Up-Date zielgerichtete Therapien mit neuen Substanzennach dem ASCO Dr. Beyhan Ataseven Oberärztin

Transkript

1 Up-Date zielgerichtete Therapien mit neuen Substanzennach dem ASCO 2008 Projektgruppensitzung Dr. Beyhan Ataseven Oberärztin ROTKREUZKLINIKUM München, Frauenklinik Ärztlicher Direktor: Prof. W. Eiermann Lehrkrankenhaus der TU München EUSOMA Brustzentrum Breast Cancer Internat. Research Group (BCIRG) Translational Research In Oncology (TRIO) Michelangelo Foundation GABG - GBG

2 Selected Targeted Agents With Potential as Breast Cancer Therapeutics Angiogenesis: Sexaminib SU6668 Bevacizumab HuMV833 Cilengitide Vitaxin 2 CAI Endostatin Angiostatin Thalidomide Neovastat 2-Methoxy Estradiol Sorafenib Sunitinib Vandetanib Motesanib diphosphate Cilengitide Erlotinib SU6668 Sexaminib Gefitinib Trastuzumab Lapatinib Growth Factors (eg, TGFα) Tipifarnib ECM BMS Hormones (eg, Bombesin) (eg, Estrogen) Survival Factors (eg, IGF1) Paclitaxel Docetaxel Dolastatin Ixabepilone Benzoylphenylurea WNT Cells Oxaliplatin Gemcitabine Irofulven 5-Azacytidine Decitabine Fazarabine Depsipeptide Flavopiridol 17AAG Bortezomib CC49 LMB-9 Mab CO17-1A Ad-p53 Oblimersen Matrix Metalloproteinases: Batimastat BB-94 Marimastat BB-2516 BMS BAY COL3 Bryostatin-1 Everolimus Temsirolimus IL-4 IL-12 IFN Cytokines Bortezomib (eg, ILs, IFNs) UCN-01 Death Factors (eg, FasL)

3 Studienauswahl (ASCO 2008) O Shaughnessy et al.: A randomised study of lapatinib (Tykerb/Tyverb) in combination with trastuzumab versus lapatinib monotherapy in heavily pretreated HER2+ metastatic breast cancer patients progressing on trastuzumab therapy Slamon et al.: Randomized phase II study of pazopanib + lapatinib vs lapatinib alone in patients with HER2+ advanced or metastatic breast cancer Rugo et al.: A phase II evaluation of lapatinib and bevacizumab in HER2+ metastatic breast cancer (MBC) Gelmon et al.: Results of a phase II trial of trastuzumab in patients with HER2-positive metastatic breast cancer MBC who had progressed during trastuzumab therapy Pegram et al. (SABCS 2006): Phase II combined biological therapy targeting the HER2 proto-oncogene and vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer

4 O Shaughnessy et al. (ASCO 2008) A randomised study of lapatinib (Tykerb/Tyverb ) in combination with trastuzumab versus lapatinib monotherapy in heavily pretreated HER2+ metastatic breast cancer patients progressing on trastuzumab therapy

5 O Shaughnessy et al. (ASCO 2008) L (n= 148) L + T (n= 148) Median prior CHT-regimen 4 5 %patients 6 prior regimen 28% 34% Median prior Trastuzumab regimen for MBC 3 3

6 O Shaughnessy et al. (ASCO 2008)

7 O Shaughnessy et al. (ASCO 2008)

8 O Shaughnessy et al. (ASCO 2008) - Zusammenfassung Bestätigung der präklinischen Daten: Lapatinib in Kombination mit Trastuzumab ist eine effektive Behandlung beim met. MaCa nach Trastuzumab-Versagen Kombination: verbessert sig. PFS (p=0.008) Verdoppelung der CBR (clinical benefit rate- auf 25%) Trend für Verbesserung der OS (p=0.106) ABER: Nebenwirkungen? Diarrhoe? Kardiale Sicherheit Adverse event-all grades (% L (n=146) L+T pats) Diarrhea (sign. difference) 48 (n=149) 60 Diarrhea grade 3 or Rash Nausea Fatigue Vomoting 18 14

9 Slamon et al. (ASCO 2008) Randomized phase II study of pazopanib + lapatinib vs lapatinib alone in patients with HER2+ advanced or metastatic breast cancer 141 pts Screening Randomisation Lapatinib 1500 mg/d Lapatinib 1000 mg/d + Pazopanib 400 mg/d Woche 12 Assessment Trastuzumab erhältlich Trastuzumab nicht erhältlich CR/PR Ggf.TH-Fortführung SD/PD Abbruch PD Abbruch CR, PR, SD Ggf. TH-Fortführung Stage III/IV invasive breast cancer No prior chemotherapy or anti-her2 therapy for metastatic or recurrent disease

10 Übersicht

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12 Slamon et al. (ASCO 2008) - Zusammenfassung erhöhte Aktivität war mit der Kombination Pazopanib + Lapatinib (vs Lapatinib mono) beobachtbar keine Differenz in PD-Rate bei Woche 12 Responseraten im Kombinationsarm sind höher nahezu alle Pats im Kombinationsarm zeigte Ansprechen in Zielläsion Woche 12 PFS-Assessment: favorisiert Kombinationsarm Sicherheitsprofil im Kombinationsarm akzeptabel

