Biologika bei onkologischen Erkrankungen älterer Menschen Österr. Gesellschaft für Geriatrie und Gerontologie BIOLOGIKA IN DER GERIATRIE 17. Jänner 2012 - Wien Biologika bei onkologischen Erkrankungen älterer Menschen Prof. Günther Steger Medizinische Universität Wien

Pivotal phase III trial – Trastuzumab in combination with chemotherapy Design and enrolment Metastatic breast cancer HER2 overexpression No prior CT for MBC Measurable disease KPS ³60% Eligible patients (n=469) No prior anthracyclines Prior anthracyclines Trastuzumab + AC (n=143) AC (n=138) Trastuzumab + Paclitaxel (n=92) Paclitaxel (n=96) AC = doxorubicin/epirubicin + cyclophosphamide

Overall survival – HER2 3+ patients 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Trastuzumab + CT CT alone p<0.05 Probability of survival 20 29 0 5 10 15 20 25 30 35 40 45 50 Time (months)

Docetaxel +/- Trastuzumab Overall Survival 1.0 0.8 0.6 0.4 0.2 Trastuzumab + docetaxel Docetaxel alone Estimated probability Median overall survival increased from 22.1 months in the docetaxel-alone arm to 30.5 months (p=0.0062) in the combination arm. This is a statistically significant difference and means that patients in the Herceptin® plus docetaxel arm survived on average 8.4 months longer than those in the docetaxel-alone arm. This difference is seen despite the fact that approximately 48% of patients in the docetaxel arm crossed over to receive Herceptin® at disease progression, which reduces the difference in survival seen between the two arms. p=0.0062 22.1 30.5 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 8.4 months Intent-to-treat population, 12-month cut-off Documented crossover = 48%

Trastuzumab Treatment in Multiple Lines

Adjuvant Treatment: Risks and Benefits 100 No benefit Death despite therapy Optimization of therapies 80 Benefit 60 No benefit Survival without therapie % of surviving patients Characterization of predicitive factors 40 Adjuvant Therapy Control 20 0 5 10 Jahre

Adjuvant Treatment: Risks and Benefits 100 Optimization of therapies No benefit Death despite therapy 80 Benefit 60 % of surviving patients 40 Characterization of predicitive factors No benefit Survival without therapie Adjuvant Therapy Control 20 0 5 10 Jahre

Adjuvant Trastuzumab Trials HERA NSABP B-31 NCCTG N9831 BCIRG 006 FinHer No. patients 5090 2030 3505 3222 232a Reference Piccart-Gebhart et al, 20051 Smith et al, 20072 Romond et al, 20053 Slamon et al, 20064 Joensuu et al, 20065 aHER2-positive subgroup 1. Piccart-Gabhart M et al. N Engl J Med 2005;353(16):1659–72; 2. Smith I et al. Lancet 2007;369:29–36; 3. Romond EH et al. N Engl J Med 2005;353(16):1673–84; 4. Slamon D et al. SABCS 2006;Abstract 52; 5. Joensuu H et al. N Engl J Med. 2006;354:809-20

Adjuvant Trastuzumab Trials: Summary of DFS data to date Median follow-up HERA1 (n=5090) 2 years Combined analysis2 (n=3351) 2 years BCIRG 006 AC–DH3 (n=1074) 3 years BCIRG 006 DCarboH3 (n=1075) 3 years FinHer VH/DHa4 (n=232) 3 years 1 2 Favours Herceptin Favours no Herceptin HR aRFS 1. Smith I et al. Lancet 2007;369:29–36; 2. Romond EH et al. N Engl J Med 2005;353(16):1673–84; 3. Slamon D et al. SABCS 2006;Abstract 52; 4. Joensuu H et al. N Engl J Med. 2006;354:809-20

