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Vibeke Kruse MD PhDMedical OncologistClinical PharmacologistDepartment of Medical OncologyUZ Gent
20 Juni 2017
Nieuwe behandelingsmethodesin de oncologie
Outline
1) Introduction
2) Systemic therapy in oncology• Chemotherapy• Targeted Therapy• Immunotherapy
3) Conclusions
Vibeke Kruse 2016Vibeke Kruse 2017
Outline
1) Introduction
2) Systemic therapy in oncology• Chemotherapy• Targeted Therapy• Immunotherapy
3) Conclusions
Vibeke Kruse 2016Vibeke Kruse 2017
Personalized medicine
Breast Cancer – an example:
Vibeke Kruse 2016
Breast cancer is NOT one disease
Vibeke Kruse 2017
Personalized medicine
Vibeke Kruse 2016
Breast cancer is NOT one disease
Diagnosis of breast cancer:
Primary tumor
Lymph node involvement
Metastatic disease
TNM classification – stage I-IV
Vibeke Kruse 2017
Personalized medicine
Vibeke Kruse 2016
Breast cancer is NOT one disease
Diagnosis of breast cancer:
Primary tumorPathology report• Size
• Differentiation
• Ki67%
• Hormone receptors
• HER2
• …
Lymph node involvement
Metastatic diseaseTNM classification – stage I-IV
Vibeke Kruse 2017
Personalized medicine
Vibeke Kruse 2016
Breast cancer is NOT one disease
Diagnosis of breast cancer:
Primary tumor
Lymph node involvement
Metastatic disease
TNM classification – stage I-IV
Surgery possible?
Systemic treatment ?
Chemotherapy ?
Targeted therapy ? Hormonal therapy ?
Anti-HER2?
Anti-VEGF?
Radiotherapy ?
Vibeke Kruse 2017
Vibeke Kruse 2016
Personalized medicine
Vibeke Kruse 2017
Vibeke Kruse 2016
Not only for breast cancer, but forall cancers
Personalized medicine
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Vibeke Kruse 2016
Personalized medicineLung cancer – another example:
Treatment:• Surgery
• Radiotherapy
• Chemotherapy
• Targeted therapy
• ImmunotherapyVibeke Kruse 2017
Outline
1) Introduction
2) Systemic therapy in oncology• Chemotherapy• Targeted Therapy• Immunotherapy
3) Conclusions
Vibeke Kruse 2016Vibeke Kruse 2017
Systemic therapy
Vibeke Kruse 2016
Chemotherapy Targeted therapy Immunotherapy
Vibeke Kruse 2017
Systemic therapy
Vibeke Kruse 2016
Chemotherapy Targeted therapy Immunotherapy
Vibeke Kruse 2017
Chemotherapy
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Chemotherapy
Mechanism of action
Not tumour specific
Inhibits cell division by targeting different phases of the cell cycle
Can’t differentiate between healthy and cancer cells
Attacks all rapidly dividing cells-Bone marrow-Digestive tract-Hair follicles-...
Vibeke Kruse 2017
Chemotherapy
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Side effects: Nausea Changed taste Aloplecia Myelosuppression Stomatitis Increased risk for infection Hand foot syndrome ….Chemotherapy
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Chemotherapy
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Treatment of side effects:
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Systemic therapy
Vibeke Kruse 2016
Chemotherapy Targeted therapy Immunotherapy
Vibeke Kruse 2017
Targeted therapy
Vibeke Kruse 2016Vibeke Kruse 2017
Targeted therapy
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Monocloncalantibodies
(surface receptors)
Smallmolecules(intracellular
targtes)
Various targets: receptors, proteins, cancer gene mutations,…
Vibeke Kruse 2017
Targeted therapy
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Same target – different organ
Vibeke Kruse 2017
Targeted therapy
Vibeke Kruse 2016
Same target – different organ
HER2
10-15% 15-20%
Vibeke Kruse 2017
Targeted therapy
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Same target – different organ
HER2
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Targeted therapy
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Gerichte anti-HER2 therapie:
blokkering van de HER2-receptor
(trastuzumab)
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Targeted therapy
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Anti-HER2
ChemotherapieVibeke Kruse 2017
Targeted therapy
Vibeke Kruse 2016Vibeke Kruse 2017
• HER2 receptor–T-DM1 complex is internalised into the tumour cell via endocytosis
Erickson HK, et al. Cancer Res2006; 66:4426–4433.
MOA, mode of action.
Werkingsmechanisme: endocytose
• Once endocytosis is complete, trastuzumab and the HER2 receptor are degraded and a cytotoxic metabolite* is released
Erickson HK, et al. Cancer Res 2006; 66:4426–4433; Lewis Phillips GD, et al.
Cancer Res 2008; 68:9280–9290.
* Lysine-bound emtansine plus linker
MOA, mode of action.
