PRINCIPLES OF ONCOLOGICALTREATMENT

DANK MAGDOLNASE ÁOK I SZ. BELGYÓGYÁSZATI KLINIKA

The place of decision: the Onkoteam

clinical oncologist

radiotherapist

Surgeon -organ specific training is needed

pathologist

psychologist

Special trainer _ phonyatry, dietetics

The Basic of the decision is the pathological result, informing about malignancy

Mire alapozza döntését az onkoteam?”

Imagines Path result (TNM)

Molecular path findings

Performance status

comorbidities

Patient’s preference

The biological behavior of the tumor

Evidence basedmedicine

Guidelines

Cost-effectivness

Financial questions

Approaches to Drug Treatment

• DARK BLUE LINE: Infrequent scheduling of

treatment courses with low (1 log kill) dosing and a late start prolongs survival but does not cure the patient (i.e., kill rate < growth rate)

• LIGHT BLUE LINE: More intensive and frequent treatment, with adequate (2 log kill) dosing and an earlier start is successful (i.e. kill rate>growth rate)

• GREEN LINE: Early surgical removal of the primary tumour decreases the tumour burden. Chemotherapy will remove persistant secondary tumours, and the total duration of therapy does not have to be as long as when chemotherapy alone is used.

Antibiotics

Antimetabolites

S(2-6h)

G2

(2-32h)

M(0.5-2h)

Alkylating agents

G1

(2-h)

G0

Vinca alkaloids

Mitotic inhibitors

Taxoids

Principles of chemotherapy

Cell cycle level

Action sites of cytotoxic agents

How to use chemotherapy?

Neoadjuvant or induction therapy

Adjuvant therapy

Palliativ therapy 1st L, 2nd L, 3rd L, salvage

Intrathecal, intraperitoneal,TACE, TAE

What is metronomic chemotherapy?

• low doses of chemotherapy administered more frequently and regularly, such as weekly or daily

• In contrast, conventional chemotherapy is given at maximum tolerated dose (MTD) every 3weeks at doses just below what would cause over 50% of patients to experience severe or dose-limiting toxicity

Anti-angiogenesis effect of metronomic chemotherapy

day 1 Day 14day 7 Day 21

Vascular endothelial cell

Conventional Chemotherapy

Metronomic Chemotherapy

Adjuvant therapy”

• No distant metastasis by imaging

• Destroying „micrometastases „– with combined therapy

• Minimising late onset side effects e.g. cardiotoxicity

Neoadjuvant tharapy Decreasing tumor mass

Risk of acute toxicity against operability e.g. organ preservating surgery

Short term therapy

Palliativtharapy, metastatic cases

• Longest survival with best possible QoL

• Managing side effects is essentialq

• Monothharapy, sequential tharapy

INCREASED EFFICACY

Different mechanisms of action Compatible side effects

Different mechanisms of resistance

ACTIVITY SAFETY

Principles of chemotherapy

Aim of combination therapy

Mucositis

Nausea/vomiting

Diarrhea

Cystitis

Sterility

Myalgia

Neuropathy

Alopecia

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

Principles of chemotherapy

Side effects of chemotherapy

Human cancers are heterogeneous

Meric-Bernstam, F. & Mills, G. B. (2012) Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2012.127

action

In case of success: became an innovativ medicine, and become

part of the standard of care

Old paradigm: „Trial and Error Medicine"

Personalized medicine

Personalized medicine

New paradigm: Personalized Medicine

Testing required, which leads to adequatetreatment

observation testtreatment Predictive for

the response

The „Trial and Error Medicine” circle disrupted

Diagnosis Saves lifeyears

Diagnosis Saves money

Personalized medicine

Why is it important?

Selection of the appropriate drug

Breast cancer trastuzumab HER2

Drug dose

Colon cancer irinothecan UGT1A1

Drug efficacy

CML Gleevec® Quant BCR-ABL

Stage

CLL Campath® Minimal residual Illiness

Relapse risk

Breast cancer Oncotype DX® Multivariance Analysis

Risk factor

Breast cancer BRCA testing Risk analysis

Personalized medicine test examples

Definition of presonalized medicine:

“Personalized medicine refers to

the tailoring of medical

treatments to the individual

characteristics of each patient …

Preventive or therapeutic

interventions can then be

concentrated on those who will

benefit, sparing expense and side

effects for those who will not.”

President’s Council of Advisors on Science and

Technology (PCAST), Priorities for Personalized

Medicine, September, 2008

LUX-Lung 2: Effect of Afatinib in a patient with brain metastasisfrom EGFR L858R mutant lung cancer

Yang CH et al. Poster number: 8026. Presented at the American Society of Clinical Oncology, Chicago, Illinois, 2008

Baseline After 1 cycle

Personalized medicine…why is it important?

