JY Blay. New horizons 2011

Transcription

1 Prevention of GIST resistance JY Blay Medical Oncology Chairman of the Soft Tissue and Bone Sarcoma Group of EORTC Chairman of the CONTICANET Network of Excellence 6th Framework Program of the European Commission UJOMM Hospices Civils il de Lyon & U590 INSERM Ctr Léon Bérard, Lyon, France

2 Imatinib in advanced GIST PFS and OS in large series New horizons 2011 Hazard Ratio: 0.887, Log-Rank test p= Median OVERALL SURVIVAL (58 months) B Median PFS (20-26 months) B2222, SO033, 62005, BFR Treatment Wks: Number at Risk Median Duration 95% CI LL UL mg 600mg Pooled Wks N/A 248 Wks 150 N/A 190 N/A 190 N/A Blanke CD et al. J Clin Oncol. 2008;26(4): Verweij et al. Lancet. 2004;364(9440):

3 Understand resistance Primary Target resistance (syndromic GIST, D842V, ) Dose? Secondary Secondary mutations Others

4 Tumor heterogeneity New horizons 2011 Molecular heterogeneity at progression After imatinib Debiec Rychter et al, Heinrich et al 2006 After sunitinib Fletcher et al ECCO Exon 13 + Exon 14 Exon 11 mutation + Exon 17

5 Demonstrate resistance (1) New horizons 2011

6 Demonstrate resistance (2) M0 M9 M12 New horizons 2011

7 Resistance in advanced phase Is it equivalent to Relapse after adjuvant treatment

8 Localized phase New horizons 2011

9 Role of Surgery in Primary Disease New horizons 2011 Surgery is the principal treatment and only curative therapy for localized, resectable primary disease Casali et al. Ann Oncol 2008;19 (suppl 2):ii35 ii38. Demetri et al. J Natl Compr Canc Netw. 2007;5 (suppl 2):S1-29.

10 rs1 MicroGIST New horizons million adults in France. 20% have micro-gists = 12 million cases 1.5/ have a clinically relevant risk GIST = 900 cases Kawanowa et al. Hum Pathol. 2006; 37:

11 Slide 10 rs1 Suggest deletion for time. switched text and diagram rsalie;

12 Surgery of Primary Disease Complete macroscopic resection with microscopically negative margins over the organ of origin (R0 resection) Extensive resections may be necessary Total gastrectomy Pancreaticoduodenectomy (Whipple procedure) Abdominoperineal resection (APR) Resection of adjacent organs maybe necessary Lymphadenectomy not indicated Thorough abdominal exploration Casali et al. Ann Oncol 2008;19 (suppl 2):ii35 ii38. Demetri et al. J Natl Compr Canc Netw. 2007;5 (suppl 2):S1-29.

13 North American Intergroup Phase III Trial ACOSOG Z9001: Recurrence Free Survival New horizons 2011 and Alive % Recu urrence-free Imatinib Placebo RFS ITT (Kaplan Meier) P< HR ( ) Time in Months Number at Risk Placebo Imatinib From 6 months At 12 months At 30 months Imatinib : 99.3% RFS Placebo : 90.7% RFS Imatinib : 97.7% RFS Placebo : 82.3% RFS Imatinib : 84.2% RFS Placebo : 69.6% RFS DeMatteo et al. Lancet 2009; 373:

14 Questions Which risk level? Substantial risk : >=30%? Duration? >=1 year Mutation subtypes? Not PDGFRA D842V Impact on secondary resistance? Not known, data from BFR14 trial reassuring? Impact on survival? 2017? 2011?

15 Adjuvant Trials in GIST Study Imatinib 1 endpoint ACOSOG Z vs. 1 year RFS EORTC/ISG/AGITG 0 vs. 2 years OS (time to imatinib resistance) Nordic/German 1 vs. 3 years RFS PERSIST 5 years RFS BFR14 locally advanced until PD RFS

16 Metastatic/relapse phase New horizons 2011

17 KIT and PDGFRα mutations in GIST KIT PDGFRα Imatinib sensitive Overall mutation frequency: 87.2% Exon 9 (11%) Membrane Exon 11 (67.5%) Exon 12 (0.9%) Exon 13 (0.9%) Exon 14 (0.3%) Cytoplasm Exon 17 (0.5%) Exon 18 (6.3%) Heinrich et al. Hum Pathol. 2002;33:484; Science 2003, Corless et al. Proc AACR. 2003

18 Outcome of patients with PDGFRA D842V mutant gastrointestinal stromal tumor (GIST) treated with imatinib (IM) for advanced disease Pierre Biron 1, Philippe A. Cassier 1, Elena Fumagalli 2, Aurore Blésius 3, Maria Debiec-Rychter 4, Antoine Adenis 5, Jaap Verweij 6, Peter Hohenberger 7, Jean-Yves Blay 1, Paolo Casali 2 and dthe EORTC 1. Centre Léon Bérard, Lyon, France; 2. Istituto Nazionale Tumori, Milano, Italy; 3. Institut Gustave Roussy, Villejuif, France; 4. Catholic University of Leuven, Leuven, Belgium; 5. Centre Oscar Lambret, Lille, France; 6. Erasmus University Medical Center, Rotterdam, The Netherlands; 7. Mannheim University Medical Center, Mannheim, Germany. Characteristic N % Age, median yrs (range) Gender Female 4 20% Male 16 80% Site of primary tumor Stomach 15 75% Small intestine 1 5% Other 4 20% Primary tumor size (mm, median, range) Site of metastatic disease Liver 12 60% Peritoneum 7 35% Lymph node 1 5% Locally advanced 2 10% WHO performance status % % % Imatinib starting dose 400 mg per day 14 70% 800 mg per day 6 30% Table 1: Main patients' characteristics Survival probability Im matinib resistance probability Prog gression-free survival probability 1,0 0,8 0,6 0,4 0,2 0,0 1,0 0,8 0,6 0,4 0,2 0,0 1,0 0,8 0,6 0,4 0,2 0,0 Median PFS : 2.8 months M onths Median TTIR : months Months Median OS : 12.7 months Months

