In my clinical practice I use
FDG-PET for the following
•
•
•
•
•
1- Staging
2- Therapeutic monitoring
3- Staging and therapeutic monitoring
4- I do not use FDG-PET; no access
5- I do not use FDG-PET; not cost
effective
“PET scans to image pharmacodynamic
effects of vemurafenib”
Grant McArthur MB BS PhD
Peter MacCallum Cancer Centre
Melbourne, Australia
Disclosure Information
• I have the following financial
relationships to disclose
–Research support from: Pfizer,
Millennium & Novartis
Talk Outline
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•
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FDG-PET response as a clinical tool in oncogene
addiction – lessons from gastrointestinal stromal
tumors (GIST).
Responses on FDG-PET in patients treated with the
BRAF inhibitor vemurafenib. Clinical and biological
implications.
FDG-PET as an early marker of response in patients
with rare BRAF mutations.
Could inhibition of glucose metabolism be important
in response to BRAF inhibitors?
p210Bcr-Abl
CML
GIST
Oncogene Addiction
Mut EGFR
APML
FDG-PET to assess response- Re-Evaluating
the Conventional Treatment Paradigm
GIST Before Imatinib
24 hours after starting Imatinib
The Limitations of Structural Imaging
6 months after commencing imatinib
Monitoring response to imatinib in GIST
1.0
0.9
0.8
PET responders
n=13
0.7
0.6
Survival
0.5
p=0.001
0.4
0.3
PET non-responders
n=8
0.2
0.1
0.0
0
100 200 300 400 500 600 700
Time (Days)
Adapted from Stroobants et al, EJC, 2003
Talk Outline
•
•
•
•
FDG-PET response as a clinical tool in oncogene
addiction – lessons from gastrointestinal stromal
tumors (GIST).
Responses on FDG-PET in patients treated with the
BRAF inhibitor vemurafenib. Clinical and biological
implications.
FDG-PET as an early marker of response in patients
with rare BRAF mutations.
Could inhibition of glucose metabolism be important
in response to BRAF inhibitors
Vemurafenib: a novel, small molecule inhibitor
Selectivity for BRAFV600E in vitro and in vivo
Selective for BRAFV600E kinase
among 70 kinases screened
Selective in cellular assays
BRAF
IC50 (nM)
V600E
10–100
100–1000
1000–10000
WT
Phospho-ERK
IC50 (nM)
A375
COLO829
COLO205
20
10
30
SW620
SKMEL2
>40,000
14,000
Dose dependent regression of V600E tumors
Kinase domain binding
Bollag et al , Nature, 2010
Bollag et al , Nature, 2010
CT Response- Phase 1 PLX06/02
Study
Flaherty et al, NEJM,
NEJM. 2010
Progression-free survival
Progression-free survival (%)
(30 Dec 2010, final pre-planned analysis at IA)
100
Hazard Ratio 0.26
90
(95% CI; 0.20 - 0.33)
Log-rank P<0.0001
Vemurafenib (N=275)
80
70
Dacarbazine
(N=274)
60
50
40
30
Median 5.3 mos
Median 1.6 mos
20
10
0
0
1
2
3
4
5
274
275
213
268
7
8
9
3
4
0
3
10
11
12
Months
No. of patients in follow up
Dacarbazine
Vemurafenib
6
85
211
48
122
28
105
16
50
10
35
6
16
McArthur et al, ESMO, 2011
Heterogeneity of ERK phosphorylation
at progression
300
300
250
250
200
200
150
100
150
100
50
50
0
0
Baseline
•
pMEK1/2 cytoplasmic H-Score
H-Score
H-Score
pERK1/2 cytoplasmic H-Score
Day 15
PD
Baseline
Day 15
Recovery of ERK and MEK phosphorylation at disease
progression was observed in some but not all patients
McArthur ASCO, 2011
PD
Patterns of Progression
Baseline
Response
Progression
Design of Clinical Study
FDG-PET FDG-PET
Procedure
CT
Day
-21
1
Screening
15
CT
CT
29
57
Vemurafenib
FDG-PET Response
Baseline
Day 15
Kim, MD Anderson
FDG-PET Response
McArthur….Hicks, J Clin Oncol, 2012
