1. Surgical resection of metastatic GIST on imatinib delays recurrence and death: results of a cross- match comparison in the EORTC Intergroup 62005 study P. Hohenberger, S. Bonvalot, S.Litiere, P. Rutkowski, F. van Coevorden, P.Meeus, S.Marreaud, V.Artigas Raventos, D. Kotasek, W. van der Graaf, A. Gronchi

2. Since the introduction of imatinib, the median survival of metastatic GIST has much improved. Several mono-institutional series have exploited the possible role of surgery in combination to IM Surgery is safely combinable to imatinib in metastatic patients Better results may be obtained if performed on patients with stable responding disease as compared to patients with progressing disease. Rationale 2

3. Residual disease (A) vs. single progressive (B) 80 patients Mannheim / Milano Mussi et al., Ann. Oncol 2009; 21: 403-8 Progression-free survivalOverall survival

4. Total number239 male : female51 : 49 Median age at diagnosis55 yr Median age at surgery for M158 yr Liver25% Peritoneum46% Liver & peritoneum18% Other11% R0/R1 resection189 (79%) R2 resection50 (21%)

5. S.Bauer et al., Eur J Surg Oncol 2014 Remission Progression

6. Factor Hazard ratioP Female > male1.9 (1-3.6).038 Interval of IM to surgery2.04 (1.14-3.6).044 R0/1 vs R22.26 (1.1-4.7).001 PR/SD vs PD3.98 (1.95-8.1).00001 Site of mets: liver vs.other3.24 (.06-16.6)0.012 Multivariate analysis S.Bauer et al., Eur J Surg Oncol 2014

7. Time to progression on imatinib and tumor load Blanke C, et al. JCO. 2008;26(4):626-632. 7

8. Figure Bardsley, Gastroenterology 2010: 139: 942-52 Heinrich, The Lancet Oncology 2010; 11:910-911The Lancet Oncology 2010; 11:910-911 Which part of the tumor do we attack ? Imatinib no effect ! Surgery ?

9. Background  EORTC 62005 aimed at assessing the clinical activity of imatinib at two dose levels in patients with unresectable or metastatic GIST  ‘sister study’: SWOG-033  Activation/closure: Feb 13, 2001 / Feb 8, 2002  No. pts: randomized/required: 946 / 600  Primary endpoint:PFS

10. Biopsy proven metastatic or unresectable GIST with immune- histochemical documentation of KIT (CD117) expression by tumor documented by DAKO antibody staining Measurable or non-measurable disease assessed within 28 days prior to treatment start. No brain metastasis. WHO PS 0-3. Age greater than 18 years. No chemotherapy, biologic therapy or any other investigational drug for any reason within 28 d prior to treatment start. Resolution of transient toxicities from any prior therapy to ≤ Grade 1. No major surgery within 14 days prior to treatment. Inclusion criteria

11. 11 Verweij J et al Lancet. 2004;364(9440):1127-34 Trial result of 62005

12. Primary: To match patients operated while the disease was in response (CR, PR, or SD) with those who were in response at the same time interval from imatinib start Compare survival of patients after surgery for residual disease with the theoretical survival after surgery of the matched patients. Aim of the analysis 12

13. All patients: for descriptive statistics of baseline characteristics by surgery yes/no Surgery populations: all patients for whom surgery was performed For matching patients with surgery of residual disease: only those patients without surgery who achieved at least a CR, PR or SD For matching patients with surgery for progressive disease: only those patients without surgery who progressed on study The clinical cut-off was May 27, 2013 Analysis population 13

14. 14 N=946 Surgery N = 175 Surgery info available N = 164 Residual disease after response N = 35 Emergency N = 15 Progressive disease N = 96 Other reason N = 18 No surgery N = 771 Best response PD N = 120 Best response CR/PR/SD N = 651