In routine cancer treatments result low response rates

Tumor response rates arebetween 20-75%

It depends on drugs and types of disease

Oncology – the fastest growing therapeutic area

TRENDS

-aging society

- increasing number of combinedtherapies

- multiple lines of therapy

- increasing number of expensive drugs

- More frequent use of drugs

- China – 100 millions of wealthy peopleor people with health insurance

Two main groups of currently administered cancertreatments (mAb vs TKI)

Monoclonal antibodies

Specific inhibition

High molecular weight proteins

Parenteral administration

ADCC effect, Activating immune system

No drug interactions

Question of biosimilarity

Low molecular weight TKI

Multiple receptor inhibition

Small promiscuous molecules

Per os administration

No proven ADCC effect, and immunesystem activation

Multiple drug interactions

Question of generics

Targeted therapies resulted in significant survival benefit

Cancer types Median survival(moths)

Before Now Reference

Breast cancer, all 12 >56 Giordano, 2004

Colorectal cancer 12 >30 Grothey, 2009

Lung cancer (NSCLC ) 10,1 11,3 Pirker, 2009

Ovarian cancer 12 36 Hoskins, 2009

Renal cancer 14 28 Cella, 2008

Head and neck 29 49 Bonner, 2006

C. Zielinski et al,Presented at DGHO 2009

Identificating tumormarkers lead us to personalizedmedicine: well defined patients, market segmentation

-Successful examples: HER2 and KRAS mutation analysis

- Limited number of proper patients for targeted therapy– increasing segmentation ofpharmaceutical market

- Administration of more efficient drugs in well characterised groups of patients

-Possibility to conduct clinical trials with limited number of patients, with the same statistical power (right drug for the right patient), but therefore more complicated and expensive studies are expected (more samples, biomarker analysis)

-The increased segmentation of cancer drug market results in decreased profitability of the newly developed drugs, moreover there is a strong pressure on prices after commercial availability drug.

- Faster government approval of the newly developed drug is required for the wellcharacterised patient groups

- Complexity of diagnostis tests (cost, logistics, validation, wide availability).

Douglas Hanahan, Robert A. Weinberg ; Hallmarks of Cancer: The Next Generation cell.2011.02.013

Therapeutic Targeting of the Hallmarks of CancerDrugs that interfere with each of the

acquired capabilities necessary for tumor growth and progression.

Targeted therapy

• The first molecular target for cancer therapy was the nuclear receptor for the female sex hormone estrogen (ER), required by many breast cancers for growth.

• Estrogen bound to its nuclear receptor (ER) will activate expression of specific genesinvolved in cell growth and proliferation.

Célzott terápia az ösztrogén receptoron• Selective Estrogen Receptor Modulators (SERMs)

– tamoxifen

• Estrogen Receptor inhibitors– fulvestrant

Inhibitors of estrogen synthesis – aromatase inhibitors– anastrozole

– letrozole

– Exemestane

brain

liver

Fat tissue

hair

Breast cancer

muscles

breast

TK TKATP ATP

Cell Proliferation

Antiapoptosis

Angiogenesis

Gene Transcription

Cell Cycle Progression

+

MetastasesSurvival

Tumor Cell Stimulation

TK TK TK

Inhibition of TK receptor singaling

-- -

tyrosine kinase

inhibitors

“-ibs”

Anti- mAbs

“-mab”

Anti-ligand mAbs

“-mab”

AT

P

Side effect of targeted therapy: mucositis

29

Hand-foot syndrome targetettherapy AE.

30

A good example for personalizedmedicine: Herceptin

Changing paradigm: Breast cancer is not a homogenous disease

HER2-positive breast cancer is a new entity

Role of HER2

-Overexpression of HER2 is an early event during the curse of the disease

- HER2 overexpression is a worse prognostic marker

-To prove HER2 overexpression or gene amplification is prerequisite for antiHER2 treatment

- One quarter of breast cancers are HER2positive

- Knowing HER2 status is required for therapeutic decision

Herceptin: one target - four mechanism

Avoiding p95HER2 (truncated receptor)Inhibition of proliferation

Activating ADCC mediatec killer cellsInhibiton of angiogenesis

Therapeutic decision based on biomarkersleads to significantly improved

therapeutic results.

The standard therapy of HER2 positve breast cancerin adjuvant setting is Trastuzumab (Herceptin)

5 large clinical trials finished with good clinical benefit

N > 13 000 patient

Herceptin therapy is recommended by all guidelines in early breast canceroverexpressing HER2

Risk of relapse decreased by 50%

Risk of death decreased to 1/4-1/3

Without HerceptinHerceptin for one year

Survival benefit with Herceptin in first line treatment

Hó

nap

ok

H + P P H + D

H0648g(IHC3+ patients)

M77001

D

25

31.2

18

22.7

0

10

20

30

Marty et al 2005; Smith et al 2001

+7 months

+ 8,5 months

H: Herceptin, P: paclitaxel, D: docetaxel

Median survival

BSC

0 2 4 6 8 10 12 14 16 18

Milestones in advanced gastric cancertreatment

(months)

Combined chemotherapy

+ 5-6 months

Combined chemotherapy + herceptin

+ 5-6 months

16 m

Novel anti HER2 monoclonal antibodies

40

Homodimers Heterodimers

Life is not for singles!

