Molekylært målrettet medicinsk kræftbehandling for ... · reached a plateau in some cancer types *p = not significant vs paclitaxel/cisplatin al Months Paclitaxel/cisplatin 7.8

Molekylært målrettet medicinsk

kræftbehandling for klinikere

Behandlingsprincipper og medicamina SKA kursus i Vejle, oktober, 2013

Morten Mau-Sørensen

Fase I Enhed, Onkologisk Klinik, Rigshospitalet

MS/2013 Målrettet behandling - Vejle 1

Outcomes with chemotherapy may have

reached a plateau in some cancer types

*p = not significant vs paclitaxel/cisplatin

% s

urv

ival

Months

Paclitaxel/cisplatin 7.8

Gemcitabine/cisplatin 8.1*

Docetaxel/cisplatin 7.4*

Paclitaxel/carboplatin 8.1*

Median Survival (mo)

100

80

60

40

20

0

0 5 10 15 20 25 30

Schiller, et al. N Engl J Med 2002;346:92.

Non-small cell lung cancer



Nøgle i lås – Glivec (Imatinib)




GIST - konstitutiv aktiv c-KIT receptor

Imatinib hæmmer c-KIT


-Sjælden mesencymal GI tumor

- 4 tilfælde per mill

- Ventrikel (70%) Tyndtarm (25 %)

- 2001: Kirurgi eneste behandlingstilbud

Ingen effekt af kemo- og radioterapi ved inop eller metastatisk sygdom

Mutation i konstitutivt aktiv c-Kit receptor

GastroInstestinal Stromal Tumor (GIST)



Er målrettet behandling nyt ?

Målrettet behanding før Glivec ?


Ja - tamoxifen


~5 years Tamoxifen vs not

RECURRENCE

ER-poor disease ER+ disease

ER+ disease

Peto SABCS 2007


Hvad er målrettet behandling

•Irinotecan rettet mod topoisomerase I ?

•Etoposid rettet mod topoisomerase II ?

•Epirubicin rettet mod topoisomerase II ?

•5-FU rettet mod thymidylat Syntase ?

•Bevacizumab mod VEGF A ?

•Sorafenib ?


Definition på målrettet

behandling •Target udelukkende/fortrinsvis til stede i

tumor væv

•Target udelukkende tilstede i en given

patient tumor

•Behandlingen retter sig specifikt mod

target

•Behandlingen er kun virksom hvis target er

til stede


MS/2013 Målrettet behandling - Vejle 15 MS/2013 15

What is targeted therapy •Target – a defined process in cancer growth

and/or development i.e hallmarks of cancer

•Target – measurable or identiable in tumors in

patients

•Outcome of targeted therapy is correlated to the

presence or absence of target

Sledge, JCO editorial, p1614, 2013


Hvad er målrettet behandling

•Irinotecan rettet mod topoisomerase I: nej

•Etoposid rettet mod topoisomerase II: nej

•Epirubicin rettet mod topoisomerase II: hmm, jae

•5-FU rettet mod thymidylat Syntase: måske

•Bevacizumab mod VEGF A: nej

•Sorafenib: nej


Benefit of epirubicin in mBC related to TOP2A status –

targeted therapy ?


MS/2013 Målrettet behandling - Vejle

6 karakteristika ved kræftcellen

• Manglende vækstkontrol

• Ikke følsomhed for væksthæmning

• Mangler apoptose (programmeret

celledød)

• Uendeligt delingspotentiale

• Angiogenese (dannelse af blodkar)

• Proteolyse (invasion, metastasering)

Hanahan and Weinberg Cell 2000 19


Flere vigtige karakteristika

UL/2012 Mab og TKI Hanahan and Weinberg Cell 2011

Signal transduction by tyrosin kinases

Signal

transduction

to nucleus

Nucleus

Binding site

Tyrosine

kinase activity

Cytoplasm

Plasma

membrane

Growth factor

Gene activation CELL

DIVISION


UL/2012 Mab og TKI

ErbB Family of Tyrosine

Kinase Receptors

• Family of evolutionarily

conserved type I receptor

tyrosine kinases

• Four members:

– ErbB-1

(EGFR/HER1)

– ErbB-2 (HER2)

– ErbB-3 (HER3)