15. Cross match groups (2) 15 No surgery N = 771 Progression-free N = 109 Progression or dead N = 662

16. 16 Surgery (RD) performed Total (N=58) Yes (N=29) No (N=29) N (%) Treatment A-400mg 19 (65.5) 38 (65.5) B-800mg 10 (34.5) 20 (34.5) Age group <40 yrs 3 (10.3) 4 (13.8) 7 (12.1) 40-50 yrs 6 (20.7) 9 (31.0) 15 (25.9) 50-60 yrs 8 (27.6) 5 (17.2) 13 (22.4) 60-70 yrs 9 (31.0) 6 (20.7) 15 (25.9) >70 yrs 3 (10.3) 5 (17.2) 8 (13.8) Performance status 0 18 (62.1) 36 (62.1) 1 11 (37.9) 22 (37.9) Gender male 17 (58.6) 15 (51.7) 32 (55.2) female 12 (41.4) 14 (48.3) 26 (44.8) Delay since initial disease diagnosis <12 months 14 (48.3) 28 (48.3) 12-24 months 5 (17.2) 10 (17.2) >24 months 10 (34.5) 20 (34.5) Site of origin Retro-intra abdominal 6 (20.7) 3 (10.3) 9 (15.5) Visceral gastro intestinal 23 (79.3) 26 (89.7) 49 (84.5) prior surgery no 5 (17.2) 6 (20.7) 11 (19.0) yes 24 (82.8) 23 (79.3) 47 (81.0) Prior radiotherapy No 28 (96.6) 56 (96.6) Yes 1 (3.4) 2 (3.4) prior chemotherapy no 20 (69.0) 23 (79.3) 43 (74.1) yes 9 (31.0) 6 (20.7) 15 (25.9) Baseline tumor load (mm) <= 50mm 4 (13.8) 5 (17.2) 9 (15.5) 50-80mm 4 (13.8) 2 (6.9) 6 (10.3) 80-120mm 6 (20.7) 1 (3.4) 7 (12.1) >120mm 15 (51.7) 21 (72.4) 36 (62.1) Kit mutation Exon 11 9 (31.0) 12 (41.4) 21 (36.2) Wild Type 2 (6.9) 4 (6.9) Unknown 18 (62.1) 15 (51.7) 33 (56.9) Cross-match for residual disease Total (N=58) Yes (N=29) No (N=29) N (%) Treatment A-400mg 19 (65.5) 38 (65.5) B-800mg 10 (34.5) 20 (34.5) Age group <40 yrs 3 (10.3) 4 (13.8) 7 (12.1) 40-50 yrs 6 (20.7) 9 (31.0) 15 (25.9) 50-60 yrs 8 (27.6) 5 (17.2) 13 (22.4) 60-70 yrs 9 (31.0) 6 (20.7) 15 (25.9) >70 yrs 3 (10.3) 5 (17.2) 8 (13.8) Performance status 0 18 (62.1) 36 (62.1) 1 11 (37.9) 22 (37.9) Gender male 17 (58.6) 15 (51.7) 32 (55.2) female 12 (41.4) 14 (48.3) 26 (44.8) Delay since initial disease diagnosis <12 months 14 (48.3) 28 (48.3) 12-24 months 5 (17.2) 10 (17.2) >24 months 10 (34.5) 20 (34.5)