19 Progression-Free Survival KIT exon 9 mutants Median PFS (months) 6 / 19 3-year estimate (%) 5 / 17 P value (logrank test) KIT exon 9 mutants: 400 mg / 800 mg Other patients: 400 mg / 800 mg Years ASCO 2007

20 Strategy to prevent progression Check compliance Check exposure? Surgery? Combination TKI? Rotation TKI?

21 Compliance of Gleevec in GIST and CML New horizons 2011 Total patients = 4,043 Time Frame = Jan 03 Dec 04 Com mpliance 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 98% 78% 73% 74% CM L G IS T G IS T/CM L N/A Average Compliance = 75% Source: Gleevec C&P Study April 2005

22 Observance study New horizons 2011

23 G.I.S.T. SURVEY Collaborative project A.F.P.G / Conticanet (20 countries) 12 languages Objectives : 1500 participants pdf version of the brochure onsur observance in 12 languages on : Invite your patients to participate to G.I.S.T. :

24 Study B2222: trough Imatinib at day 29 New horizons Demetri et al JCO 2009

25 Study B2222: trough Imatinib at day 29 and survival New horizons 2011 <1110 >1110 & <2040 >2040 Demetri et al JCO 2009

26 BFR14 Study design Imatinib 400 mg/d 1 year 12 months Imatinib until PD GIST stage 4 CR PR SD CT scans: - monthly 3 months - every er 3 months Surgery if CR «achievable» STOP PD mg/d at progression

27 Interruption in advanced 1 year: Median PFS: 5,7 months (JCO 3 years: Median PFS: 6,3 months (ASCO 2008, 5 years: Median PFS: 12 months (ASCO 2010)

28 Results : interruption at 5 years Median follow-up : 11.9 months CONT group 0 evt / 12 patients Surviva al probability STOP group evts / 13 patients median PFS : 12.6 months 0.1 (CI9 % 86216) Months STOP group : median PFS : 12.6 months (CI95% = 8.6;21.8) CONT group : median not reached Log-rank test: p value =

29 3-Year Results: Imatinib-Resistant PFS Survival probabil lity Number at risk Continuation group Interruption group Median time of imatinib reintroduction: 24.9 months Continuation group (first progression) 7 events in 25 patients 2-year PFS 80% (95% CI 58-91) Continuation group Interruption group Interruption group (second progression) 6 events in 25 patients 2-year PFS 87% (95% CI 66-96) New horizons Time from random assignment (months) CI = confidence interval; PFS = progression-free survival Le Cesne A, et al. Lancet Oncol. 2010;11:

30 Reducing surgically tumor volume a strategy to prevent resistance?

31 bl9 bl8 New horizons 2011 Useful to prevent relapse since it reduces tumor volume? Raut CP et. al., J Clin Oncol 24: , 2006

32 Slide 30 bl8 bl9 Titles should be added to all the slides in this format. The template of this slide could be used to add bullets, enalarge graphs, and align to improve layout of all slides that have this arrangment (bullets to right side, graph, banner) bloechlinger; Changed banner from black to red because looked like a technical problem when black blended in with background of slide bloechlinger;

33 Advanced GIST Imatinib Metastatic GIST in response on IM PD Imatinib + surgery at best response (within 1 yr) Follow for PFS&OS Benjamin et al. Proc Am Soc Clin Oncol. 2003;22:814. Abstract Rankin et al. Proc Am Soc Clin Oncol. 2004;23:815. Abstract Verweij et al. Proc Am Soc Clin Oncol. 2003;22:814. Abstract 3272.

34 Strategy to prevent progression Check compliance Check exposure? Surgery? Combination TKI? Rotation TKI?

35 Combinations + everolimus + PKC412 + sunitinib + nilotinib + doxorubicin

36 Combination or sequential? New horizons 2011

37 Continuous o KIT blockade after progression Rationale -Prolonged survival after imatinib failure : B2222: Median OS & PFS: 58 vs 26 months - Resistance to imatinib: most often focal with persistence of imatinib sensitive clones - Continuous maintenance of a blockade of KIT to treat sensistive clones

38 Discrepancy between PFS and OS in IM trials Impact of others TKIs on survival Hazard Ratio: 0.887, Log-Rank test p= Median OVERALL SURVIVAL 0.8 nearly 5 years (58 months) B Median PFS nearly 2 years (20-24 months) EORTC Treatment 400mg 600mg Pooled Number at Risk Wks: Median Duration 248 Wks N/A 248 Wks 95% CI LL UL 150 N/A 190 N/A 190 N/A Blanke CD et al. J Clin Oncol. 2008;26(4): Verweij et al. Lancet. 2004;364(9440):

39 Conclusions Optimal primary treatment Compliance Surgery? Combinations? Understanding mechanisms of resistance: translational research