– ErbB-4 (HER4)

Extracellular Domain

(Binds Ligand)

TM

Domain

Cytoplasmic Domain

(Kinase Activity)

Mab og TKI

Overexpression of ErbB-1 and

ErbB-2 in Solid Tumors Tumor Type

Overexpressing ErbB-1

(%)

Overexpressing ErbB-2

(%)

Bladder 31%-48% 7%-36%

Breast 14%-91% 10%-37%

Colorectal 25%-77% 7%

Esophageal 71% 13%-73%

Glioma 40%-50% –

NSCLC 40%-80% 3%-56%

Ovary 30%-75% 20%-32%

Pancreatic 30%-50% –

Renal 50%-90% 24%-40%

Head and Neck 30%-75% 32%-62%

Stomach – 5%-55%

Rowinsky. Horiz Cancer Ther 2001; 2:3-35; Itakura et al. Cancer 1994; 74:795-804

ErbB-1 • Also known as epidermal growth

factor receptor (EGFR)

• First family member identified

• Involved in normal cell growth and differentiation

• Disturbances in ErbB-1 signaling can lead to cell transformation

• Ligands specific for ErbB-1 include EGF, transforming growth factor (TGF)-α, and amphiregulin

ErbB-2 • Also known as HER2/neu

• No known ligands

• Activation thought to occur through heterodimerization with other ErbB family members

• ErbB-2 is the preferred heterodimerization partner with other family members

• Most resistant to intracellular degradation, slower to inactivate compared to other family members

• ErbB-2 overexpression in tumors correlates with poor prognosis and decreased survival times

UL/2012 Mab og TKI

ErbB-3 • Lacks intrinsic tyrosine kinase activity

• Often found in heterodimers with ErbB-2

• Cytoplasmic domain contains 6 sites where the p85 subunit of PI3 kinase can bind

• Heterodimers containing ErbB-3 (especially ErbB-2/ErbB-3) are thought to be particularly strong activators of the PI3K/Akt pathway that is associated with cell survival and resistance to cancer therapy

PI3K Binding Site

PI3K

Cell survival

Akt

UL/2012 Mab og TKI

ErbB-4

• Important in cardiac and brain development

• Expression might correlate with presence of hormone receptors in breast tumors, more favorable prognosis

• Multiple splice variants, some of which contain binding sites for PI3K

• Slow internalization

• Ligands include neuregulins, betacellulin, epiregulin, and heparin-binding (HB) EGF

UL/2012 Mab og TKI

Homodimers and Heterodimers

• Ligand binding causes ErbB receptors to associate in pairs in a process called dimerization.

• Dimerization and autophosphorylation must occur for downstream signal transmission.

• Pairs can be formed between 2 identical receptors (homodimers) or between 2 different family members (heterodimers).

• ErbB-2 is the preferred dimerization partner with other ErbB receptors.

1+1 2+2 1+2 2+3 2+4

UL/2012 Mab og TKI

Strategies to Inhibit ErbB • MoAbs to block

ligand binding or receptor dimerization

• Small-molecule kinase inhibitors

• Competitive receptor antagonists

• Ligand-toxin or Ab-toxin conjugates

• Antisense oligonucleotides

• Vaccines

Antagonist MoAb Kinase

Inhibitor

Ligand-

toxin

Nib og Mab

• nib’er (tyrosinkinase inhibitorer)

• mab’er (monoklonale anti-bodies)


Monoklonale antistoffer - Mab

• Kimerisk antistof – en af to kæder stammer fra en anden art (ex mus), resten humant.

- Højt allergent potentiale

- ”xi” foran ”mab” - ex. Cetuximab (Erbitux), Rituximab (MabThera)

• Humaniseret antistof – begge kæder er humane. Mindre bindende del er artsfremmed eller syntetisk

Lavt allergent potentiale

- ”zu” foran ”mab” - ex. Trastuzumab, Bevacizumab

• Humant antistof – rent humant

-Minimalt allergent potential

- ”u” foran ”mab”

- ex. Panitumumab, Zalutumumab



Targeted agents at NCI’s website januar 2011

• 44 nib’er (tyrosinkinase inhibitorer)

• 109 mab’er (monoklonale anti-bodies)

• 6 imus’er (immun-suppression)

