metastatic breast cancer HER2-positive breast cancer is an aggressive cancer and is associated with a poor prognosis Herceptin ® is currently licensed for the treatment of HER2-positive metastatic breast cancer (MBC) –first-line in combination with docetaxel in patients with no prior chemotherapy for MBC –first-line in combination with paclitaxel in patients who have received prior anthracyclines or for whom an anthracyline is not suitable –as monotherapy in patients who have received prior treatment for MBC

Herceptin ® plus docetaxel (M77001)

Herceptin ® plus docetaxel (M77001): trial design HER2-positive MBC (IHC 3+ and/or FISH+) n=188 Docetaxel* 100mg/m 2 q3w x 6 Docetaxel 100mg/m 2 q3w x 6 Herceptin ® 4mg/kg loading,  2mg/kg weekly until PD + *Patients progressing on docetaxel alone could crossover to receive Herceptin ® Two patients did not receive study medication n=92 n=94 Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): inclusion criteria MBC –measurable disease HER2-positive –IHC 3+ and/or FISH+ –IHC 2+ initially allowed (July 1999–August 2000) ECOG  2 Life expectancy  12 weeks LVEF >50% Adequate bone marrow, hepatic and renal function Prior chemotherapy –none for MBC –no prior taxanes or anti-HER therapy Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): patient demographics *Eight patients IHC 2+/FISH–; one patient IHC 0/1+/FISH unknown (docetaxel alone) Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): patient demographics Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): OS at 24 months Intent-to-treat population, 24-month cut-off Documented crossover = 57% Estimated probability Months 8.5 months Herceptin ® + docetaxel Docetaxel alone Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): OS at 24 months Intent-to-treat population, 24-month cut-off Estimated probability Months Herceptin ® + docetaxel (n=92) Docetaxel alone/crossover (n=45) Docetaxel alone (n=49) Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): efficacy 24 month follow up Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): non-haematological toxicity (grade 3/4) Adverse events occurring in ≥5% and congestive heart failure (CHF) Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): haematological toxicity (grade 3/4) Marty M, et al. J Clin Oncol 2005;23:4265–74

Herceptin ® plus docetaxel (M77001): conclusions Adding Herceptin ® to docetaxel improves all clinical outcomes parameters –ORR (from 34 to 61%) –TTP (from 6.1 to 11.7 months) –OS (from 22.7 to 31.2 months) Herceptin ® adds little to the toxicity profile of docetaxel Herceptin ® plus docetaxel should be used upfront for greatest clinical benefit in patients with HER2-positive MBC These 24-month data provide evidence of a long-term survival benefit following the addition of Herceptin ® to docetaxel

Herceptin ® plus paclitaxel (H0648g)

Herceptin ® plus paclitaxel (H0648g): design and enrolment No prior anthracyclinesPrior anthracyclines Paclitaxel (n=96) Herceptin ® + paclitaxel (n=92) AC (n=138) Herceptin ® + AC (n=143) MBC HER2 IHC 2+/3+ (CTA) No prior CT for MBC Measurable disease KPS  60% Patients (n=469) Slamon DJ, et al. N Engl J Med 2001;334:783–92

Herceptin ® plus paclitaxel (H0648g): treatment plan Chemotherapy q3w x 6 –AC = doxorubicin (60mg/m 2 ) or epirubicin (75mg/m 2 ) + cyclophosphamide (600mg/m 2 ) –Paclitaxel (175mg/m 2 ) Herceptin ® –4mg/kg loading, 2mg/kg qw until PD Slamon DJ, et al. N Engl J Med 2001;334:783–92

Herceptin ® plus paclitaxel (H0648g): demographics Slamon DJ, et al. N Engl J Med 2001;334:783–92

Herceptin ® plus paclitaxel (H0648g): prior therapy Slamon DJ, et al. N Engl J Med 2001;334:783–92

*p<0.05 Herceptin ® plus paclitaxel (H0648g): efficacy (all patients) Slamon DJ, et al. N Engl J Med 2001;334:783–92

Herceptin ® + chemotherapy Chemotherapy Time (months) Probability p= Herceptin ® plus paclitaxel (H0648g): TTP Slamon DJ, et al. N Engl J Med 2001;334:783–92

Herceptin ® plus paclitaxel (H0648g): OS (all patients) Slamon DJ, et al. N Engl J Med 2001;334:783–92 Crossover 72%

