1. Twelve vs. 36 months of adjuvant imatinib as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO) H. Joensuu, M. Eriksson, J.Hartmann, K. Sundby Hall, J. Schütte, A. Reichardt, M. Schlemmer, E. Wardelmann, G. Ramadori, S. Al-Batran, B.E.Nilsson, O. Monge, R. Kallio, M. Sarlomo-Rikala, P. Bono, M. Leinonen, P. Hohenberger, T.Alvegård, P. Reichardt

2. Gastrointestinal stromal tumor (GIST) Most common mesenchymal tumor of the GI-tract –Incidence ~10 cases/million/year GISTs have variable malignancy potential High-risk GIST –Consist of large (>5 cm) tumors with a high cell proliferation rate –Associated with ≥50% 5-year risk of recurrence after surgery 1-3 1 Nilsson B et al. Cancer 2005; 103:821-9; 2 Hassan I et al. Ann Surg Oncol 2008; 15:52-9; 3 Rutkowski P et al. Ann Surg Oncol 2007; 14:2018-27

3. Adjuvant imatinib in GIST: Rationale Inhibits the tyrosine kinases frequently mutated in GIST: KIT and PDGFR  Effective in the treatment of advanced GIST One year of adjuvant imatinib improved RFS compared to placebo in the ACOSOG Z9001 trial 1 KIT Mutated in ~75% of GISTS PDGFRA Mutated in ~10% of GISTs 1 DeMatteo RP et al. Lancet 2009; 373:1097-104

4. SSGXVIII: Study hypothesis Three years of adjuvant imatinib may result in longer RFS as compared to 1 year of imatinib

5. Imatinib for 12 months An open-label Phase III study Imatinib for 36 months Follow-up SSGXVIII: Study design Random assignment 1:1 Stratification: 1) R0 resection, no tumor rupture 2) R1 resection or tumor rupture

6. SSGXVIII: Objectives Primary: RFS –Time from randomization to GIST recurrence or death Secondary objectives included: –Safety –Overall survival

7. SSGXIII: Key inclusion criteria Histologically confirmed GIST, KIT-positive High risk of recurrence according to the modified Consensus Criteria*: –Tumor diameter >10 cm or –Tumor mitosis count >10/50 HPF** or –Size >5 cm and mitosis count >5/50 HPFs or –Tumor rupture spontaneously or at surgery *Fletcher CD et al. Hum Pathol 2002; 33:459-65 **HPF, High Power Field of the microscope

8. SSGXVIII: Key exclusion criteria Inoperable, recurrent or metastatic GIST* Age <18 ECOG** performance status >2 >12 weeks between the date of surgery and study entry Clinically significant cardiac, hepatic, renal or bone marrow disease *Patients with operable metastases were allowed to enter until protocol amendment in October 2006; **Eastern Cooperative Oncology Group

9. Imatinib administration 400 mg daily orally with food Dose reduced to 300 mg/day when –Grade 3/4 non-hematological toxicity occurred –Grade 2 non-hematological or Grade 3/4 hematological toxicity recurred

10. Clinical assessment Assessment Interval between assessments Study months 1-36 Study months >36 Clinical examination 1 to 3 months6 months Blood cell counts and chemistry 2 to 12 weeks6 months CT/MRI of the abdomen and pelvis 6 months Grading of adverse events: the National Cancer Institute Common Toxicity Criteria version 2.0

11. Tumor pathology review Performed by 1 of the 2 study pathologists* after study entry –Confirmation of GIST diagnosis –Counting of tumor mitoses KIT and PDGFRA** mutation analysis performed centrally after study entry *E. Wardelmann, Univ. Cologne; M. Sarlomo-Rikala, Univ. of Helsinki **Platelet-derived growth factor A gene

12. Study analysis populations Intention-To-Treat Population (ITT) –Patients who signed informed consent

13. Study analysis populations Intention-To-Treat Population (ITT) –Patients who signed informed consent Efficacy Population –Patients who signed informed consent, –had GIST at pathology review, and –had no overt metastases at study entry

14. Study analysis populations Intention-To-Treat Population (ITT) –Patients who signed informed consent Efficacy Population –Patients who signed informed consent, –had GIST at pathology review, and –had no overt metastases at study entry Safety Population –Patients who took ≥1 dose of imatinib

15. Estimation of the sample size 110 RFS events required in the Efficacy Population 400 patients to be entered –Assuming a hazard ratio (HR) of 0.44 in favor of the 36-month group –Using a significance level of.05, power 0.80, 20% drop-out rate, 2-sided testing

16. Patient disposition Category 12 Months 36 Months No. (%) No. (%) Randomized (Feb 2004 to Sep 2009) 200 200 Included in ITT Population* 199 198 - No GIST at pathology review 5 (3) 10 (5) - GIST metastases at study entry 13 (7) 11 (6) Included in Efficacy Population 181 177 Included in Safety Population 194 198 - On treatment at data collection cut-off 0 (0) 19 (10) Discontinued assigned treatment 29 (15) 63 (32) - GIST recurred during treatment 4 (2) 12 (6) - Adverse event 15 (8) 27 (14) - Other reason 10 (5) 24 (12) *3 patients who withdrew consent excluded

17. Baseline characteristics (ITT) Characteristic 12-Mo group 36-Mo group Median age (range) - years 62 (23-84) 60 (22-81) Male - (%) 52 49 ECOG performance status 0 - (%) 85 86 Gastric primary tumor - (%) 49 53 Median tumor size (range) - cm 9 (2-35) 10 (2-40) Median mitosis count - /50 HPFs 10 (0-250) 8 (0-165) Tumor rupture - (%) 18 22 GIST gene mutation site - (%)* - KIT exon 9 6 7 - KIT exon 11 69 71 - KIT exon 13 2 1 - PDGFRA (D842V) 13 (10) 12 (8) - wild type 10 8 *Available for 366 (92%) out of the 397 tumors

