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 PhDPeter MacCallum Cancer Centre

Melbourne, Australia

Disclosure Information

• I have the following financial relationships to disclose–Research support from: Pfizer,

Millennium & Novartis

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?

Oncogene Addiction

GISTCML

Mut EGFR APML

p210Bcr-Abl

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

Survival

Adapted from Stroobants et al, EJC, 2003

Time (Days)

PET respondersn=13

PET non-respondersn=8

0 100 200 300 400 500 600 700

0.00.10.20.30.40.50.60.70.80.91.0

p=0.001

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

Phospho-ERK IC50 (nM)

A375COLO829COLO205

SW620SKMEL2

201030

>40,000 14,000

Selective in cellular assays

V600E

WT

Selective for BRAFV600E kinaseamong 70 kinases screened

10–100

IC50 (nM)

100–10001000–10000

Kinase domain binding

Bollag et al , Nature, 2010

BRAF

Bollag et al , Nature, 2010

Dose dependent regression of V600E tumors

CT Response- Phase 1 PLX06/02 Study

Flaherty et al, NEJM. 2010Flaherty et al, NEJM, 2010

1009080706050403020100

Prog

ress

ion-

free

sur

viva

l (%

)

No. of patients in follow upDacarbazineVemurafenib

0 1 2 3 4 5 6 7 8 9 10 11 12

Hazard Ratio 0.26 (95% CI; 0.20 - 0.33)Log-rank P<0.0001

Months274275

213268

85211

48122

28105

1650

1035

616

34

03

Dacarbazine (N=274)

Vemurafenib (N=275)

Progression-free survival (30 Dec 2010, final pre-planned analysis at IA)

Median 1.6 mos Median 5.3 mos

McArthur et al, ESMO, 2011

Heterogeneity of ERK phosphorylation at progression

• Recovery of ERK and MEK phosphorylation at disease progression was observed in some but not all patients

300

250

200

150

100

50

0

H-S

core

Baseline Day 15 PD

pERK1/2 cytoplasmic H-Score300

250

200

150

100

50

0H

-Sco

reBaseline Day 15 PD

pMEK1/2 cytoplasmic H-Score

McArthur ASCO, 2011

Patterns of Progression

Baseline

Response

Progression

Design of Clinical Study

Day 1

VemurafenibScreening

ProcedureFDG-PET

CT

15

FDG-PET

-21 29 57

CT CT

FDG-PET ResponseBaseline

Day 15

Kim, MD Anderson

FDG-PET Response

McArthur….Hicks, J Clin Oncol, 2012

Response Assessment-quantitative analyses

PLX4032 ≥320mg bid (n=27)

Controls (n=4) 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 ml (range)

816±423 (7-6945)

597±1012 (16-2113)

Response Assessment-summary

PLX4032 ≥320mg bid (n=27)

Controls (n=4)

Overall Assessment of FDG-response (N, %)

Complete Metabolic Response

3 (11%) 0

Partial Metabolic Response

41(89%) 1

No Response 0 3

Overall Assessment of response RECIST (N, %)

CR 2 (7%) 0

PR 21(78%) 0

SD 3 (11%) 0

100% of patients with BRAF V600E melanoma achieved an FDG-PET response

An example of precision 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

B

Day 17

K601E represents 1-2% of all BRAF mutations in melanoma

Day 0

BRAF T599 ins I V601 treated with the vemurafenib

A

B

Day 0

Day 18

BRAF L597R treated with the vemurafenib

A

B

Day 0

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?

Baseline

Day 15

Kim, MD Anderson

Could inhibition of glucose metabolism be a driver of response?

A

B

Day 0

Day 15

McArthur….Hicks, J Clin Oncol, 2012

Could inhibition of glucose metabolism be a driver of response?

Conclusions

• Mechanistic preclinical studies and correlations with reactivation of the MEK/ERK pathway suggest FDG-PET 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

AcknowledgementsKeith FlahertyAntoni RibasPaul ChapmanKeith NolopJeff SosmanKevin Kim

Igor PuzanovJoe GrippoRichard LeeGideon Bollag

Tiffany ParmenterRod Hicks

Jason CallahanFergal KelleherAlex DobrovicCliff Meldrum

PET-imaging colleaguesStudy

CoordinatorsPatients & their

families