Tzahar et al. Mol Cell Biol 1996;16:5276–5287

Activation of HER2 signaling – tumorprogression

HER1:HER1

HER2:HER2

HER3:HER3HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4

HER2:HER3HER2:HER4

HER3:HER4

41

Herceptin and pertuzumab binding to HER2 receptor

HER2HERCEPTIN PERTUZUMAB

Subdomain IV Dimerisation domain

HER 1,2,3 4

Herceptin inhibits activation, but notdimerisation of HER2 receptors

Pertuzumab inhibits HER2 receptor dimerisation and activation

Both drugs can activate the patient’s anti cancer immune response

42

What is T-DM1?

Monoconal antibody:

HERCEPTIN

Drug target: HER2

Effective chemotherapy

(maytansine derivate)

Cytotoxic drug: DM1

Extracellularly stable, intracellularlybreaks and the chemotherapy agentwill detach

LinkerT-DM1

43

TDM1 mechanism of action

1. TDM1 binds to HER2-receptor with the „trastuzumabpart”

2. TDM1-HER2 receptor is internalized via endocytosis

3. The antibody and the receptor parts are destroyed bylisosomal proteolysis

4. The citotoxic component is released from the lysosomeand acts intracellularly

Another example of personalizedmedicine: history of mCRC therapy– from

chemotherapy to targeted biologicaltherapy

Currently approved drugs in the treatment of mCRC

5-FU/LV Capecitabine Irinotecan

OxaliplatinBevacizumab

Ramucirumab

Cetuximab

panitumumab

AfliberceptRegorafenib

Bevacizumab4

Median OS

Idő

(hó

nap

)

BSC

5-FU

30

Irinotecan1

Capecitabine2

Oxaliplatin3

Cetuximab5,6

1980s 1990s 2000s 2010

Panitumumab7

Aflibercept8

Regorafenib9

20

10

0

In the last 3 decades, therapy improvements in mCRC, resulted increased survival rates…

1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004

3. Rothenberg, et al. JCO 2003; 4. Hurwitz, et al. NEJM 2004

5. Cunningham, et al. NEJM 2004; 6. Van Cutsem, et al. NEJM 2009

7. Van Cutsem, et al. JCO 2007; 8. Van Cutsem, et al. JCO 2012

9. Grothey, et al. Lancet 2012

ramucirumab

2015

Colon Cancer Genetic Pathways

CK7+/p53−/MLH-1−/BRAF-mutated/K-ras-wt/M SI

CK7+/CK20+/p53−/MLH-1+/BRAF wt/K-ras-mutated/MSS

Quality of life

Patient preference

Toxicity

Tumour

burdenResecability

Tumor

localization

Tumor charateristics

Patient’s characteristics

Age

ComorbiditiesPrevious

adjuvant th.

Molecular characteristics

RAS BRAF

MSI highPerformance

status

MSI, microsatellite instability; mCRC, metastatic colorectal cancer. ; * FOLFOXIRI: oxaliplatin és irinotecan alkalamzási előírás alapján nem rendelkezik indikációval; a Roche nem javasolja ennek a protokollnak a használatát

van Cutsem et al., Ann Oncol 25 (Supplement 3): iii1–iii9, 2014; www .esmo.org/Guidelines/Pocket-Guidelines-Mobile-App accessed 11.11.2015; D Arnold Colorectal cancer case discussion ESMO 2015 ecco.hybridwebcast.com/ecc2015/library ;

How to decide about the first-line therapy in mCRC?

TRIPLET• FOLFOXIRI*

DOUBLET• FOLFOX• FOFIRI• XELOX

+/- Biological th

MONOTHERAPY• Fluoropyrimidine

Reevaluation of diagnostics

The cost of medical diagnostics is less than 2% of the healthcare expenses inthe world, YET it influences more than60% of the critical treatment decisions.

American goverment bailout: 8,5 trillion $(Bloomberg News)

Cost?

At the cost of the Iraq war,all cancer patients inthe world could be treated fo 20 years!

Cost of Iraq war(yet): 710 billion $(cost of war website)

Annual cost of cancer drugs: 40 billion $ (IMS)

Role of immune system in tumorigenesis

Equilibrium EscapeElimination

• Effective antigeneproduction/presenting

• Sufficient effector cellactivation and function

Tumour cells

Normal cells

• The tumor escapes fromcontrol, cell lines areproliferating wich ar able todownregulate the immunesystem

Treg

• At first, immune system protects against tumors, but later it can help thetumor progresson

Vesely MD, et al. Ann Rev Immunol 2011;29:235–271

• Instability• Tumor heterogenity• Immun selection

Daganat felismerés „sleeping” tumor Daganat progresszió

CD8+

T cellCD4+

T cell NK cell

MHC

PD-L1

PD-1 PD-1

PD-1 PD-1

Nivolumab, PD-1 receptor inhibiting antibody

T cellreceptor

T cellreceptor

PD-L1PD-L2

PD-L2

MHC

CD28 B7

T-sejt

NFOther

PI3KDendritikus

sejtTumor sejt

IFN

IFNγR

Shp-2

Shp-2

Role of PD-1 pathway in inhibiton of antitumoralimmune system

Ribas A. N Engl J Med 2012;366(26):2517–2519

Thank You