Overview of New Drugs for GIST following resistance to standard TKIs (imatinib and sunitinib)

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1 Overview of New Drugs for GIST following resistance to standard TKIs (imatinib and sunitinib) George D. Demetri, M.D. Center for Sarcoma and Bone Oncology Dana-Farber Cancer Institute Harvard Medical School Boston, Massachusetts USA

2 Disclosures for George Demetri, M.D. Consulting and Research Support to Dana-Farber Novartis, Pfizer, Infinity, Johnson & Johnson, Merck, Genentech/Roche, Amgen, Glaxo Smith Kline, Daiichi-Sankyo Consultant only Sanofi, Plexxikon, ZioPharm, EMD Serono, N-of-1, G-Zero, Momenta, EmergingMed.com, PamGene, Millenium; 23andme; Kolltan, Nereus, Blueprint Medicines Research Support only to Dana-Farber Bayer

3 An Important Signal

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5 + = X 2

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8 Resistance Concern #1 Need for continuous therapy This would be unacceptable for an antibacterial therapy

9 Continuous Dosing with imatinib vs. Stopping imatinib after maximal response Advanced/ metastatic GIST on imatinib Evaluate for randomization at 3 yrs Stable Disease or better Surgery if resectable R A N D O M I Z A T I O N STOP IMATINIB CONTINUE IMATINIB 400 mg daily Disease Progression RESTART IMATINIB 400 mg daily Continue Imatinib And Follow-up GIST Update

10 Progression-Free Survival probability Continuous vs. Stopping Imatinib Progression-Free Survival CONTINUOUS DOSING group 6 evts / 25 patients 1-year PFS: 92% ; CI95 = [72-98] 2-years PFS: 78% ; CI95 = [55-90] STOP DOSING group 21 evts / 25 patients 1-year PFS: 32% ; CI95 = [15-50] 2-years PFS: 16% ; CI95 = [5-33] Log-rank P value < Months GIST Update

11 Resistance Concern #2 Resistance DEFINITELY occurs Immediately ( primary ) in few Delayed ( acquired ) in virtually 90% of patients

12 5 July September 2000 Learning From Drug Failure: Primary Resistance to Imatinib in GIST PET / GIST

13 BASELINE 1 month on Imatinib This drug effect is a form of resistance WHY are there not COMPLETE RESPONSES? WHAT is keeping the tumor cells viable and why is the shape of the tumor preserved? GIST Update

14 Overall Survival (%) Days Exon RESISTANCE to 1 st Line Imatinib is NOT ABSOLUTE : GISTs Exon with different mutations behave differently No Mutation P-value = No KIT Mutation Days KIT mutant Exon 9 KIT mutant Exon 11 Different Genotypic and Structural Variants Fail Imatinib Therapy at Different Rates Heinrich, Corless, Fletcher, Demetri et al.

15 Patients Identify with Personalized Medicine

16 The Challenge of Multiple Progressing Tumors in Metastatic GIST Failing TKI Therapy 46 Tumors All Started with Exon 9 KIT Mutant but now demonstrate >10 different secondary resistance mutations in KIT Courtesy of Drs. Chan Raut, Yuexiang Wang, and Jon Fletcher, Dana-Farber/Harvard

17 Resistant Clones Complicate Personalized Medicine + Exon 13 + Exon 17

18 Resistance Concern #3 TKI therapy does not molecularly select patients for a homogeneous mechanism of resistant GIST Conventional diagnostic pathology has not caught up with the reality of disease heterogeneity

19 Overcoming TKI Resistance in GIST Strategy #1 A new and structurally unique TKI targeting KIT Best example: Sunitinib following Resistance to Imatinib

20 Structural Resistance to imatinib in KIT does not affect sunitinib: Selective Steric Hindrance Courtesy of K Gajiwala, Pfizer Oncology 1 Gajiwala et al. Proc Natl Acad Sci USA 2009;106: Mol et al. J Biol Chem 2004;279:31655

