Paolo G. Casali, John Zalcberg , Jaap Verweij , Axel Le Cesne ,

1. LONG-TERM ANALYSIS OF A PHASE III RANDOMIZED, INTERGROUP, INTERNATIONAL TRIAL • ASSESSING THE CLINICAL ACTIVITY OF IMATINIB • AT TWO DOSE LEVELS • IN PATIENTS WITH UNRESECTABLE OR METASTATIC GASTROINTESTINAL STROMAL TUMORS (GIST) Paolo G. Casali, John Zalcberg, JaapVerweij, Axel Le Cesne, Peter Reichardt, Jean-Yves Blay, Lars Lindner, Ian R. Judson, Elena Fumagalli, PancrasHogendoorn, Agnes Natukunda, SandrineMarreaud, SaskiaLitière, WinetteT.A. Van DerGraaf

2. Speaker’spotentialconflicts of interest EmplConsStocks Honor Res Test Other Amgen Dompél l ARIAD l Bayer ll Glaxo SK l l ImClonel Infinityl JanssenCilagl l Lilly l Merck SD ll Molmedl Novartis llll Pfizer lll PharmaMarllll Sanofi Aventis ll ScheringPloughl

3. Study design 946 eligiblepts: • GIST (CD117+) • metastatic and/or unresectable • WHO PS = 0-3 • previouschemoaccepted February 2001 / February 2002 imatinib 400 mg /d R progression imatinib 800 mg /d

4. End points primary secondary • PFS • OS • OR • TOX

7. Long-term update 946 randomized 473: 400mg/day 1 did not start treatment 9 ineligible 473: 800mg/day 1 did not start treatment 9 ineligible 379 progressed 360 died 82 still alive 31 lost to follow up 358 progressed 339 died 95 still alive 39 lost to follow up Database lock on May 27, 2013 • Median follow-up: 10.9 years (IQR: 8.1 - 11.3) • Maximum follow up: 11.8 years 7

8. Objectiveresponse

9. Progression-free survival HR 0.91 (95%CL 0.80, 1.05 ) • Median PFS: • 400mg 1.7 years (95% CI 1.5, 2.0) • 800mg 2.0 years (95% CI 1.9, 2.3)

10. Overallsurvival HR 0.93(95% CL 0.80, 1.07) • Median OS: • 400mg 3.9 years (95% CI 3.3, 4.4) • 800mg 3.9 years (95% CI 3.4, 4.9

12. 10-y survivors (120 pts) 946 randomized patients 473 at 400mg/day 473 at 800mg/day 61(12.9%) were 10-y survivors 62 censored prior to 10 years 350 dead before 10 years 59 (12.5%) were 10-y survivors 82 censored prior to 10 years 332 dead before 10 years

13. 10-y progression-free survivors (59 pts) 946 randomized patients 473 at 400mg/day 473 at 800mg/day 30 (6.3%) were 10-y prog-free 26 censored prior to 10 years 415 progressed before 10 years 29 (6.1%) were 10-y prog-free 41 censored prior to 10 years 403 progressed before 10 years

14. Surgery of residualdisease

15. Surgery of residualdisease

16. Dose intensity 400 mg 800 mg

17. 10-y survivors

18. 10-y progression-free survivors

19. Prognosticfactoranalysis • Univariateand multivariate analyses were done using: • Cox regression for PFS and OS • Logistic regression for RR • For prognostic factor analysis a full model was built and reduced using backward selection method at a 5% significance level • Factors included in the full model were: • age • PS • sex • time delay between diagnosis and registration • prior surgery • prior chemotherapy • prior radiotherapy • primary site of disease • KIT mutation • initial tumor load and diameter of longest lesion

20. Multivariate model

21. Objectiveresponse

22. Progression-free survival

23. Overallsurvival

25. Conclusions • A large trial in a rare cancer, carried out on a wide inter-groupbasisat the beginning of the imatiniblearning curve • At a median FU of 10 yrs, lessthan 10% and 15% of pts, respectively, were long-termprogression-free and overallsurvivors • No differencebetween400 and 800 mg /d, though the subgroup of exon 9 mutatedptswasalreadyshownseparately to benefit from the higher dose • Mutational status and initialtumorburdenwereprognosticfactorsalso on a long follow-up • An evenlonger follow-up and «high-resolution» assessmentsneeded to characterize long-termprogression-free survivorseitheras a specific subset biologically, or just the expression of stochasticprocessesleading to secondaryresistance

28. Participatinginstitutions