Response Assessment
-quantitative analyses
PLX4032 ≥320mg Controls (n=4)
bid (n=27)
p
Mean±SD
Mean±SD
Drug Exposure day 15
µM.hr
1683±153
69±16
0.0007
Change Target Lesions
SUVmax (%)
80±17
8±19
<0.0001
Change Whole Body
Lesions % Injected
Dose(%)
84±15
1±41
<0.0001
Metabolic Disease Volume 816±423
ml (range)
(7-6945)
597±1012
(16-2113)
Response Assessment
-summary
PLX4032 ≥320mg bid Controls
(n=27)
(n=4)
Overall Assessment of
FDG-response (N, %)
Complete Metabolic
Response
3 (11%)
Partial
Metabolic
100% of patients
with
BRAF V600E41(89%)
melanoma
Response
achieved an FDG-PET response
No Response
0
1
0
3
2 (7%)
0
PR
21(78%)
0
SD
3 (11%)
0
Overall Assessment of
CR
response An
RECIST
(N, %) of precision
example
medicine
McArthur….Hicks, J Clin Oncol, 2012
Homogeneity of Molecular Response
A
B
McArthur….Hicks, J Clin Oncol, 2012
Conclusions
• FDG-PET is a useful marker of early biological
response to a vemurafenib with 100% of
patients achieving partial or complete metabolic
response.
• FDG-PET responses were obtained in patients
with high volumes of disease.
Conclusions
• Limited heterogeneity in FDG-PET response
was found between lesions in individual pts
suggesting minimal intrapatient molecular
heterogeneity.
• In this small patient cohort, very early FDG-PET
response does not appear to be correlated with
conventional clinical endpoints of PFS, Best
Overall Response by RECIST, time to PR, or
Duration of Response.
Talk Outline
•
•
•
•
FDG-PET response as a clinical tool in oncogene
addiction – lessons from gastrointestinal stromal
tumors (GIST).
Responses on FDG-PET in patients treated with the
BRAF inhibitor vemurafenib. Clinical and biological
implications.
FDG-PET as an early marker of response in patients
with rare BRAF mutations.
Could inhibition of glucose metabolism be important
in response to BRAF inhibitors?
BRAF K601E treated with the
MEK-inhibitor trametinib
A represents 1-2% of all BRAF mutations in melanoma
K601E
Day 0
B
Day 17
BRAF T599 ins I V601 treated with
the vemurafenib
A
Day 0
B
Day 18
BRAF L597R treated with the
vemurafenib
A
Day 0
B
Day 14
Talk Outline
•
•
•
•
FDG-PET response as a clinical tool in oncogene
addiction – lessons from gastrointestinal stromal
tumors (GIST).
Responses on FDG-PET in patients treated with the
BRAF inhibitor vemurafenib. Clinical and biological
implications.
FDG-PET as an early marker of response in patients
with rare BRAF mutations.
Could inhibition of glucose metabolism be important
in response to BRAF inhibitors?
Could inhibition of glucose
metabolism be a driver of response?
Baseline
Day 15
Kim, MD Anderson
Could inhibition of glucose
metabolism be a driver of response?
A
Day 0
B
Day 15
McArthur….Hicks, J Clin Oncol, 2012
Conclusions
•
•
Mechanistic preclinical studies and correlations with
reactivation of the MEK/ERK pathway suggest FDGPET is pharmacodynamic marker activity of MEK/ERK.
Inhibition of glycolytic metabolism with siRNAs
phenocopies the effects of vemurafenib on cell viability,
suggesting inhibition of glycolytic metabolism maybe
one component of the anti-tumor activity of BRAF
inhibitors
Acknowledgements
Tiffany Parmenter
PET-imaging
Keith Flaherty
Rod Hicks
colleagues
Antoni Ribas
Jason Callahan Study Coordinators Paul Chapman
Fergal Kelleher
Patients & their
Keith Nolop
Alex Dobrovic
families
Jeff Sosman
Cliff Meldrum
Kevin Kim
Igor Puzanov
Joe Grippo
Richard Lee
Gideon Bollag