21 Estimated TTP probability (%) Sunitinib Improves Progression-Free Survival in GIST following failure of Imatinib Sunitinib (N=207) Placebo (N=105) Hazard ratio = P< Median TTP (95% CI) 6.3 mo ( ) 1.5 mo ( ) Time (Months) Demetri GD, et al. Lancet 2006

22 Test a new drug from imatinib scaffold to inhibit the Kinase Courtesy Paul Manley, Novartis Oncology Nilotinib

23 Nilotinib Activity in TKI-Resistant GIST Montemurro et al.

24 A Word of Caution Caveat emptor The quality of evidence matters.

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27 A partial list of KIT-targeting TKIs Imatinib, sunitinib Nilotinib Masitinib Pazopanib

28 Overcoming TKI Resistance in GIST Strategy #2 Add an important new action to a TKI targeting KIT Best example: Regorafenib following Resistance to Imatinib and Sunitinib

29 Change from baseline (%) Regorafenib in Patients with Metastatic GIST following failure of Imatinib and Sunitinib 80,0% Waterfall Plot of Best Response of Target Lesions 60,0% 40,0% 20,0% 0,0% -20,0% -40,0% -60,0% -80,0% Patient number

30 Regorafenib in GIST following failure of IM and SU: Overall Progression-Free Survival (all patients) Progression Free Survival Median PFS: 10.0 months 95%CI (7.3 mo - ) Months

31 Summary of Phase 3 GIST: GRID Study FULLY ACCRUED: January to July 2011 Primary endpoint: PFS Secondary endpoint: OS Page 31

32 The Best Strategy to Overcome TKI Resistance in GIST Add a NEW DRUG with a NOVEL ACTIVITY to a KIT-Targeted TKI Examples: - mtor inhibitor + imatinib - HSP90 inhibitor + imatinib - PI3K inhibitor + imatinib

33 Another Signaling Analogy from Milan

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35 Combined Blockade of Multiple Cellular Pathways in GIST KIT P P P P KIT or PDGFRA PI3K Ras AKT mtor mtor S6K Raf Mek Erk Nucleus Transcription factors Cell proliferation Angiogenesis Cell adhesion Apoptosis Cell survival Cell differentiation

36 mtor+ KIT Inhibition: Everolimus plus Imatinib for Imatinib-Resistant GIST Schoffski P, et al.

37 Combined Blockade of Multiple Cellular Pathways in GIST KIT P P P P KIT or PDGFRA PI3K Ras AKT mtor mtor S6K Raf Mek Erk Nucleus Transcription factors Cell proliferation Angiogenesis Cell adhesion Apoptosis Cell survival Cell differentiation

38 Combination PI3K-mTOR inhibition with GDC0980 in TKI-resistant GIST Resistant GIST following prior imatinib, sunitinib, sorafenib, and STA-9090 (Hsp90 inhibitor) GDC mg daily; 98% decrease in pakt Durable stable disease Baseline End of Cycle 1 Baseline next slide End of Cycle 1 Wagner A., et al. 2011

39 New Trial of PI-3-Kinase + KIT Combined Blockade in TKI-Resistant GIST KIT or PDGFRA KIT Imatinib P P P P PI3K BKM120 Ras AKT mtor S6K Raf Mek Erk Nucleus Transcription factors Cell proliferation Angiogenesis Cell adhesion Apoptosis Cell survival Cell differentiation

40 New Trial of MAP-kinase + KIT Combined Blockade in TKI-Resistant GIST KIT or PDGFRA KIT Imatinib P P P P PI3K Ras AKT mtor S6K Raf Mek MAP k Erk Nucleus Transcription factors Cell proliferation Angiogenesis Cell adhesion Apoptosis Cell survival Cell differentiation

41 Hammering Multiple Molecular Pathways Molecular Whack-A-Mole with only one hammer may never be enough in GIST

42 Conclusions New drugs and new strategies are needed to cure metastatic GIST Following failure of standard TKI therapy with imatinib and sunitinib, clinical trial participation should be encouraged Promising signals of activity in TKI-resistant GIST should be tested before resistance occurs

43 THANK YOU and Thanks to all our patients, colleagues and collaborators worldwide