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Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Monoclonal antibodies in solid tumors.

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Presentation on theme: "Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Monoclonal antibodies in solid tumors."— Presentation transcript:

1 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria Monoclonal antibodies in solid tumors

2 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) FAMILY MEMBRANE RECEPTORS WITH INTRACELLULAR TYROSIN-KINASE ACTIVITY FOUR HOMOLOGOUS RECEPTORS  EGFRerbB1 HER1  erbB2HER2/neu  erbB3HER3  erbB4HER4

3 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria EXPRESSION OF EGFR-FAMILY IN BREAST CANCER OVEREXPRESSION GENE-AMPLIFICATION (% CASES) EGFR 30 - 50NO HER-2/neu 30 - 40YES erbB3 20 - 70NO erbB4 7YES

4 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria ANTIBODIES IN THE TREATMENT OF SOLID TUMORS Anti-Her-2/neu Antibodies (Trastuzumab, Herceptin R ) Anti-EGF-R-Antibodies (mAb 225, Cetuximab) Anti-17-1A-Antibodies (Edrecolomab,Panorex R )

5 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CONCEPT OF IMMUNOGENEITY OF THE HER-2/neu PROTEIN Tyrosin- kinase- Activity PP Her2/neu

6 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria AB-mediated blockade ADCC IMMUNOMEDIATED TUMORTHERAPY

7 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria HER2/neu IN BREAST CANCER  Prognostic factor  Predictor of efficacy of hormonal and cytotoxic therapy  Therapeutic target for antibody therapy  Therapeutic target for vaccination IHC WB FISH Gene- amplification Protein Overexpression

8 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria HER-2/neu PROTEIN OVEREXPRESSION AND GENE-AMPLIFICATION IN BREAST CANCER: METHODS OF DETECTION IHC FISH Gene- amplification Protein Overexpression IMMUNOHISTOCHEMISTRY (IHC) FISH CORRELATION...?

9 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria HER2/neu OVEREXPRESSION (IHC) IN DIFFERENT TUMORS Inflammatory breast cancer50% Breast cancer18% Lung cancer7% Pancreatic cancer4% Colon cancer3%

10 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria  Receptor down-regulation  Inhibition of heterodimerization  Cell cylce arrest in G1  Induction of apoptosis  Inhibition of angiogenesis  Mediation of ADCC & CDC ANTI-HER2/neu: MODE OF ACTION

11 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria HERCEPTIN ® (TRASTUZUMAB) – HUMANIZED ANTI-HER2 MONOCLONAL ANTIBODY  High affinity (K d =0.1nM) and specificity  95% human, 5% murine  Reduced immunogenic potential

12 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria  Patients (intent-to-treat)222  Complete Remission8  Partial Remission26  Response rate in % 15 Cobleigh MA et al. J Clin Oncol 17: 2639–48, 1999 Mass RD et al. Proc. Am. Soc. Clin. Oncol. 19: 291, 2000 TRASTUZUMAB: MONOTHERAPY

13 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TRASTUZUMAB AND CHEMOTHERAPY: SYNERGY AND ADDITIVE EFFECTS. ADDITIVE SYNERGY STRONG SYNERGY ANTAGONISTIC TAXOL TAXOTERE CISPLATIN FLUOROURACIL VINORELBINE CARBOPLATIN GEMCITABINE (RADIOTHERAPY)

14 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CHEMOTHERAPY PLUS TRASTUZUMAB IN METASTATIC BREAST CANCER OVEREXPRESSING HER-2/neu: RESULTS OF A RANDOMIZED PHASE-III STUDY.* CHEMO+T CHEMO p Response rate50% 32% <0.001 Duration9.1 MON. 6.1 MON. <0.001 1-Year-Death-rate 22% 33% =0.008 Overall Survival25.1 MON. 20.3 MON. =0.046 * D.J. SLAMON ET AL., NEJM 344: 783, 2001

15 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CHEMOTHERAPY PLUS TRASTUZUMAB IN METASTATIC BREAST CANCER OVEREXPRESSING HER2/neu * * Slamon et al., N Engl J Med 344: 783, 2001 Progression Free Survival

16 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CHEMOTHERAPY PLUS TRASTUZUMAB IN METASTATIC BREAST CANCER OVEREXPRESSING HER2/neu * * Slamon et al., N Engl J Med 344: 783, 2001 Overall Survival

17 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria PHASE II STUDY OF TRASTUZUMAB PLUS VINORELBINE: CLINICAL RESPONSE. * *Burstein HJ et al. Proc Am. Soc. Clin. Oncol. 19: 392, 2000.