Werkingsmechanisme: lysosomale degradatie
Targeted therapy
Vibeke Kruse 2016
Same target – different organ
Vibeke Kruse 2017
Targeted therapy
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Same target – different organ
BRAFmutation
5-10%50%
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Targeted therapy
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BRAF mutation melanoma
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Targeted therapy
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BRAF mutation Coloncarcinoma
Kopetz S et al. JCO.2015.Vibeke Kruse 2017
Targeted therapy
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The value of a target depends on the localisation of the tumor
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Targeted therapy
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Targeted therapy
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Targeted therapy
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Resistance Heterogeneity
Two big challenges:
The treatment only works for a limited period of time… Not all metastases behave the same…
Targeted therapy
Vibeke Kruse 2016
Side effects:
Vibeke Kruse 2017
Systemic therapy
Vibeke Kruse 2016
Chemotherapy Targeted therapy Immunotherapy
Vibeke Kruse 2017
Immunotherapy
Vibeke Kruse 2016Vibeke Kruse 2017
Vibeke Kruse 2016
Immunotherapy
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Vibeke Kruse 2016
Immunotherapy
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Immunotherapy
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Immunotherapy
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Reimbursed drugs since 01/01/2017:
Melanoma MelanomaNSCLC, 1st line : PDL1 pos ≥ 50% no EGFR or ALK mutations, from 2nd
line on PDL1 pos ≥ 1%
Melanoma (monotherapy or incombination with Yervoy®)NSCLC (from 2nd line)RCC (from 2nd line)Hodgkin Lymfoom
Vibeke Kruse 2017
Vibeke Kruse 2016
Immunotherapy
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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 melanoma1-5
1. Hamid O et al. N Engl J Med. 2013;392:134-144; 2. Robert C et al. Lancet. 2014;384:1109-1117; 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.
Human IgG4KD: ~29 pMPD-L1 IC50: ~0.1-0.3 nMPD-L2 IC50: ~0.5-0.9 nM
Reprinted with permission from Ribas A. N Engl J Med 2012;366:2517-9.Copyright © 2012 Massachusetts Medical Society.
Non-Conventional Response and I-O Therapy
45
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
T cells infiltrating the
tumor site
Appearance of new lesions upon imaging
I-O therapy
Tumor cells
I-O, immuno-oncology.1. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420.2. Ribas A et al. Clin Cancer Res. 2009;15:7116-7118.
Patient With Melanoma Treated in KEYNOTE-001
Week 12Baseline Week 24 Week 52
Case courtesy of C. Robert, Gustave Roussy, Villejuif, France.
P001
Patient With Melanoma Treated InKEYNOTE-001
Baseline Week 4• SLD increased 17%
• SD by RECIST v1.1
• SPD increased 56%• PD by irRC
Week 16• SLD decreased 55%
• PR by RECIST v1.1
• SPD decreased 85%• PR by irRC
Week 24• SLD decreased 55%
• PR by RECIST v1.1
• SPD decreased 86%• PR by irRC
Week 60• SLD decreased 49%
• PR by RECIST v1.1
• SPD decreased 85%• PR by irRC
SLD, sum of the longest diameters.SPD, sum of the longest diameter x perpendicular diameters.
P001
Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions affect certain organ systems1
48
Nervous system2 Respiratory system1,2Eyes1,3 Skin1,2,4
Liver2,4 Hematopoietic cells5Endocrine system2,4 Gastrointestinal tract1-4
1. Amos SM et al. Blood. 2011;118(3):499-509. 2. Chow LQ. Am Soc Clin Oncol Educ Book. 2013:280-285. 3. Robinson MR et al. J Immunother. 2004;27(6):478-479. 4. Phan GQ et al. Proc Natl Acad Sci U S A. 2003;100(14):8372-8377.5. Lin TS et al. J Clin Oncol. 2010;28(29):4500-4506.
irAE – prognostic value?
Vibeke Kruse 2016
Freeman-Keller et al. Clin Cancer Res; 22(4) February 15, 2016
• 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
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Immunotherapy
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Immunotherapy
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Immunotherapy
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Immunotherapy
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KV Mar 2016
growing base of preclinical and translational research activity in cancer immunology
Medicine and Health SciencesImmunology – HematologyExperimental ImmunologyDermatology Research UnitThoracic Tumor Immunology labGastroenterology-HepatologyRadiation OncologyLab of Experimental Cancer Research
Pharmaceutical Sciencesbiopharmaceutical technology unit
VIB Inflamm. Research CenterMolecular & cellular oncologyMolecular signalling and cell deathInflammation and immunity
Veterinary ScienceLaboratory of gene therapy
ION | key assets in Ghent
Bioscience EngineeringStatistics and Bioinformatics
VIB BiochemistryNanobody labNuclear receptor labCytokine receptor labMolecular immunology
KV Mar 2016
UZ Gent
VIB-UGentBioscience Engineering
Pharmaceutical Sciences
Veterinary Sciences
IO in clinical trials& routine practice
immuno-profilingimmuno-monitoring
translational research
biomarker discoveryimmuno-assays
• tumor boards
• biobanks
patients
LABS CLINICS
KV Mar 2016
The ION-Ghent steering groupVibeke Kruse, Medical OncologyLieve Brochez, Dermatologic OncologyTessa Kerre, Hematological Oncology & ImmunologyKatrien De Wolf, Piet Ost, Radiation OncologyKarim Vermaelen, Thoracic Oncol. & Immunologywith support from Sofie Bekaert (BIMETRA) Pieter Rondou (CRIG)
Outline
1) Introduction
2) Systemic therapy in oncology• Chemotherapy• Targeted Therapy• Immunotherapy
3) Conclusions
Vibeke Kruse 2016Vibeke Kruse 2017
ConclusionsFuture 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
Vibeke Kruse 2016Vibeke Kruse 2017
Conclusion
Vibeke Kruse 2016Vibeke Kruse 2017
Vibeke Kruse 2016
Tak for opmærksomheden!
Bedankt voor uw aandacht!
Vibeke Kruse 2017