Nieuwe behandelingsmethodes in de oncologie

Transcription

1 Nieuwe behandelingsmethodes in de oncologie Vibeke Kruse MD PhD Medical Oncologist Clinical Pharmacologist Department of Medical Oncology UZ Gent 20 Juni 2017

2 Outline 1) Introduction 2) Systemic therapy in oncology Chemotherapy Targeted Therapy Immunotherapy 3) Conclusions

3 Outline 1) Introduction 2) Systemic therapy in oncology Chemotherapy Targeted Therapy Immunotherapy 3) Conclusions

4 Personalized medicine Breast Cancer an example: Breast cancer is NOT one disease

5 Personalized medicine Diagnosis of breast cancer: Primary tumor Lymph node involvement Metastatic disease TNM classification stage I-IV Breast cancer is NOT one disease

6 Personalized medicine Diagnosis of breast cancer: Primary tumor Pathology report Size Differentiation Ki67% Hormone receptors HER2 Lymph node involvement Metastatic disease TNM classification stage I-IV Breast cancer is NOT one disease

7 Personalized medicine Diagnosis of breast cancer: Primary tumor Lymph node involvement Metastatic disease Surgery possible? Systemic treatment? Chemotherapy? Targeted therapy? Hormonal therapy? Anti-HER2? Anti-VEGF? Radiotherapy? TNM classification stage I-IV Breast cancer is NOT one disease

8 Personalized medicine

9 Personalized medicine Not only for breast cancer, but for all cancers

10 Personalized medicine Lung cancer another example: Treatment: Surgery Radiotherapy Chemotherapy Targeted therapy Immunotherapy

11 Outline 1) Introduction 2) Systemic therapy in oncology Chemotherapy Targeted Therapy Immunotherapy 3) Conclusions

12 Systemic therapy Chemotherapy Targeted therapy Immunotherapy

13 Systemic therapy Chemotherapy Targeted therapy Immunotherapy

14 Chemotherapy Mechanism of action Not tumour specific Inhibits cell division by targeting different phases of the cell cycle Chemotherapy Can t differentiate between healthy and cancer cells Attacks all rapidly dividing cells -Bone marrow -Digestive tract -Hair follicles -...

15 Chemotherapy Chemotherapy Side effects: Nausea Changed taste Aloplecia Myelosuppression Stomatitis Increased risk for infection Hand foot syndrome.

16 Chemotherapy Treatment of side effects:

17 Systemic therapy Chemotherapy Targeted therapy Immunotherapy

18 Targeted therapy

19 Targeted therapy Monocloncal antibodies (surface receptors) Small molecules (intracellular targtes) Various targets: receptors, proteins, cancer gene mutations,

20 Targeted therapy Same target different organ

21 Targeted therapy Same target different organ HER % 15-20%

22 Targeted therapy Same target different organ HER2

23 Targeted therapy Gerichte anti-her2 therapie: blokkering van de HER2-receptor (trastuzumab)

24 Targeted therapy Anti-HER2 Chemotherapie

25 Targeted therapy

26 Werkingsmechanisme: endocytose HER2 receptor T-DM1 complex is internalised into the tumour cell via endocytosis MOA, mode of action. Erickson HK, et al. Cancer Res 2006; 66:

27 Werkingsmechanisme: lysosomale degradatie Once endocytosis is complete, trastuzumab and the HER2 receptor are degraded and a cytotoxic metabolite* is released * Lysine-bound emtansine plus linker MOA, mode of action. Erickson HK, et al. Cancer Res 2006; 66: ; Lewis Phillips GD, et al. Cancer Res 2008; 68:

28 Targeted therapy Same target different organ

29 Targeted therapy Same target different organ BRAFmutation 50% 5-10%

30 Targeted therapy BRAF mutation melanoma

31 Targeted therapy BRAF mutation Coloncarcinoma Kopetz S et al. JCO.2015.

32 Targeted therapy The value of a target depends on the localisation of the tumor

33 Targeted therapy

34 Targeted therapy

35 Targeted therapy Two big challenges: Resistance Heterogeneity The treatment only works for a limited period of time Not all metastases behave the same

36 Targeted therapy Side effects:

37 Systemic therapy Chemotherapy Targeted therapy Immunotherapy

38 Immunotherapy

39 Immunotherapy

40 Immunotherapy

41 Immunotherapy

42 Immunotherapy Reimbursed drugs since 01/01/2017: Melanoma Melanoma (monotherapy or in combination with Yervoy ) NSCLC (from 2 nd line) RCC (from 2 nd line) Hodgkin Lymfoom Melanoma NSCLC, 1 st line : PDL1 pos 50% no EGFR or ALK mutations, from 2 nd line on PDL1 pos 1%

43 Immunotherapy

44 Checkpoint Blockade and Cancer CTLA-4 blocking antibodies release an immune checkpoint at the activation step of an immune response to cancer PD-1 blocking antibodies release an immune checkpoint at the effector step of an immune response to cancer Pembrolizumab is a PD-1 blocking antibody with robust efficacy and manageable toxicity in patients with advanced melanoma 1-5 Reprinted with permission from Ribas A. N Engl J Med 2012;366: Copyright 2012 Massachusetts Medical Society. Human IgG4 K D : ~29 pm PD-L1 IC 50 : ~ nm PD-L2 IC 50 : ~ nm 1. Hamid O et al. N Engl J Med. 2013;392: ; 2. Robert C et al. Lancet. 2014;384: ; 3. Daud A et al. Presented at: Society for Melanoma Research 2014 Annual Meeting; November 13-16, 2014; Zurich, Switzerland; 4. Robert C et al. Abstract LBA34. Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain; 5. Ribas A et al. Presented at: Society for Melanoma Research 2014 Annual Meeting; November 13-16, 2014; Zurich, Switzerland.

