How it began, how it continues

  • 876 views
Uploaded on

Prof. Dr. Heikki Joensuu - How it began, how it continues

Prof. Dr. Heikki Joensuu - How it began, how it continues

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
876
On Slideshare
0
From Embeds
0
Number of Embeds
3

Actions

Shares
Downloads
6
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 1. How it began, how it continuesHeikki Joensuu, MD, Dept. of Oncology, University of Helsinki
  • 2. How it began?
  • 3. Alexander LevitzkiSiverman Institute of Life Sciences,The Hebrew University of JerusalemPhase 1: ”It is not possible.”Phase 2: ”It might be possible,but...”Phase 3: ”We new it all along.”Phases of ground-breakingresearchEarly investigators of tyrosine kinasesinhibitors met disbelief11Levitzki A. Eur J Cancer 2002; 38 (Suppl 5):S11-18)
  • 4. Discovery of mutations in the KIT gene in GISTProf. Seiichi HirotaFound activatingmutations in KIT inin 1998Hirota et al. Science 1998
  • 5. Brian DrukerimatinibiSTI-571
  • 6. ”Patient zero”• Metastatic aggressive GIST diagnosed in 1996 (KIT exon 11 deletion)• In 1998: second surgery, chemo (MAID x 7)• March 1999, third operation• April 1999 to Feb 2000, thalidomide + interferon– Cancer stabilization for 10 months• Imatinib started in March 2000
  • 7. Apoptosis of GIST cells induced by imatinibPrior to startingimatinib4 weeks later
  • 8. Apoptosis of GIST cells induced by imatinibPrior to startingimatinib4 weeks laterKITKI-67H & E
  • 9. Before STI5714 weeks8 monthsBefore STI571 4 weeksNEJM 2001;344:1052-6 (Apr 5)
  • 10. Randomized Trial of STI571 inRandomized Trial of STI571 in MetastaticMetastaticGISTGIST(STI(STI--B2222, the U.S.B2222, the U.S.--Finland study)Finland study)SCREENREGISTER400 mg/day600 mg/dayTreat Dailyx 24 monthsProgressionDemetri G et al. NEJM 2002
  • 11. Fast clinical developmentFast clinical development•• The first GIST patient started imatinib The first GIST patient started imatinib therapy in March  in 2000therapy in March  in 2000•• The first multicenter study (B2222 trial) The first multicenter study (B2222 trial) was started in July 2000, all 147 patients was started in July 2000, all 147 patients entered to the study in April 2001entered to the study in April 2001
  • 12. 147 patients with advanced GIST treated with first-lineimatinib (400 or 600 mg/day) in the B2222 trialDemetri GD et al. N Engl J Med 2002;347:472-480.
  • 13. Advanced GIST usually responds to imatinib Study Responses No Notresponse evaluableB22221 123 (84%) 17 (12%) 7 (5%)EORTC2 794 (84%) 103 (11%) 49 (5%)S00333 375 (69%) 79 (15%) 86 (16%)Total 1292 (79%) 199 (12%) 142 (9%)1Demetri GD et al. New Engl J Med 2002;347:472-80; Blanke CD et al. J Clin Oncol2008; 2Verwieij J et al. Lancet 2005; 3Blanke CD et al. J Clin Oncol 2008
  • 14. 0 5 10 15 20 25 30051015202530400 mg/d700 mg/d1000 mg/dTUMORVOLUMEMONTHS ON IMATINIBPatient zero: One liver metastasisstarted to grow
  • 15. Copyright © American Society of Clinical OncologyBlanke, C. D. et al. J Clin Oncol; 26:620‐625 2008Time to GIST progression with first‐line imatinib in the B2222 trialmedian, ~24 months
  • 16. Severalresistancemutationsin a singlepatient
  • 17. Copyright © American Society of Clinical OncologyBlanke, C. D. et al. J Clin Oncol; 26:620-625 2008B2222 Trial: Time to progression on imatinib andtumor bulk9-year overallsurvival 35%
  • 18. How to continue?
  • 19. Adjuvant therapy
  • 20. Recurrence‐free survival after surgery~60% are likely cured by surgery alonePooled data from 10 population-based series on GIST (n=2560), nonereceived adjuvant imatinib1Joensuu et al. Lancet Oncol 2012; 13:265-74~40% couldpotentially benefitfrom adjuvanttreatmentYears
  • 21. SGXVIII/AIO trial: 1 versus 3 years of adjuvant imatinib inhigh-risk GISTNumber at risk36 months of imatinib 198 184 173 133 82 39 8 012 months of imatinib 199 177 137 88 49 27 10 0Recurrence-freeandalive(%)60.1%47.9%86.6%65.6%36 months of imatinib12 months of imatinibHazard ratio 0.46 (95% CI 0.32-0.65)p<0.0001Years since randomisation0 1 2 3 4 5 6 7020406080100Median follow-up time: 54 months Joensuu H et al. JAMA 2012;307:1265-72
