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
MS/2013 Målrettet behandling - Vejle 2
MS/2013 Målrettet behandling - Vejle 3
Nøgle i lås – Glivec (Imatinib)
MS/2013 Målrettet behandling - Vejle 4
MS/2013 Målrettet behandling - Vejle 5
MS/2013 Målrettet behandling - Vejle 6
GIST - konstitutiv aktiv c-KIT receptor
Imatinib hæmmer c-KIT
MS/2013 Målrettet behandling - Vejle 7
-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)
MS/2013 Målrettet behandling - Vejle 8
MS/2013 Målrettet behandling - Vejle 9
Er målrettet behandling nyt ?
Målrettet behanding før Glivec ?
MS/2013 Målrettet behandling - Vejle 10
Ja - tamoxifen
MS/2013 Målrettet behandling - Vejle 11
~5 years Tamoxifen vs not
RECURRENCE
ER-poor disease ER+ disease
ER+ disease
Peto SABCS 2007
MS/2013 Målrettet behandling - Vejle 12
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 ?
MS/2013 Målrettet behandling - Vejle 13
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 14
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
MS/2013 Målrettet behandling - Vejle 16
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
MS/2013 Målrettet behandling - Vejle 17
Benefit of epirubicin in mBC related to TOP2A status –
targeted therapy ?
MS/2013 Målrettet behandling - Vejle 18
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
MS/2013 Målrettet behandling - Vejle 20
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
MS/2013 Målrettet behandling - Vejle 21
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)
MS/2013 Målrettet behandling - Vejle 30
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
MS/2013 Målrettet behandling - Vejle 31
MS/2013 Målrettet behandling - Vejle 32
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
MS/2013 Målrettet behandling - Vejle 33
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
MS/2013 Målrettet behandling - Vejle 34
MS/2013 Målrettet behandling - Vejle 35
Herceptin adjuvant trials:
HER2 pos. breast
MS/2013 Målrettet behandling - Vejle 36
MS/2013 Målrettet behandling - Vejle 37
First line HER 2 mBC
Trastuzumab+docetaxel+pertuzumab vs.
Trastuzumab+docetaxel+placebo
UL/2012 Mab og TKI
UL/2012 Mab og TKI
On Target
MS/2013 Målrettet behandling - Vejle 41
Off Target
. .
. . . .
. . . .
. . . .
. .
MS/2013 Målrettet behandling - Vejle 42
~5 years Tamoxifen vs not
RECURRENCE
ER-poor disease ER+ disease
ER+ disease
Peto SABCS 2007
MS/2013 Målrettet behandling - Vejle 43
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
MS/2013 Målrettet behandling - Vejle 44
MS/2013 Målrettet behandling - Vejle 45
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
MS/2013 Målrettet behandling - Vejle 46
Survival – ISEL EGRF pos og negativ
EGRF pos
EGRF neg
Iressa
Iressa
Placebo
Placebo
MS/2013 Målrettet behandling - Vejle 47
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
MS/2013 Målrettet behandling - Vejle 49
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
MS/2013 Målrettet behandling - Vejle 50
MS/2013 Målrettet behandling - Vejle 51
MS/2013 Målrettet behandling - Vejle 52
MS/2013 Målrettet behandling - Vejle 53
MS/2013 Målrettet behandling - Vejle 54
NSCLC - EGFR mut (exon 19 deletion + L858R in exon 21)
Erlotinib vs Chemotherapy
MS/2013 Målrettet behandling - Vejle 55
On target – off target
• Ingen target – ingen effekt
• Target skal være tilstede – EGRF
• Target skal være følsomt - muteret
MS/2013 Målrettet behandling - Vejle 56
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
MS/2013 Målrettet behandling - Vejle 57
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
MS/2013 Målrettet behandling - Vejle 58
Vismodegib – inhibitor of hedge hog signaling in basal cell
carcinoma – Gorlin Syndrome
MS/2013 Målrettet behandling - Vejle 59
Vismodegib – inhibitor of hedge hog signaling in basal cell
carcinoma – Gorlin Syndrome
MS/2013 Målrettet behandling - Vejle 60
Vismodegib – inhibitor of hedge hog signaling in basal cell
carcinoma – Gorlin Syndrome
Epidermal growth factor receptor (EGFR) signal transduction via K-ras
MS/2013 Målrettet behandling - Vejle 61
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
MS/2013 Målrettet behandling - Vejle 62
Mutant K-ras
Wild-type K-ras
MS/2013 Målrettet behandling - Vejle 63
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)
MS/2013 Målrettet behandling - Vejle 64
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.
MS/2013 Målrettet behandling - Vejle 66
MS/2013 Målrettet behandling - Vejle 67
UL/2012 Mab og TKI
MS/2013 Målrettet behandling - Vejle 69
UL/2012 Mab og TKI
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
UL/2012 Mab og TKI
UL/2012 Mab og TKI
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
MS/2013 Målrettet behandling - Vejle 85
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
MS/2013 Målrettet behandling - Vejle 86
MS/2013 Målrettet behandling - Vejle 87
MS/2013 Målrettet behandling - Vejle 88
MS/2013 Målrettet behandling - Vejle 89
Waterfall plot - MoA against PD-1 in melanoma
MS/2013 Målrettet behandling - Vejle 90
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
MS/2013 Målrettet behandling - Vejle 93
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)
MS/2013 Målrettet behandling - Vejle 98
Tak for opmærksomheden
MS/2013 Målrettet behandling - Vejle 99
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
MS/2013 Målrettet behandling - Vejle 100
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
MS/2013 Målrettet behandling - Vejle 101
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
MS/2013 Målrettet behandling - Vejle 102