Targeted agents at NCI’s website januar 2012

• 60 nib’er (tyrosinkinase inhibitorer)

• 146 mab’er (monoklonale anti-bodies)

• 7 imus’er (immun-suppression)

Herceptin® (trastuzumab):

humanised anti-HER2 monoclonal antibody

• Targets HER2 oncoprotein

• High affinity (Kd=0.1nM) and specificity

• 95% human, 5% murine

– decreased potential for immunogenicity

– increased potential for recruiting immune-effector mechanisms


Trastuzumab plus paclitaxel:

39% increase in survival (IHC 3+)

Smith IE. Anticancer Drugs 2001;12:S3–10

1.0

0.8

0.6

0.4

0.2

0

Time (months)

0 5 10 15 20 25 30 35 40 45 50

17.9 24.8

Pro

bab

ilit

y o

f su

rviv

al

39%

trastuzumab + paclitaxel

Paclitaxel



Herceptin adjuvant trials:

HER2 pos. breast



First line HER 2 mBC

Trastuzumab+docetaxel+pertuzumab vs.

Trastuzumab+docetaxel+placebo

UL/2012 Mab og TKI

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On Target


http://images.google.dk/imgres?imgurl=http://www.dinmarketingafdeling.dk/Skydeskive2.jpg&imgrefurl=http://www.dinmarketingafdeling.dk/taenker.htm&h=100&w=100&sz=4&hl=da&start=8&um=1&usg=__j7PRDqWVOeSukIMTrGQCQKS_mIk=&tbnid=Zcj_17iomIu7PM:&tbnh=82&tbnw=82&prev=/images%3Fq%3Dskydeskive%26ndsp%3D18%26um%3D1%26hl%3Dda%26sa%3DN

Off Target

. .

. . . .

. . . .

. . . .

. .


http://images.google.dk/imgres?imgurl=http://www.dinmarketingafdeling.dk/Skydeskive1.jpg&imgrefurl=http://www.dinmarketingafdeling.dk/taenker.htm&h=100&w=100&sz=4&hl=da&start=14&um=1&usg=__LO1Iaa4Ly5S18GnUxD5r6U-qM4Y=&tbnid=4EcqQNYZkiyPMM:&tbnh=82&tbnw=82&prev=/images%3Fq%3Dskydeskive%26ndsp%3D18%26um%3D1%26hl%3Dda%26sa%3DN

~5 years Tamoxifen vs not

RECURRENCE

ER-poor disease ER+ disease

ER+ disease

Peto SABCS 2007


Randomization

IRESSA® (250 mg) + BSC

Placebo + BSC

Primary

endpoint:

SURVIVAL

2:1 ratio

ISEL 2nd an 3rd treatment of NSCLC

Randomization

Tarceva® (150 mg) + BSC

Placebo + BSC

Primary

endpoint:

SURVIVAL

2:1 ratio

BR21 2nd an 3rd treatment of NSCLC



0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Month: 0 2 4 6 8 10 12 14

At risk: 1692 1348 876 484 252 103 31

Pati

en

ts s

urv

ivin

g (

%)

IRESSA Placebo

Median (mo) 5.6 5.1

1 yr survival 27% 22%

HR = 0.89 (0.78, 1.03), P = .11

N = 1692, deaths = 969

Cox analysis, P = .042

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

—— IRESSA®

------ Placebo

Survival - ISEL


Survival – ISEL EGRF pos og negativ

EGRF pos

EGRF neg

Iressa

Iressa

Placebo

Placebo


HER1/EGFR TK mutations and

response to gefitinib in patients

with NSCLC

• 275 patients with advanced chemorefractory NSCLC received gefitinib at

Massachusetts General Hospital (clinical trial, compassionate use, or on-

label)

– 25 patients responded

• All exons were sequenced in nine of the 25 responders

– eight had TK mutations

• DNA from seven non-responders were sequenced – no mutations

• In 25 patients not treated with gefitinib (15 BAC), two patients had TK

mutations (both BAC)

Lynch TJ, et al. N Engl J Med 2004;350:2129–39


EGFR mutations and response to

EGFR-TKI in advanced NSCLC

• Mutation frequency approximately 12% in Caucasians

• More frequent in never-smokers, women, adenocarcinoma, BAC and Asians

• Rare or absent in other tumor types

• Presence of a mutation predicts response to small molecules EGFR inhibitors






NSCLC - EGFR mut (exon 19 deletion + L858R in exon 21)