13 Pegram et al. (SABCS 2006) Phase II combined biological therapy targeting the HER2 proto-oncogene and vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer Interim efficacy Data (37 pts/50 planned) Patients were treated in the 1st line MBC and with no prior exposure to bevacizumab or trastuzumab The trial population was generally similar to those in trials of trastuzumab plus chemotherapy The combination of bevacizumab and trastuzumab generated a response rate of 54% Overall response rate: 54.1% Clinical benefit rate: 83.8%

14 Pegram et al. (SABCS 2006) Event Grade 1 Grade 2 Grade 3 Grade 4 Total Hypertension Fever/chills/headache/ infusion reactions Cardiac events AST/ALT increase Fatigue Epistaxis Prolonged prothrombin time Proteinuria Nausea Mucositis Diarrhoea

15 Multitargeted therapies Studienkonzepte in MÜNCHEN Rotkreuzklinikum-Frauenklinik

16 Study CIRG 011 / NSABP B-44/BO20906 BETH Study A Multicenter Phase III Randomized Trial of Adjuvant Therapy for Patients with HER2-Positive Node-Positive or High Risk Node-Negative Breast Cancer Comparing Chemotherapy Plus Trastuzumab with Chemotherapy Plus Trastuzumab Plus Bevacizumab

17 Study treatment Group 1A and 1B 6 x Docetaxel and Carboplatin Group 2A and 2B 3 x Docetaxel and 3 x FEC TCH RT TH-FEC-H RT 1 Year Trastuzumab 43wks Trastuzumab 6 x Docetaxel and Carboplatin 3 x Docetaxel and 3 x FEC TCHB RT RT 1 Year Trastuzumab 1 Year Bevacizumab THB-FEC-BH 43 wks Trastuzumab 43 wks Bevacizumab Doses of Study Drugs Bevacizumab 15 mg/kg Carboplatin target AUC = 6 mg/ml/min Docetaxel 75 mg/m2 Groups 1A/1B Trastuzumab 8 mg/kg loading dose; 6 mg/kg subsequent doses Doses of Study Drugs Bevacizumab 15 mg/kg Cyclophosphamide 600 mg/m2 Docetaxel 100 mg/m2 Groups 2A/2B Epirubicin 90 mg/m2 5-Fluorouracil 600 mg/m2 Trastuzumab 8 mg/kg loading dose; 6 mg/kg subsequent doses

18 ALTTO-Studiendesign: Lapatinib in der adjuvanten Therapie von ErbB2-positivem Brustkrebs 1 Operation Abschluss aller (neo)-adjuvanten, Anthracyclinbasierten Chemotherapien ( 4 Zyklen) Design 1 Kein Taxan Design 2 Gleichzeitig Paclitaxel (12 Wo) Randomisierung Trastuzumab Trastuzumab Lapatinib Wash out Lapatinib + Trastuzumab Lapatinib 12 Wo 6 Wo 34 Wo 52 Wo N = 8000 (2000 Patientinnen pro Behandlungsarm) 1. ALTTO (EGF106708) Überblick des Studiendesigns

19 FM-B07-01 A Multinational Double-Blind, Randomized Phase IIb Cooperative Group Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo when administered in Combination with Chemotherapy and/or Endocrine Therapy in Patients with Locally Recurrent or Metastasic Breast Cancer

20 Randomisation- FM-B07-01 Arm A Sorafenib 400mg (2 tablets) twice daily Arm B Placebo (2 tablets), twice daily Best Standard Treatment (chemotherapy, endocrine therapy, both) Best Standard Treatment (chemotherapy, endocrine therapy, both) Best standard treatment: ER+ or PgR+ and bone or soft tissue disease or both Endocrine Therapy: Letrozole 2,5 mg orally once daily till progression ER+ or PgR+ and visceral lesions (with or without bone /soft tissue) Chemotherapy (up to 6 cycles or after toxicity or best response) followed by Endocrine Therapy (starting on day 15 of last cycle till progression) ER- and PgR- and Her2- Chemotherapy: Up to 6 cycles Docetaxel initially 75mg/m² as a 1-hour infusion on day 1 every 21 days.

21 VEG Phase III - Design Randomisierte, multizentrische Studie der Phase III zum Vergleich der Kombination aus Pazopanib und Lapatinib mit einer Lapatinib-Monotherapie bei Patientinnen mit ErbB2 überexprimierendem entzündlichem Brustkrebs n=160 Paz (800mg) + Lapatinib (1500mg) Screen Her2+ PFS OS n=160 Lapatinib (1500 mg) weltweit: 320 Patientinnen Her2+ Pat. mit IBC, Rezidiv/ Progress, vorbehandelt mit Chemotherapie und Trastuzumab Doppelblind 1:1 Randomisierung:

22 Study: VEG Phase I Program - Pazopanib A phase Ib study to evaluate the safety and tolerability of pazopanib administered in combination with trastuzumab and lapatinib in patients with advanced or metastatic breast cancer

23 Cave: Neues Nebenwirkungsspektrum Hypertension Diarrhoe Hautveränderungen/-ausschlag Hand-Fuß-Syndrom Kardiovasukläre Probleme Andere (Übelkeit, Erbrechen, Appetitlosigkeit, Leberwerterhöhung)

24 Vielen Dank für Ihre Aufmerksamkeit