Herceptin ® adjuvant therapy: “a triumphal narrative of translational research” Brian Leyland-Jones McGill University Department of Oncology Montreal, Quebec, Canada Burstein, H. NEJM 2005:353;1652

NSABP B-31 (US) (n=1960) Paclitaxel q3w x 4 or qw x 12 Paclitaxel q3w x 4 or qw x 12 + H qw HERA Trial (ex- US) (n=5090) Observation H q3w* x 12 months H q3w* x 24 months Any CT ± RT Intergroup N9831 (US) (n=3046) Paclitaxel qw x 12 Paclitaxel qw x 12 + H qw BCIRG 006 (global) (n=3222) Carboplatin + docetaxel q3w x 6 + H qw Herceptin ® adjuvant trials (>13,000 patients) H qw AC x 4 Docetaxel q3w x 4 Docetaxel q3w x 4 + H qw *q3w at 6mg/kg H = Herceptin ® H q3w* AC x 4

Herceptin ® in the adjuvant setting: how four trials complement each other Covers all currently accepted EU and US treatment strategies Combinations of a number of regimens and both taxanes Compares AC followed by H with novel treatment concepts Investigates optimal treatment duration Investigates sequential versus combination therapy

Joint analysis: disease-free survival Years from randomisation Romond et al % 85% 67% 75% HR=0.48; p< year median follow-up Patients (%) AC T AC TH nEvents ACTH ACTP

Joint analysis: time to first distant recurrence N Events AC  TH AC  T HR=0.47, 2P=8x AC  TH AC  T Years from randomization 90% 90% 81% 74% % Romond et al 2005

Joint analysis: hazard of distant recurrence Rate per 1000 Women /Yr Years from randomization AC  TH AC  T Romond et al 2005

Joint analysis: overall survival Romond et al 2005 AC  TH 94% 91% 87% 92% AC  T NDeaths AC  T AC  TH HR=0.67, 2P=0.015 % Years from randomisation

NSABP B-31: cumulative incidence of cardiac events in the evaluable cohort Yrs Post Day 1 Cyc 5 Cum Inc Arm 1 (%) Cum Inc Arm2 (%) Number At Risk Arm 2: AC→PTX + H N=850, 31 CHFs, No Cardiac Deaths Arm 1: AC→PTX N=814, 4 CHFs, 1 Cardiac Death HR= % 0.8%

NSABP-B31: post – AC LVEF and age are independent predictors of Herceptin ® - associated CHF Age and LVEF were statistically significant predictors of CHF. Careful cardiac monitoring must be done. LVEFAge < 50Age ≥ – 543/48 (6.3%)9/47 (19.1%) 55 – 645/229 (2.2%)10/194 (5.2%) 65+1/160 (0.6%)2/159 (1.3%) P(Age) = 0.04 P(LVEF) < 0.001

Joint analysis: conclusions Herceptin ® given concurrently with paclitaxel following AC –significantly reduces the risk of DFS events by 52% –significantly reduces the risk of distant recurrence by 53% –significantly improves overall survival, with a 33% reduced risk of mortality The number of cardiac events was low –<4% incidence, Herceptin ® versus non-Herceptin ® in both trials

HERA: key inclusion criteria Centrally confirmed HER-2 overexpression or amplification Centrally confirmed HER-2 overexpression or amplification Node-positive or (sentinel) node-negative with  T1c Node-positive or (sentinel) node-negative with  T1c Completed  4 cycles of approved (neo)adjuvant chemotherapy regimen Completed  4 cycles of approved (neo)adjuvant chemotherapy regimen Baseline LVEF  55% (Echo or MUGA) Baseline LVEF  55% (Echo or MUGA) Known hormone receptor status Known hormone receptor status Piccart-Gebhart et al 2005

HERA: patient and tumour characteristics (%) Observation (n=1,693) 1-year Herceptin (n=1,694) Age (years) <35 35–49 50–59 ≥ Adjuvant CT (%) No AC, no T AC AC + T Nodal status Any (neoadjuvant) Node-negative 1–3 + ≥ Hormone Receptor (%) HR-negative HR-positive AC=anthracycline; T=taxane Piccart-Gebhart et al 2005

HERA: endpoints and analysis plan Target accrual was 4,482 patients, 5,090 enrolled –HR=0.77 (80% power two sided α=0.025) for nil versus 1 year, nil versus 2 years Primary endpoint DFS Secondary endpoints RFS, DDFS, OS, 2 years versus 1-year Herceptin ® One interim efficacy analysis (n=475 events), 1 year median follow up One primary core analysis (n=951 events) Safety – tolerability, incidence of cardiac dysfunction Three safety interim analyses of cardiac endpoints after n=300, 600, 900 patients. Stopping rule ≥4% increase in cardiac events Piccart-Gebhart et al 2005

Patients (%) Months from randomisation year Herceptin ® Observation 0 No. at risk EventsHR95% CIp value , 0.67< year DFS HERA: disease-free survival Median follow-up: 1 year; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval Piccart-Gebhart et al 2005

HERA: efficacy endpoints HR 95% CI p value 2-year outcome, % , 0.63 < vs , vs 96.0 Distant recurrence Overall mortality No. events Observation 1 year Herceptin ® Piccart-Gebhart et al , 0.67 < vs 85.8 DFS