Erlotinib vs Chemotherapy


On target – off target

• Ingen target – ingen effekt

• Target skal være tilstede – EGRF

• Target skal være følsomt - muteret


Survival

Normal cell

Repair by

Homologous

Recombination

No effective repair

(No HRR pathway)

Cell death

Cancer cell with HRD

Tumour-specific

killing by single agent

olaparib

(Synthetic Lethality)

10,000’s DNA SSBs occur

each day in cells

During replication unrepaired

SSBs bound by PARP result in

fork collapse and DNA DSBs

Replicating

cells

olaparib

Combination with DNA

damaging therapies

(chemotherapy and IR)

Mechanism of action: synthetic lethality in

DNA repair defective backgrounds

Olaparib traps PARP on the DNA

single strand break preventing

repair and effectively generating a

protein-DNA adduct

PARP


Study 19: PFS by BRCA mutation

status

0

Time from randomization (months)

0

1.0

Pro

po

rtio

n o

f p

ati

ents

pro

gre

ssio

n-

free

3 6 9 12 15

Olaparib BRCAm

Olaparib BRCAwt

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

BRCA mutated (n=136) BRCA wildtype (n=118)

Olaparib Placebo Olaparib Placebo

Events: total pts (%) 26:74 (35.1) 46:62 (74.2) 32:57 (56.1) 44:61 (72.1)

Median PFS, months 11.2 4.3 5.6 5.5

HR=0.18

95% CI (0.11, 0.31);

P<0.00001

HR=0.53

95% CI (0.33, 0.84);

P=0.007

Placebo BRCAm

Placebo BRCAwt

Number at risk

Olaparib BRCAm

Olaparib BRCAwt

Placebo BRCAm

Placebo BRCAwt

74 59 33 14 4 0

57 44 17 9 2 0

62 35 13 2 0 0

61 35 10 4 1 0

Ledermann J et al. ASCO 2013

• Statistically significant treatment benefit in patients with and without a BRCA

mutation


Vismodegib – inhibitor of hedge hog signaling in basal cell

carcinoma – Gorlin Syndrome







Epidermal growth factor receptor (EGFR) signal transduction via K-ras


Panitumumab

Wild-type K-ras Panitumumab

Mutant K-ras

Best supportiv care

Mutant K-ras Best supportiv care

Wild-type K-ras

Waterfall plots in wild-type and mutant K-ras

Randomised to Panitumumab or Best Supportiv Care


Mutant K-ras

Wild-type K-ras


On target – off target

• Selv om target er tilstede - Ingen effekt

• Det hjælper ikke at blokkere højt (EGRF) i strømmen af

vækst signaler hvis uhæmmet vækst signaler opstår distalt

herfor (K-ras)


UL/2012 Mab og TKI

ALK-inhibitorer Anaplastic lymphoma kinase (ALK) inhibitor

• Abnorm expression of ALK drives certain types of non-small cell lung cancer (NSCLC), neuroblastomas, and anaplastic largecell lymphoma.

• ALK is not expressed in normal tissue, representing a promising molecular target for cancer therapy.

• 31 heavily pre-treated patients with NSCLC with ALK re-arrangement studied

• Among these 20 had regression, (1 CR; durable reponse - median 24 weeks) .

• The fusion gene was first described in NSCLC in 2007, and clinical activty was reported for the first time in 2009.



UL/2012 Mab og TKI


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70

BRAF V600E Mutation

• Oncogenic mutation of BRAF

~8-15% of all solid tumors

~50% of malignant melanomas

• shRNA knock down experiments support its role in neoplastic behavior

• BRAF mutation knock-in mice develop melanoma-like malignancies

• RG7204 arrests abnormal cell growth in melanoma models

B-Raf ~ 50%

Melanoma

UL/2012 Mab og TKI

UL/2012 Mab og TKI

The Target: BRaf Kinase An important mediator of cellular proliferation

RG7204 co-Structure with kinase

domain of B-RAFV600E

(Bollag et al., Nature 2010) Cellular

Proliferation

RTK

Raf

RG7204 ATP

ATP

ERK

MEK

BRAFV600E

RAS

UL/2012 Mab og TKI

73

-100

-75

-50

-25

0

25

50

75

100

%C

ha

ng

e F

rom

Ba

se

lin

e

(Su

m o

f L

es

ion

Siz

e)