Herceptin ® plus paclitaxel (H0648g): summary of SAEs Slamon DJ, et al. N Engl J Med 2001;344:783–92

Herceptin ® plus paclitaxel (H0648g): summary of cardiac safety Suter T, et al. Breast 2004;13:173–83

*p< :n=349 All:n=469 Slamon DJ, et al. N Engl J Med 2001;344:783–92 Baselga J. Oncology 2001;61 (Suppl 2):15–21 Herceptin ® plus paclitaxel (H0648g): efficacy (IHC 3+ versus all)

Herceptin ® plus paclitaxel (H0648g): conclusions Adding Herceptin ® to paclitaxel improves all clinical outcome parameters –ORR (from 17 to 49%*) –TTP (from 3 to 7 months*) –OS (from 18 to 25 months*) Herceptin ® adds little to the toxicity profile of paclitaxel Herceptin plus paclitaxel should be considered as first-line therapy in HER2-positive MBC *IHC 3+ patients

Other Herceptin ® trials in MBC

Phase II Herceptin ® plus vinorelbine: efficacy Vinorelbine (n=33) Vinorelbine + Herceptin (n=35) Overall response (%) 27.3 (95% CI 12.1, 42.5) 51.4 (95% CI 32.9, 68) Complete response (%) Partial response (%) Stable disease (%) Progressive disease Median TTP (months) 6.0 (95% CI: 4, 8)9.0 (95% CI: 7, 11) Median OS (months) 22 (95% CI: 12, 32)27 (95% CI: 19, 35) Papaldo P, et al. Ann Oncol 2006

Phase II Herceptin ® plus vinorelbine: safety Toxicity (Grade 3/4) (%)Vinorelbine (n=33)Vinorelbine + Herceptin (n=35) Leucopenia3- Neutropenia5149 Febrile neutropenia6- Anaemia63 Thrombocytopenia3- Nausea/vomiting-- Mucositis3- Peripheral neuropathy-- Liver-- Diarrhoea3- Stipsis-- Cardiac toxicity-3 Papaldo P, et al. Ann Oncol 2006

Herceptin ® q3w: rationale Ghahramani P, et al. The Breast 2003;12(Suppl. 1):S40 (Abstract P89) 1, Serum concentration (µg/mL) Time (weeks) 3-weekly regimen Weekly regimen

Herceptin q3w plus paclitaxel(BO15935) Leyland-Jones B, et al. J Clin Oncol 2003;21:3965–71

Herceptin ® monotherapy trials in MBC H0650gWO16229H0649g Line of therapy First Second/third Regimen 4mg/kg LD, 2mg/kg qw or 8mg/kg LD, 4mg/kg qw 8mg/kg LD, 6mg/kg q3w 4mg/kg LD, 2mg/kg qw No of patients 11483*222 ORR (%) Overall IHC 3+ 35NR18 IHC 2+ 0NA6 FISH positive 34NR19 FISH negative 7NR0 TTP (months) 3.5, 3.8 † DR (months) NR OS (months 24.4NR13 LD=loading dose; NR=not recorded; NA=not applicable; qw=weekly; q3w= every 3 weeks *Results from per protocol subset † TTP given for standard and higher Herceptin ® dose regimens, respectively

Summary: Herceptin ® combinations in MBC 1 Slamon DJ, et al. N Engl J Med 2001;344:783–92 2 Leyland-Jones B, et al. J Clin Oncol 2003;21:3965–71 3 Marty M, et al. J Clin Oncol 2005;23: Papaldo P, et al. Ann Oncol 2006 H0648g 1 BO M H + P P aloneH + PH + D D aloneH + V 4 V alone 4 ORR (%) TTP (months) OS (months) NR NR=not recorded H=Herceptin ® ; P=paclitaxel; D=docetaxel; V=vinorelbine

Herceptin ® in MBC: conclusions In metastatic breast cancer patients –Herceptin ® in combination with chemotherapy leads to an improvement in survival compared to chemotherapy alone adverse events associated with chemotherapy are not exacerbated by addition of Herceptin ® –Herceptin ® monotherapy has also been shown to be effective Cardiac events are reversible and manageable –the rate of asymptomatic cardiac events in clinical trials has fallen to 2% based on selection criteria and cardiac monitoring