18 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria PHASE II STUDY OF TRASTUZUMAB AND GEMCITABINE IN PATIENTS WITH METASTATIC BREAST CANCER. * N= 38 PRIOR CHEMOTHERAPY (ADRIAMYCIN, TAXOL, TAXOTERE): 2 CHEMOTHERAPY-REGIMEN: 53% 3 CHEMOTHERAPY-REGIMEN: 16% PR: 32% (12 PATIENTS) SD: 42% (16 PATIENTS) MEDIAN RESPONSE DURATION: 8.6 MONTHS MEDIAN OVERALL SURVIVAL: 10.2 MONTHS * J. O’shoughnessy, personal communication, 2001

19 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CRITERIA OF THERAPY FOR OPTIMAL TREATMENT OF METASTATIC BREAST CANCER. CRITERIA OF THERAPY FOR OPTIMAL TREATMENT OF METASTATIC BREAST CANCER.  TYPE OF METASTATIC SPREAD  HORMONRECEPTORSTATUS  HER-2/neu - STATUS

20 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CARDIOTOXICITY OF TRASTUZUMAB. *  IN COMBINATION WITH ANTHRACYCLINES (n=143): 16%  IN COMBINATION WITH PACLITAXEL (n=91): 2% * SLAMON et al., N. Engl. J. Med. 344: 783, 2001.

21 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria FUTURE DIRECTIONS: CLINICAL STUDIES WITH TRASTUZUMAB.  DEFINING OPTIMAL THERAPY INTERVALS  IDENTIFICATION OF CYTOTOXIC SUBSTANCES FOR COMBINATION THERAPY  ROLE OF TRASTUZUMAB IN THE ADJUVANT SETTING  IDENTIFICATION OF CO-FACTORS FOR CARDIOTOXICITY

22 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria TRASTUZUMAB: Conclusions  TREATMENT WITH TRASTUZUMAB IN COMBINATION WITH CHEMOTHERAPY IS STATE-OF-THE-ART IN THE TREATMENT OF HER-2/NEU - POSITIVE METASTATIC BREAST CANCER.  STATUS OF HER-2/NEU CAN BE ASSESSED USING IHC, PREFERABLY, HOWEVER, BY USING FISH.  FOR THE TIME BEING TRASTUZUMAB IS NOT APPLICABLE IN ROUTINE ADJUVANT THERAPIES.  APPLICATION IN OTHER TUMOR ENTITIES IS CURRENTLY BEING TESTED IN CLINICAL STUDIES.

23 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria  Inhibition of proliferation, accumulation of tumor cells in G1 Phase  Up-regulation of p27(KIP1)  Inhibition of Cyclin E / CDK2 Activity  Hypophosphorylisation of Rb  Increase in proapoptotic molecules  Activation of caspases  Reduction of vascularisation in vivo  Reduction of VEGF- and FGF-production by tumor cells Anti EGFR Antibody (mAb 225, Cetuximab): Mode of action * * J. Mendelsohn, ASCO Educational Book: 39-41, 2001

24 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria "Immune mechanisms could be contributing to the efficacy of mAb225 in vivo, although this is not believed to be its primary cancer activity.“ Anti EGF-R Antibodies (mAb 225): Mode of Action* * J. Mendelsohn, ASCO Educational Book: 39-41, 2001

25 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CLINICAL STUDIES WITH CETUXIMAB PHASE II * PANCREATIC CANCER (+ GEMCITABINE) (ABBRUZZESE et al., PROC. AM. SOC. CLIN. ONCOL. 20, 518, 2001) * HEAD AND NECK CANCER (+ CISPLATIN) (HONG et al., PROC. AM. SOC. CLIN. ONCOL. 20, 895, 2001) * COLON CANCER (+ CPT-11) (SALTZ et al., PROC. AM. SOC. CLIN. ONCOL. 20, 7, 2001) Randomized, PHASE III * HEAD AND NECK CANCER (+ CISPLATIN) * HEAD AND NECK CANCER (+ RADIOTHERAPY) * COLON CANCER (+ CPT-11/LV/FU)

26 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria CETUXIMAB PLUS CPT-11 IN PATIENTS WITH CPT-11-REFRACTORY COLON CARCINOMA * 121 PATIENTS WITH COLON CARCINOMA PROGRESSING DURING 5-FU + CPT-11 72% POSITIVE FOR EGFR (IHC) UPHOLDING OF CHEMOTHERAPY REGIMEN + CETUXIMAB (400mg/m 2, following 250 mg/m 2 weekly) PR : 21 (17%) PATIENTS, MEDIAN DURATION: 84 DAY MR OR SD: 37 (31%) PATIENTS * L. SALTZ et al., Proc. Am. Soc. Clin. Oncol. 20: 7, 2001

27 Clinical Division of Oncology Department of Medicine I Medical University of Vienna, Austria SIDE EFFECTS OF CETUXIMAB ACNE-LIKE EXANTHEMA: GRADE 1-2 (53%) TO GRADE 3 (8%) FOLLICULITIS (16%) FATIGUE (41%) FEVER GRADE 1-2 (38%) SALTZ et al., Proc. Am. Soc. Clin. Oncol. 20: 7, 2001 ABBRUZZESE et al., Proc. Am. Soc. Clin. Oncol. 20, 518, 2001


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