02 - Dummer Melanoma Resistence - Klinik für Radio

Mechanismen intrinsischer und extrinsischer Resistenzentwicklung
gegen zielgerichtete Therapie – ist die
Oligo-progression ein potentielles Target für eine lokale Therapie?
Reinhard Dummer, Ralph Braun, Simone Goldinger, Lars
100 Jahre
French, Joanna
Mangana, Mitch Levesque et al.
DERMATOLOGIE
Department of Dermatology, Zürich, Switzerland
Melanocyte-
Melanoma
Functional unit of
Mutations
Amplifications
Translocations
K
Deletions
melanocyte/keratinocytes
M
ASCO 2012
2013
Results of NEMO: A Phase 3 Trial of
Binimetinib (BINI) vs Dacarbazine (DTIC) in
NRAS-Mutant Cutaneous Melanoma
Reinhard Dummer, Dirk Schadendorf, Paolo A. Ascierto,
Ana Arance, Caroline Dutriaux, Michele Maio, Piotr Rutkowski,
Michele Del Vecchio, Ralf Gutzmer, Mario Mandala, Luc Thomas, Ernesto
Wasserman, James Ford, Marine Weill, Andres Sirulnik, Valentine Jehl,
Viviana Bozόn, Georgina V. Long, Keith Flaherty
Progression-Free Survival by Prior Immunotherapy Stratum
Stratum: Prior immunotherapy
Kaplan-Meier medians, mo
Binimetinib: 5.5 (95% CI, 2.8–7.6)
Dacarbazine: 1.6 (95% CI, 1.5–2.8)
80
Censoring times
Binimetinib (n/N=32/57)
Dacarbazine (n/N=20/28)
60
40
20
0
1.5
3.0
4.5
6.0
7.5
9.0
10.5 12.0 13.5 15.0 16.5 18.0
Time (mo)
Number still at risk
Censoring times
Binimetinib (n/N=147/212)
Dacarbazine (n/N=68/105)
60
40
20
0.0
1.5
3.0
4.5
6.0
7.5
1.5
3.0
4.5
6.0
7.5
9.0
10.5
12.0
13.5
15.0
57
36
24
16
11
11
6
4
4
3
2
1
28
12
6
5
3
2
1
0
0
0
0
0
16.5 18.0
9.0
10.5 12.0 13.5 15.0 16.5 18.0
Time (mo)
Number still at risk
Months 0.0
DTIC
80
0
0.0
BINI
Kaplan-Meier medians, mo
Binimetinib: 2.8 (95% CI, 2.7–2.9)
Dacarbazine: 1.5 (95% CI, 1.5–1.7)
100
Progression-Free Survival (%)
100
Progression-Free Survival (%)
Stratum: No prior immunotherapy
0.0
1.5
3.0
4.5
6.0
7.5
9.0
10.5
12.0
13.5
0
212
139
66
40
19
14
9
7
5
4
2
0
0
0
105
44
21
16
6
6
5
3
0
0
0
0
0
BINI=binimetinib; DTIC=dacarbazine
Presented by: Reinhard Dummer
15.0 16.5
18.0
Differential impact on mutated vs Normal cells
BRAFV600
mutant melanoma
Wild type
normal cell
RAS
BRAFi
BRAFi
Paradoxical
MAPK
activation
BRAFV600
CRAF
BRAF
MEK1/2
MEK1/2
P
P
ERK
ERK
P
P
CCND1
CDK4/6
CCND1
CDK4/6
RASopathic skin
eruptions1
Rinderknecht JD, et al. PLoS ONE 2013
Resistance during kinase inhibition
2012
Intrinsic resistance:
transcriptional adaptations
Phenotype switch / induction of stemness/slow
cycling tumor cells
Acquired resistance:
mutations, amplifications, alternative splicing etc
Selection for mutated clones
2012
ras
Braf splice variants
Braf amplifications
COT
MET
plasma
membrane
PDGF R
RTK
Growth factor
Shc
Grb-2
SOS
raf
mek1/2
PI3k
raf
raf
dimers
dimers
PTEN
AKT
mTor
erk1/2
nuclear
membrane
erk1/2
DNA
Coexisting Baseline RAS Mutations
Were Not Associated With Worse PFS
Grant A. McArthur et al. ECCO 2015
12
PercentageProgressionFree
Addition of Cobimetinib to Vemurafenib
Overcomes the Negative Impact of PTEN
Loss on PFS
VemPTEN+(N=82)
VemPTEN loss(N=32)
Vem+cobiPTEN+(N=92)
Vem+cobiPTEN loss(N=32)
100
80
60
40
20
0.0
0
PTEN+:Hscore≥50
PTEN loss:Hscore<50
200
400
Days
600
800
HR0.36(CI0.19-0.65)
ForPTENlossVem+Cobivs.Vem
Grant A. McArthur et al. ECCO 2015 13
BRAF/MEK inhibitor combination therapy
Results of clinical studies
BRAFimonotherapy
Dabrafenib
RAS
Dabrafenib+trametinib
PFSHR0.37vs DTIC1
Vemurafenib
PFSHR0.38vs DTIC2
HyperproliferativeskinAEs
(cuSCC/KA)1,2
MEKimonotherapy
Trametinib
PFSHR0.45vs
chemotherapy3
BRAFi+MEKi
combinationtherapy
mutBRAF
BRAF
MEK
PFSHR0.67vs dabrafenib4
OSHR0.71vs dabrafenib4
PFSHR0.56vs vemurafenib5
OSHR0.69vs vemurafenib5
Vemurafenib+cobimetinib
PFSHR0.51vs vemurafenib6
OS HR 0.70 vs vemurafenib
pERK
Encorafenib+binimetinib
PFSHR0.54vs vemurafenib7
Proliferation
Survival
Invasion
Metastasis
FewerhyperproliferativeskinAEs
withBRAFi+MEKivs BRAFi4–6
1. Hauschild A, et al. Poster presented at ASCO 2013; Abstract
9013;
2. McArthur GA, et al. Lancet Oncol 2014;15:323–32;
3. Flaherty KT, et al. N Engl J Med 2012;367:107–14;
AE=adverse event; BRAFi=BRAF inhibitor; cuSCC=cutaneous squamous cell
4. Long GV, et al. Lancet 2015;386:444–51;
5. Robert C, et al. N Engl J Med 2015;372:30–9;
carcinoma; DTIC=dacarbazine; HR=hazard ratio; KA=keratoacanthoma;