Adjuvant trastuzumab trials: summary of OS data to date Median follow-up HERA Herceptin 1 year arm1 2 years Combined analysis2 2 years BCIRG 006 AC–DH3 3 years BCIRG 006 DCarboH3 3 years FinHer VH/DH4 p=NS 3 years 1 2 Favours Herceptin Favours no Herceptin HR NS, not significant 1. Smith I et al. Lancet 2007;369:29–36; 2. Romond EH et al. N Engl J Med 2005;353(16):1673–84; 3. Slamon D et al. SABCS 2006;Abstract 52; 4. Joensuu H et al. N Engl J Med. 2006;354:809-20

SAFETY ANALYSIS POPULATION Cardiotoxicity Observation N=1736 1 year trastuzumab N=1677 Decrease by  10 EF points and LVEF < 50% 2.2 % 7.1 % 0 % (95% CI: 0.00-0.21) 0.5% (95% CI: 0.25-1.02) Same LVEF criteria and symptomatic CHF NYHA class III/IV, confirmed by cardiologist Cardiac death 0.1% 0%

DFS BENEFIT IN SUBGROUPS HR: 1 year trastuzumab vs observation Hazard Hazard ratio ratio n n All All 3387 3387 0.54 0.54 Nodal Nodal status status Any, neo Any, neo - - adjuvant chemotherapy adjuvant chemotherapy 358 358 0.53 0.53 0 pos, no neo 0 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 1100 1100 0.52 0.52 1 1 - - 3 pos, no neo 3 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 972 972 0.51 0.51   4 pos, no neo 4 pos, no neo - - adjuvant chemotherapy adjuvant chemotherapy 953 953 0.53 0.53 Adjuvant chemotherapy regimen Adjuvant chemotherapy regimen No anthracycline or taxane No anthracycline or taxane 203 203 0.64 0.64 Anthracycline, no taxane Anthracycline, no taxane 2307 2307 0.43 0.43 Anthracycline + taxane Anthracycline + taxane 872 872 0.77 0.77 Receptor status/endocrine therapy Receptor status/endocrine therapy Negative Negative 1674 1674 0.51 0.51 Pos + no endocrine therapy Pos + no endocrine therapy 467 467 0.49 0.49 Pos + endocrine therapy Pos + endocrine therapy 1234 1234 0.68 0.68 Age group Age group <35 yrs <35 yrs 251 251 0.47 0.47 35 35 - - 49 yrs 49 yrs 1490 1490 0.52 0.52 50 50 - - 59 yrs 59 yrs 1091 1091 0.53 0.53   60 yrs 60 yrs 549 549 0.70 0.70 Region Region Europe, Nordic, Canada, SA, Aus, NZ Europe, Nordic, Canada, SA, Aus, NZ 2430 2430 0.58 0.58 Asia Pacific, Japan Asia Pacific, Japan 405 405 0.42 0.42 Eastern Europe Eastern Europe 364 364 0.31 0.31 Central + South America Central + South America 188 188 0.90 0.90 Favors Favors 1 1 Favors Favors 2 2 trastuzumab trastuzumab observation observation

Trastuzumab provides DFS benefit across a range of ages N9831 / B-31 <40 years 40-49 years 50-59 years ≥60 years 0.0 0.5 1.0 1.5 2.0 2.5 Favours Herceptin Favours no Herceptin References Perez EA et al. J Clin Oncol (Meeting Abstracts) 2007; 25: 6s, abs 512. Smith IE et al. Lancet 2007; 369: 29-36. HR Perez et al 2007; Smith et al 2007 18

Trastuzumab treatment in elderly patients with advanced breast cancer: results from a large observational study Jackisch et al. Poster #3144 SABCS 2008

METHODEN I

METHODEN II

Gesamtüberleben: Vergleich der Patienten unter 65 und über 65

Zeit bis zur Progression

Sicherheitsprofil bei älteren Patienten

Konklusionen - Effektivität

Konklusionen - Toxizität

Gesamtkonklusionen

}30% Breast Cancer Mortality in Europe 1.2 }30% Standardized Mortality Rate 0.8 Auch „elderly patients“ haben das Recht auf diesen Survival-Benefit 0.4 1960 1970 1980 1990 2000