Phase I Trial:

• Tumor responses

occurred in majority

(81%) of patients in

V600E+ melanoma

extension cohort

(960 mg BID)

• Investigator assessments

• Includes confirmed & unconfirmed responses

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75

Tumor Regression (Target Lesions)

Occurred in Majority of Patients (IRC)

*** 7 patients had 100% tumor shrinkage, 3 of which had confirmed CR;

1 patient had unconfirmed CR and 3 patients had non-target lesions present

• 122 patients had baseline and ≥ 1post-baseline scan with measurable disease

RECIST 30% Decrease

***

UL/2012 Mab og TKI

BRIM 3

UL/2012 Mab og TKI

BRIM 3

78

Potential Mechanisms of Drug

Resistance

After Lo, et al. Nature, in press.

BRAF mut malign melanom

MEK hæmmer vs chemotherapy

UL/2012 Mab og TKI

80

Characteristics of KA subtype

• Raised button-like, central crater

• Well-differentiated neoplasm with low probability of invasion/metastasis

• Can grow rapidly; may involute and regress

• Typically treated by excision

• Observed with other agents (e.g., sorafenib)

KA in the Phase I RG7204 Trial

• Occurred on sun-exposed skin

• Did not result in treatment discontinuation

Cutaneous SCC – Keratoacanthoma (KA) Subtype

76 yr old pt with st IV BRAF V600K mut MM

treated with vemurafenib


Why is vemurafenib less active in BRAF V600K mut Colon Cancer

• In colon cancer ERK inhibits EGFR/RAS via negative feed back

• Vemurafenib distrubts negative feed back resulting in increased RAS signaling





Waterfall plot - MoA against PD-1 in melanoma


Anti-tumor activity of anti PD-L1 MoA in melanoma and NSCLC

Goal Select the right patients

for the right treatment

at the right time

and in the right sequence

Solution: Biomarkers

Caveats: Small numbers

Subpopulations

Loss of statistical power MS/2013 Målrettet behandling - Vejle 91

UL/2012 Mab og TKI

Modern drug development:

Biomarker driven early clinical trials


Marker x Treatment Interaction

Design Marker Strategy Design

UL/2012 Mab og TKI

New track for clinical trials

UL/2012 Mab og TKI

UL/2012 Mab og TKI

Genetic Intratumor Heterogeneity and Phylogeny in Patient 1.

Gerlinger M et al. N Engl J Med 2012;366:883-892

Causes of failure (or relative ineffectiveness)

• Biological redundancy, either by escape through

alternative pathways or input to downstream

convergence sites (EGRF og K-ras)

• Lack of biological information or tools to identify

patients who will benefit (Tarceva og Iressa i

NSCLC)


Tak for opmærksomheden


Indicators of increased HER2 production

1 = gene copy number

2 = mRNA transcription

3 = cell surface receptor protein expression

4 = release of receptor extracellular domain

Normal Amplification/Overexpression

Cytoplasm

HER2 receptor

protein

Cytoplasmic

membrane

Nucleus

HER2 DNA

HER2

mRNA

1

2

3

4


IHC Images courtesy of MJ Kornstein, MD, Medical College of Virginia

Abnormal 2+ Abnormal 3+ Normal 0

Normal

Normal 1+

Normal Abnormal low

amplification

Abnormal high

amplification

Positive or negative HER2 status


Randomised evidence of effect of trastuzumab in 1. line

HER2+ ABC

• AC or paclitaxel +/- trastuzumab (1)

• Paclitaxel +/- trastuzumab (2)

• Docetaxel +/- trastuzumab (3)

(1) Slamon N Engl J Med 2001;345:783

(2) Gasparini Breast Cancer Res Treatment 2007;101:355

(3) Marty JCO 2005;23:4265


Documents

Molekylært målrettet medicinsk kræftbehandling for ... · reached a plateau in some cancer types *p = not significant vs paclitaxel/cisplatin al Months Paclitaxel/cisplatin 7.8