45 Non-Conventional Response and I-O Therapy Apparent progression upon radiographic imaging after initial I-O therapy can actually be a sign of non-conventional response to I-O therapy. This response may occur when T cells infiltrate the tumor site and cause tumors to flare or appearance of new lesions upon imaging. 1,2 I-O therapy Tumor cells T cells infiltrating the tumor site Appearance of new lesions upon imaging I-O, immuno-oncology. 1. Wolchok JD et al. Clin Cancer Res. 2009;15: Ribas A et al. Clin Cancer Res. 2009;15:

46 Patient With Melanoma Treated in KEYNOTE-001 P001 Baseline Week 12 Week 24 Week 52 Case courtesy of C. Robert, Gustave Roussy, Villejuif, France.

47 Patient With Melanoma Treated In KEYNOTE-001 P001 Baseline Week 4 SLD increased 17% SD by RECIST v1.1 Week 16 SLD decreased 55% PR by RECIST v1.1 Week 24 SLD decreased 55% PR by RECIST v1.1 Week 60 SLD decreased 49% PR by RECIST v1.1 SPD increased 56% PD by irrc SPD decreased 85% PR by irrc SPD decreased 86% PR by irrc SPD decreased 85% PR by irrc SLD, sum of the longest diameters. SPD, sum of the longest diameter x perpendicular diameters.

48 Immune-Mediated Adverse Reactions Immune-mediated adverse reactions affect certain organ systems 1 Nervous system 2 Eyes 1,3 Skin 1,2,4 Respiratory system 1,2 Liver 2,4 Endocrine system 2,4 Gastrointestinal tract 1-4 Hematopoietic cells 5 1. Amos SM et al. Blood. 2011;118(3): Chow LQ. Am Soc Clin Oncol Educ Book. 2013: Robinson MR et al. J Immunother. 2004;27(6): Phan GQ et al. Proc Natl Acad Sci U S A. 2003;100(14): Lin TS et al. J Clin Oncol. 2010;28(29):

49 irae prognostic value? Is there a link between response to immunotherapy and development of an irae? Some data support an association between clinical benefit and the induction of a cutanous iraes Freeman-Keller et al. Clin Cancer Res; 22(4) February 15, 2016 Vibeke Kruse Kruse

50 Immunotherapy Vibeke Kruse Kruse

51 Immunotherapy Vibeke Kruse Kruse

52 Immunotherapy Vibeke Kruse Kruse

53 Immunotherapy Vibeke Kruse Kruse

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55 ION key assets in Ghent growing base of preclinical and translational research activity in cancer immunology Bioscience Engineering Statistics and Bioinformatics VIB Biochemistry Nanobody lab Nuclear receptor lab Cytokine receptor lab Molecular immunology Pharmaceutical Sciences biopharmaceutical technology unit Medicine and Health Sciences Immunology Hematology Experimental Immunology Dermatology Research Unit Thoracic Tumor Immunology lab Gastroenterology-Hepatology Radiation Oncology Lab of Experimental Cancer Research VIB Inflamm. Research Center Molecular & cellular oncology Molecular signalling and cell death Inflammation and immunity Veterinary Science Laboratory of gene therapy KV Mar 2016

56 LABS CLINICS Bioscience ngineering VIB-UGent patients biomarker discovery UZ Gent immuno-assays translational research tumor boards biobanks IO in clinical trials & routine practice immuno-profiling immuno-monitoring Veterinary Sciences Pharmaceutic al Sciences KV Mar 2016

57 The ION-Ghent steering group Vibeke Kruse, Medical Oncology Lieve Brochez, Dermatologic Oncology Tessa Kerre, Hematological Oncology & Immunology Katrien De Wolf, Piet Ost, Radiation Oncology Karim Vermaelen, Thoracic Oncol. & Immunology with support from Sofie Bekaert (BIMETRA) Pieter Rondou (CRIG) KV Mar 2016

58 Outline 1) Introduction 2) Systemic therapy in oncology Chemotherapy Targeted Therapy Immunotherapy 3) Conclusions

59 Conclusions Future perspectives of cancer care? Personalized / PRECISION medicine Targeted therapy is a cornerstone of cancer care However not cancers have a targets so far.and not all targets have a treatment Immunotherapy is gaining more importance For some cancers chemotherapy still plays an important role

60 Conclusion

61 Tak for opmærksomheden! Bedankt voor uw aandacht! Vibeke Kruse Kruse