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In my clinical practice I use FDG-PET for the following

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 ”

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In my clinical practice I use FDG-PET for the following

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  1. 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

  2. “PET scans to image pharmacodynamiceffects of vemurafenib” Grant McArthur MB BS PhD Peter MacCallum Cancer Centre Melbourne, Australia

  3. Disclosure Information • I have the following financial relationships to disclose • Research support from: Pfizer, Millennium & Novartis

  4. 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?

  5. p210Bcr-Abl Oncogene Addiction CML GIST Mut EGFR APML

  6. FDG-PET to assess response- Re-Evaluating the Conventional Treatment Paradigm GIST Before Imatinib 24 hours after starting Imatinib

  7. The Limitations of Structural Imaging 6 months after commencing imatinib

  8. Monitoring response to imatinibin GIST 1.0 0.9 0.8 PET responders n=13 0.7 0.6 0.5 Survival 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

  9. 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

  10. 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 Dose dependent regression of V600E tumors Kinase domain binding Bollag et al , Nature, 2010 Bollag et al , Nature, 2010

  11. CT Response- Phase 1 PLX06/02 Study Flaherty et al, NEJM. 2010 Flaherty et al, NEJM, 2010

  12. 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Progression-free survival (30 Dec 2010, final pre-planned analysis at IA) Hazard Ratio 0.26 (95% CI; 0.20 - 0.33) Log-rank P<0.0001 Vemurafenib (N=275) Dacarbazine (N=274) Progression-free survival (%) Median 5.3 mos Median 1.6 mos Months No. of patients in follow up Dacarbazine Vemurafenib 274 275 213 268 85 211 48 122 28 105 16 50 10 35 6 16 3 4 0 3 McArthur et al, ESMO, 2011

  13. 300 300 250 250 200 200 150 150 100 100 50 50 0 0 Heterogeneity of ERK phosphorylation at progression • Recovery of ERK and MEK phosphorylation at disease progression was observed in some but not all patients pERK1/2 cytoplasmic H-Score pMEK1/2 cytoplasmic H-Score H-Score H-Score Baseline Day 15 PD Baseline Day 15 PD McArthur ASCO, 2011

  14. Patterns of Progression Baseline Response Progression

  15. Design of Clinical Study FDG-PET CT FDG-PET CT CT Procedure Day -21 1 15 29 57 Screening Vemurafenib

  16. FDG-PET Response Baseline Day 15 Kim, MD Anderson

  17. FDG-PET Response McArthur….Hicks, J ClinOncol, 2012

  18. Response Assessment-quantitative analyses

  19. Response Assessment-summary 100% of patients with BRAF V600E melanoma achieved an FDG-PET response An example of precision medicine McArthur….Hicks, J ClinOncol, 2012

  20. Homogeneity of Molecular Response A B McArthur….Hicks, J ClinOncol, 2012

  21. 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.

  22. 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.

  23. 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?

  24. BRAF K601E treated with the MEK-inhibitor trametinib A K601E represents 1-2% of all BRAF mutations in melanoma Day 0 B Day 17

  25. BRAF T599 ins I V601 treated with the vemurafenib A Day 0 B Day 18

  26. BRAF L597R treated with the vemurafenib A Day 0 B Day 14

  27. 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?

  28. Could inhibition of glucose metabolism be a driver of response? Baseline Day 15 Kim, MD Anderson

  29. Could inhibition of glucose metabolism be a driver of response? Day 0 A B Day 15 McArthur….Hicks, J ClinOncol, 2012

  30. 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 siRNAsphenocopies the effects of vemurafenib on cell viability, suggesting inhibition of glycolytic metabolism maybe one component of the anti-tumor activity of BRAF inhibitors

  31. Acknowledgements PET-imaging colleagues Study Coordinators Patients & their families Keith Flaherty AntoniRibas Paul Chapman Keith Nolop Jeff Sosman Kevin Kim Igor Puzanov Joe Grippo Richard Lee Gideon Bollag Tiffany Parmenter Rod Hicks Jason Callahan Fergal Kelleher Alex Dobrovic Cliff Meldrum

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