6. Larkin J, et al. N Engl J Med 2014;371:1867–76.
MEKi=MEK inhibitor;
mut=mutant; OS=overall survival; PFS=progression-free survival.
2.7. Dummer et al. SMR 2016
1
5
Genetic models of tumor progression
(Navin and Hicks molecular oncology 2010)
Sample acquisition
•Primary tumor areas
•Autopsy program
• DNA isolation from FFPE tissue
Daniel Widmer, Mitch Levesque
Sample sets from three patients
Daniel Widmer, Mitch Levesque
Michael Krauthammer
Bioinformaticspipeline
Daniel Widmer, Mitch Levesque
Michael Krauthammer
Results from whole-exome sequencing
• Somatic mutations in
– driver oncogenes
• BRAF, NRAS, KIT
– tumor suppressor genes
• CDKN2a, PTEN, P53
• Inherited mutations in oncogenes
• MITF
• Presence of known and new candidate
mutations that cause treatment resistance
Daniel Widmer, Mitch Levesque
Single Nucleotide Variations (Patient-E)
Daniel Widmer, Mitch Levesque
Michael Krauthammer
Phylogenetic analyses
Rob Desalle PhD
Curator of Entomology at the American Museum of Natural History
Genetic models of tumor progression
(Navin and Hicks molecular oncology 2010)
RTK*
ETR
Salirasib
GNAQ/11*
GNAQ/11mutation:
~50%ocularmels
CDK
EWS-ATF1
MITF
MITFamp:
~30-40%
mels
PI3-K
NRAS*
NRAS
mutation:
~20%ofcut
mels
BRAFmutation:
50-60%ofcutmels
PTENmutation:
~10%mels
Vemurafenib
Dabrafenib
Encorafenib
AKT*
BRAF*
PTEN*
AKT3
activation/amp:
~60%mels
Trametinib
Binimetinib
Selumetinib
Nucleus
EWS-ATF1
transl:
clearcell
sarcoma
NF-1
KITmutation/amp:
~40%acral,muc
mels
Imatinib
Sunitinib
Nilotinib
MEK1/2
Survivalvs.
apoptosis
TFs
ERK1/2
1st biopsy
LOGIC II: A Phase II rational combination study
Primary endpoint: ORR
BRAFV600 melanoma
LGX818 + MEK
BRAFV600 melanoma
LGX818 + MEK
Relapse/
PD
Biopsy
•
•
2nd biopsy
Biopsy
Define mechanism of resistance at relapse
Analyze select panel of genes within ≤15 days
+
PI3Ki
BKM120
+
FGFRi
BGJ398
+
cMeti
INC280
+
CDK4i
LEE001
Next generation sequencing in the Zürich skin cancer
center
Biopsie bei Progression
Therapieentscheid ?
B
Biobank
Diskussion
der
Therapieoptionen
im molekularen
Tumorboard
In vitro Test von Therapeutika
Tumor Biopsie und
DNA Extraktion
Whole exome
Sequenzierung
(WES)
und MelArray
Bioinformatische
Analyse der
Sequenzdaten
Assoziation von
genetischen
Varianten mit
Therapieoptionen
Zusammenfassung
im molekularen
Bericht
Patient, male 63 y
• March 2015: metastatic Melanoma
(lung,liver, bones)
• pTx
• LDH 1100U/ml
• BRAF Mutation pV600_K601delinsEl
• April 2015: Triple-Kinaseinhibition
using LGX, MEK und LEE)
MAPK kinase pathways: a triple hit
BRAFV600
mutant melanoma
BRAFi encorafenib
BRAFV600
MEKi binimetinib
MEK1/2
P
ERK
P
CCND1
CDK4/6
CDK4/6i ribociclib
63y male Patient, Triple-Therapy
• 12/2015: PR- then PD of a Lung met (Lingula)
• Removed by surgery
• -> Wedge-Resektion Januar 2016 für Whole exome
Sequenzierung
63y male Patient, Triple-Therapy
PET-CT
22.2.16
• Triple continues
• Irradiation BWK 7 with 5x7gy March
2016
• 03/2016: ongoing PR
• PD 6/2016
63y male Patient, Whole exome sequencing
63y Patient, Whole exome results
Ipilimumab / Nivolumab
PDL1 0% in the lung met
63y male Patient, Whole exome results
63y Patient, Whole exome results
PTEN Verlust: PI3K/mTOR Inhibitoren
• Re staging after Ipi + Nivo: deep PR!
Education and trials
Biobanks – focus on primary tumors
Bioinformatics
Empowerment of patients
doctors and university hospitals
Team
Clinic
SimoneGoldinger
JoannaMangana
Research&Biobanking
MitchLevesque
AnjaIrmisch
AliceLanger
DanielHug
MirkaSchmidt
TabeaKoch
AgatheDuda
NexusPersonalized Health Technologies(ETH)
FranziskaSinger
NoraToussaint
DanielStekhoven