nieuwebehandelingsmethodes in de oncologie 20 juni 2017_.pdfvibeke kruse md phd medical oncologist...

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

Personalized medicine

Breast Cancer – an example:

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Breast cancer is NOT one disease

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Diagnosis of breast cancer:

Primary tumor

Lymph node involvement

Metastatic disease

TNM classification – stage I-IV

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Primary tumorPathology report• Size

• Differentiation

• Ki67%

• Hormone receptors

• HER2

• …


Metastatic diseaseTNM classification – stage I-IV

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Primary tumor


Metastatic disease

TNM classification – stage I-IV

Surgery possible?

Systemic treatment ?

Chemotherapy ?

Targeted therapy ? Hormonal therapy ?

Anti-HER2?

Anti-VEGF?

Radiotherapy ?

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Not only for breast cancer, but forall cancers


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Personalized medicineLung cancer – another example:

Treatment:• Surgery

• Radiotherapy

• Chemotherapy

• Targeted therapy

• ImmunotherapyVibeke Kruse 2017

Outline

1) Introduction


3) Conclusions


Systemic therapy

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Chemotherapy Targeted therapy Immunotherapy

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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-...

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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

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Targeted therapy


Targeted therapy

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Monocloncalantibodies

(surface receptors)

Smallmolecules(intracellular

targtes)

Various targets: receptors, proteins, cancer gene mutations,…

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Targeted therapy

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Same target – different organ

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Targeted therapy

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HER2

10-15% 15-20%

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Targeted therapy

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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


• 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

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Targeted therapy

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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


Targeted therapy


Resistance Heterogeneity

Two big challenges:

The treatment only works for a limited period of time… Not all metastases behave the same…

Targeted therapy

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Side effects:

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Systemic therapy

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Immunotherapy


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Immunotherapy

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Immunotherapy


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

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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

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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







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?

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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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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


3) Conclusions


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


Conclusion


Vibeke Kruse 2016

Tak for opmærksomheden!

Bedankt voor uw aandacht!

[email protected]

Vibeke Kruse 2017

mailto:[email protected]

nieuwebehandelingsmethodes in de oncologie 20 juni 2017_.pdfvibeke kruse md phd medical oncologist...

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