HERA: cardiac safety Cardiac events have been manageable and reversible Decrease by >10 EF points and LVEF <50% a Symptomatic CHF, including severe CHF Severe CHF Cardiac death Observation year Herceptin % patients a Many were single observations not confirmed at subsequent time points p value < Piccart-Gebhart et al 2005CHF = congestive heart failure

HERA: conclusions At 1-year follow up, Herceptin ® given after chemotherapy –significantly reduces the risk of DFS events by 46% –significantly reduces the risk of distant recurrence by 51% –is associated with a low incidence of severe CHF (0.5%) Piccart-Gebhart et al 2005

BCIRG 006: disease-free survival % Disease Free Year from randomization 77% 86% 80% 73% 84% 80%86% 93% 91% Patients Events AC->T AC->TH TCH HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P< HR (TCH vs AC->T) = 0.61 [0.47;0.79] P= Slamon et al SABCS 2005

BCIRG 006: mean LVEF - all observations AC->T (N=1012) AC->TH (N=1040) TCH (N=1029) AC->T TCH AC->TH 189 pts 290 pts 205 pts Slamon et al SABCS 2005

BCIRG 006: HER2 and TOPO II HER2 core region 17q 1217q q % n=2120 4% Topo II Non co-amplified Slamon et al 2005 Normal AmplifiedDeletion TOPO II region 35% Co-amplified 2120 of 3222 patients analysed

BCIRG 006: disease-free survival non-amplified Topo II by arm % Disease Free Months Patients EventsTreatment 45892AC->T 47245AC->TH 44654TCH Logrank P= <0.001 TCH AC->TH AC->T Press et al SABCS 2005

BCIRG 006: disease-free survival amplified Topo II by arm % Disease Free Months Patients EventsTreatment AC->T 26513AC->TH 25221TCH Logrank P= 0.24 TCH AC->TH AC->T Press et al SABCS 2005

BCIRG 006: conclusions Herceptin ® provided a significant DFS benefit in both regimens –in combination with docetaxel after AC (HR=0.49) –in combination with docetaxel and carboplatin without an anthracycline (HR=0.61) It is too early to tell whether a non-anthracycline- containing Herceptin ® regimen has efficacy comparable to anthracycline-based regimens Cardiac safety appears to be higher with non- anthracycline-based therapy Slamon et al 2005

FinHER: trial design 502 pts. Docetaxel 507 pts. Vinorelbine 1010 pts. EBC pN+ or pN0 (tumour >2 cm, PR-) R 115 pts. HER pts. HER pts. HER pts. HER2 - R R 57 pts. + Herceptin ® 58 pts. 58 pts. + Herceptin ® 58 pts. 392 pts. HER pts. HER patients were recruited and after 2 randomisations allocated to 6 treatment arms (1 patient excluded from efficacy analyses)

FinHER: recurrence-free survival in HER2-positive subgroup Recurrence-free survival (%) Time (years) 89.3% 77.6% Herceptin Events=12 No Herceptin Events=27

FinHER: cardiac safety in HER2-positive subgroup Cardiac failure LVEF decrease >15% from baseline Joensuu et al 2005 Herceptin ® 0 (0%) 4 (3%) No Herceptin ® 1 (1%) 7 (6%)

FinHER: conclusions Compared with vinorelbine, adjuvant docetaxel –improves DFS –results in more adverse events Brief use of adjuvant Herceptin ® administered concomitantly with docetaxel or vinorelbine was well-tolerated and effective for HER2-positive breast cancer and warrants further study

Summary: Herceptin ® in EBC 012 HERA1 year Combined analysis2 years Median follow-up Favours Herceptin ® Favours no Herceptin ® HR BCIRG 006 DCarboH2 years BCIRG 006 AC DH FinHER VH / DH CEF3 years Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2005; Joensuu et al 2005

Summary: Herceptin ® in EBC Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2005; Tan-Chiu et al 2005 Trial HERA NSABP B-31 NCCTG N9831 BCIRG 006 FinHER Arm H 1 year Nil AC  P AC  PH AC  D AC  DH DCarboH H No H Baseline LVEF, % >55 >50 CHF, n (%) 0 9 (0.5) 4 (0.8) a 31 (4.1) a 0 a 20 (2.9) a 3 (0.3) 17 (1.6) 4 (0.4) 0 (0) 1 (1) a Cumulative percent Cardiac death, n

Herceptin ® adjuvant therapy: conclusions and future prospects Benefits seen with Herceptin ® are independent of chemotherapy and patient characteristics Radiotherapy can be given before or concurrent with Herceptin ® Data are currently not available on benefit of Herceptin ® –as monotherapy or combined with endocrine agents in patients not indicated for chemotherapy –in patients with primary tumours <1cm Five studies have demonstrated a substantial DFS advantage with adjuvant Herceptin ® in women with HER2-positive EBC Optimal duration of treatment is uncertain

Herceptin ® in the news Herceptin is the cure for early stages of breast cancer? MedIndia, India, Jan 06 …thanks to Herceptin, breast cancer sufferers could now look forward to a long life The Observer, UK, Jan 06 … superdrug that has changed the face of modern medicine The Observer, UK, Jan 06 Cancer wonder drug campaigner gets all clear Mirror.co.uk, Jan 06 “Herceptin is the best chance for women like me” Barbara Clarke, Telegraph.co.uk, Jan 06