18. RFS events and deaths* (ITT) Event12- Month group (n=199) No. (%) 36- Month group (n=198) No. (%) RFS events (recurrences or deaths) 84 (42) 50 (25) Cause of death** 25 (13)12 (6) - GIST14 (7) 7 (4) - Another cause, with recurred GIST6 (3) 3 (2) - Another cause, no GIST recurrence 5 (3) 2 (1) *Median follow-up time 54 months ** As reported by investigators

19. SSGXVIII: Recurrence-free survival (ITT) No. at risk (n=397) 36 Months of imatinib 198 184 173 133 82 39 8 0 12 Months of imatinib 199 177 137 88 49 27 10 0 60.1% 47.9% 86.6% 65.6% 36 Months 12 Months Hazard ratio 0.46 (95% CI, 0.32-0.65) P <.0001 0123456 7 0 20 40 60 80 100 % Median follow-up time 54 months Years

20. Subgroup No. of patients Hazard ratio (95% CI), RFS P value Age ≤65 2560.47 (0.30-0.74).001 >65 1410.49 (0.28-0.85).01 Sex Male 2010.46 (0.28-0.76).002 Female 1960.46 (0.28-0.76).002 Tumor site Stomach 2020.42 (0.23-0.78).005 Other 1930.47 (0.31-0.73)<.001 Tumor size ≤ 10 cm 2190.40 (0.23-0.69)<.001 >10 cm 1760.47 (0.29-0.76).002 Mitoses/50 HPF (local) ≤ 10 mitoses 2090.76 (0.43-1.32).33 > 10 mitoses 1540.29 (0.17-0.49)<.001 Mitoses/50 HPF (central) ≤ 10 mitoses 2560.58 (0.34-0.99).04 > 10 mitoses 1370.37 (0.23-0.61)<.001 Tumor rupture No 3180.43 (0.28-0.66)<.001 Yes 790.47 (0.25-0.89).02 Tumor mutation site KIT exon 9 260.61 (0.22-1.68).34 KIT exon 11 2560.35 (0.22-0.56)<.001 Wild type 330.41 (0.11-1.51).16 Other 510.78 (0.22-2.78).70 0.11.010 36 mo better 12 mo better 0.1 1.0 10

21. SSGXVIII: RFS in Efficacy Population* No. at risk (N=358) 36 Months of imatinib 177 167 157 121 71 35 7 0 12 Months of imatinib 181 163 126 81 46 25 10 0 01234567 0 20 40 60 80 100 Hazard ratio 0.46 (95% CI, 0.31-0.68) P <.0001 36 Months 12 Months 62.1% 50.3% 88.1% 67.4% % Years *Excluded: Consent withdrawn, no GIST at pathology review, or overt metastases at study entry

22. No. at risk (n=397) 36 Months of imatinib 198 192 184 152 100 56 13 0 12 Months of imatinib 199 188 176 140 87 46 20 0 SSGXVIII: Overall survival (ITT) Hazard ratio 0.45 (95% CI, 0.22-0.89) P =.019 96.3%92.0% 94.0% 81.7% 36 Months 12 Months 01234567 0 20 40 60 80 100 % Years

23. Treatment safety Category 12-month group (n=194) No. (%) 36-month group (n=198) No. (%) P Any adverse event192 (99) 198 (100).24 Grade 3 or 4 event 39 (20) 65 (33).006 Cardiac event 8 (4) 4 (2).26 Second cancer14 (7)13 (7).84 Death, possibly imatinib- related 1* (1) 0 (0).49 Discontinued imatinib, no GIST recurrence 25 (13) 51 (26).001 *Lung injury

24. Most frequent adverse events Adverse event Any GradePGrade 3 or 4P 12 Mo % 36 Mo % 12 Mo % 36 Mo % Anemia7280.08111.00 Periorbital edema 5974.002111.00 Elevated LDH*4360.00100- Fatigue48 1.0011.62 Nausea4551.2321.37 Diarrhea4454.04412.37 Leukopenia3547.01423.75 Muscle cramps3149<0.001111.00 *LDH, lactate dehydrogenase

25. Conclusions Compared to 1 year of adjuvant imatinib, 3 years of imatinib improves –RFS –Overall survival as treatment of GIST patients who have a high estimated risk of recurrence after surgery. Adjuvant imatinib is relatively well tolerated; severe adverse events are infrequent.

26. Acknowledgements Study patients Steering Group: T.Alvegård, M.Eriksson, H.Joensuu, P.Reichardt, K.Sundby-Hall. Investigators: Finland P.Bono, H.Joensuu, R.Kallio, P.-L.Kellokumpu-Lehtinen, K.Pulkkanen, R.Ristamäki Germany S.-E.Al-Batran, S.Bauer, J.Duyster, J.T.Hartmann, P.Hohenberger, D.Pink, G.Ramadori, A.Reichardt, P.Reichardt, M.Schlemmer, J.Schütte Norway O.R.Monge, A.Seternes, E.Smeland, K.Sundby Hall Sweden M.Eriksson, M.Erlanson, H.Hagberg, A.Folin, C. Linder-Stragliotto, B.Nilsson, N.Wall. Pathology review/Mutation analysis: M.Sarlomo-Rikala, H.Sihto, E.Wardelmann. Statistician: M.Leinonen. Data Safety Monitoring Board: J.-Y.Blay (Chair), A.Gronchi, D.Perol, I.Judson. SSG secretariat: J.Ceberg, E.Johansson, E.-M.Olofsson, M.Rejmyr-Davis. Study nurses, data managers and monitors. Financial support: Novartis, Academic funds. Study drug: Novartis Oncology.