17. 17 surgery performed Total (N=122) Yes (N=61) No (N=61) N (%) Treatment A-400mg 32 (52.5) 35 (57.4) 67 (54.9) B-800mg 29 (47.5) 26 (42.6) 55 (45.1) Age group <40 yrs 6 (9.8) 12 (9.8) 40-50 yrs 14 (23.0) 12 (19.7) 26 (21.3) 50-60 yrs 17 (27.9) 21 (34.4) 38 (31.1) 60-70 yrs 21 (34.4) 19 (31.1) 40 (32.8) >70 yrs 3 (4.9) 6 (4.9) Performance status 0 34 (55.7) 36 (59.0) 70 (57.4) 1 26 (42.6) 24 (39.3) 50 (41.0) 2 1 (1.6) 2 (1.6) Gender male 41 (67.2) 52 (85.2) 93 (76.2) female 20 (32.8) 9 (14.8) 29 (23.8) Delay since initial disease diagnosis <12 months 40 (65.6) 32 (52.5) 72 (59.0) 12-24 months 8 (13.1) 9 (14.8) 17 (13.9) >24 months 13 (21.3) 20 (32.8) 33 (27.0) Site of origin Retro-intra abdominal 10 (16.4) 5 (8.2) 15 (12.3) Visceral gastro intestinal 50 (82.0) 56 (91.8) 106 (86.9) Other sites 1 (1.6) 0 (0.0) 1 (0.8) prior surgery no 5 (8.2) 1 (1.6) 6 (4.9) yes 56 (91.8) 60 (98.4) 116 (95.1) Prior radiotherapy No 58 (95.1) 54 (88.5) 112 (91.8) Yes 3 (4.9) 7 (11.5) 10 (8.2) prior chemotherapy no 43 (70.5) 41 (67.2) 84 (68.9) yes 18 (29.5) 20 (32.8) 38 (31.1) Baseline tumor load (mm) <= 50mm 10 (16.4) 9 (14.8) 19 (15.6) 50-80mm 13 (21.3) 10 (16.4) 23 (18.9) 80-120mm 10 (16.4) 9 (14.8) 19 (15.6) >120mm 28 (45.9) 33 (54.1) 61 (50.0) Kit mutation Exon 11 22 (36.1) 24 (39.3) 46 (37.7) Exon 9 5 (8.2) 10 (8.2) Wild Type 3 (4.9) 1 (1.6) 4 (3.3) Other 2 (3.3) 3 (4.9) 5 (4.1) Unknown 29 (47.5) 28 (45.9) 57 (46.7) Cross-match for progressive disease surgery performed Total (N=122) Yes (N=61) No (N=61) N (%) Treatment A-400mg 32 (52.5) 35 (57.4) 67 (54.9) B-800mg 29 (47.5) 26 (42.6) 55 (45.1) Age group <40 yrs 6 (9.8) 12 (9.8) 40-50 yrs 14 (23.0) 12 (19.7) 26 (21.3) 50-60 yrs 17 (27.9) 21 (34.4) 38 (31.1) 60-70 yrs 21 (34.4) 19 (31.1) 40 (32.8) >70 yrs 3 (4.9) 6 (4.9) Performance status 0 34 (55.7) 36 (59.0) 70 (57.4) 1 26 (42.6) 24 (39.3) 50 (41.0) 2 1 (1.6) 2 (1.6) Gender male 41 (67.2) 52 (85.2) 93 (76.2) female 20 (32.8) 9 (14.8) 29 (23.8) Delay since initial disease diagnosis <12 months 40 (65.6) 32 (52.5) 72 (59.0) 12-24 months 8 (13.1) 9 (14.8) 17 (13.9) >24 months 13 (21.3) 20 (32.8) 33 (27.0)

18. 58 pts were available for the analysis of post-surgery survival, 29 whose metastatic tumor was resected while in response and 29 matched non operated patients. 13 events were observed in the surgical group, 17 in the non-resected group. 2-yr post-surgery survival:95.5% (95% CI 87.2-100) vs. 82.5% (95% CI 74.4-90.6) 5-yr post-surgery survival:63.9% (95% CI 52.4-75.3) vs. 56.0% (95% CI 43.3-68.6) Results 18

19. 19 Post-surgery PFS (residual disease)

20. Post-surgery survival (residual disease) 20

21. 21 Post-surgery PFS (residual disease)

22. 22 Post-surgery PFS (residual disease)

23. 23 Post-surgery survival (progressive disease)

24. 24 Post-surgery survival (progressive disease)

25.  Study 62005 was never intended to include surgery  Decision of surgery (yes/no) was not the result of a randomization, but clinical decision  Surgery details assessed retrospectively  Patients with high tumor load, after typical sarcoma chemotherapy, surgery, intraperitoneal chemotherapy, radiation…..  Despite large cohort only 29+29 patients to match Limitations 25

26.  Patients who underwent surgery for residual disease had a better survival “after surgery” than those who did not, especially during the first 3 years  A similar result was seen for post-surgery PFS, during the first year after surgery.  A prospective comparison, either randomized or in a comparative effectiveness fashion would be of great value. Conclusions 26