  • 22. Number at risk36 Months of imatinib 198 192 184 152 100 56 13 012 Months of imatinib 199 188 176 140 87 46 20 0Years since randomisationSSGXVIII/AIO trial: overall survivalAlive(%)Hazard ratio 0.45 (95% CI 0.22-0.89)p=0.01996.3%92.0%94.0%81.7%36 months of imatinib12 months of imatinib0 1 2 3 4 5 6 7020406080100
  • 23. Copyright © American Society of Clinical OncologyBlanke, C. D. et al. J Clin Oncol; 26:620-625 2008B2222 Trial: Time to GIST progression on imatiniband tumor bulk9-year overallsurvival 35%
  • 24. SSG18: Time to GIST coming back (recurrence)Recurrence-freeandalive(%)36 months of imatinib12 months of imatinibYears since randomisation0 1 2 3 4 5 6 7020406080100Intensivemonitoring?Intensivemonitoring?Joensuu et al. JAMA, March 28, 2012, 307(12):1265-1272.
  • 25. High-Lowest risk (n=197, censored 165)High-Intermed. risk (n=104, censored 58)High-Highest risk (n=39, censored 9)020406080100Alivewithoutrecurrence(%)0 1 2 3 4 5 6 7Time (years)p<0.001SSGXVIII: Time to GIST coming back: tumor mitoticcount and siteGastric, ≤ 10 mit,Non-gastric, ≤5 mitGastric, 11-50 mitNon-gastric, 6-20 mitGastric, >50 mitNon-gastric, >20 mit
  • 26. Imatinib 36 mo ± 3 moStop imatinibThe SSGXXII Trial DesignRANDOMIZEScreen•High‐risk GIST*•R0 or R1 resection*Gastric GIST with >10 mitoses/50 HPFs; or nongastric GIST with >5 mitoses/50 HPFsFollow-up with CT or MRI at 6-month intervals during imatinib, at 4-month intervalsfor 2 years after stopping imatinib, then at 6-12 month intervalsStratify for:•Tumour site•Mutation type•Imatinib dose at randomization (<400, 400, >400 mg/d)•CentreArm AArm BImatinib for 24 months
  • 27. New drugsTested first in advanced disease 
  • 28. Demetri GD et al. The Lancet 2006; 368: 1329 - 1338Efficacy of sunitinib in patients with advanced GIST afterfailure of imatinib: a randomised controlled trial
  • 29. Demetri GD et al. The Lancet 2012Efficacy of regorafenib for advanced GIST afterfailure of imatinib and sunitinib: a ranomised trialRegorafenib inhibits KIT, PDGFR,VEGFR1–3, TEK, RET, RAF1, BRAF,BRAFV600E, and FGFRTime toGISTprogressionOverall survival
  • 30. Under testing• New agents and drug combinations– 13 novel agents are being tested for advanced GIST– Multikinase inhibitors (dovitinib, dasatinib, masitinib, nilotinib, pazopanib, sorafenib), immunomodulating agents (ipilimumab, peginterferon), heat shock protein inhibitors (AT13387, AUY922), a PI3K inhibitor (BKM120) – Crenolanib probably efficient for D842‐mutated GISTs
  • 31. Individually tailored dosing
  • 32. Copyright © American Society of Clinical OncologyDemetri, G. D. et al. J Clin Oncol; 27:3141-3147 2009B2222 trial: Low plasma imatinib concentrationsmeasured one month after starting IM are associatedwith short time to progression in advanced GIST<1110 ng/mL)>1110ng/mL
  • 33. Getting rid of GIST stem cells
  • 34. Heinrich M et al. LancetOncol 2010; 11:910-11
  • 35. monthssolubleKITserumSCFmonthsSoluble KIT (bindsSoluble KIT (bindsstem cell factor, SCF)stem cell factor, SCF)decreases in all GISTdecreases in all GISTpatients treated with IMpatients treated with IMSerum growth factorSerum growth factor(SCF) levels increase in(SCF) levels increase inGIST patients treatedGIST patients treatedwith IMwith IM13 patientstreated inHelsinkiBono P et al., Blood 2004
  • 36. RImatinib, continuousIMA IMAREGO REGOweeks0 3 4 7 8 11 12 15ALT-study in advanced GIST(first-line treatment)1 week washout period – mightthese revive GIST progenitor cells?
  • 37. Entirely new molecular targets
  • 38. BRAFHIF1HIF1SDHBSDHDSDHASDHCFumarateSuccinateProlylHydroxylaseVEGF IGF2ETV1 mediated transcriptionJoensuu H, Hohenberger P,Corless CL. Lancet, in press 2013
  • 39. Future cancer biology0,2,4,6,810,2,4,6,810 5 10 15 20 25 30 YearsKIT ex11 insKIT ex11 pmKIT ex11 delKIT ex11 complexPDGFRA ex 18wtKIT ex 11KIT ex 9From mutation classes tosingle mutationsIdentification of moredriver mutations with the”next generationsequencing”Individualizedcharacterization of tumorsMutation analyses fromthe blood
  • 40. Early detection of GIST• Better and cheaper imaging tools• Finding cancer from the blood
  • 41. How to continue: Summary• New agents, combinations of targeted drugs• More efficient adjuvant treatments• Early detection of GIST and disease recurrence• Identification of novel biological targets