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

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 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:

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:

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

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

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

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: **HPF, High Power Field of the microscope

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

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

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

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

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

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

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

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

Patient disposition Category 12 Months 36 Months No. (%) No. (%) Randomized (Feb 2004 to Sep 2009) Included in ITT Population* No GIST at pathology review 5 (3) 10 (5) - GIST metastases at study entry 13 (7) 11 (6) Included in Efficacy Population Included in Safety Population 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

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

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

SSGXVIII: Recurrence-free survival (ITT) No. at risk (n=397) 36 Months of imatinib Months of imatinib % 47.9% 86.6% 65.6% 36 Months 12 Months Hazard ratio 0.46 (95% CI, ) P < % Median follow-up time 54 months Years

Subgroup No. of patients Hazard ratio (95% CI), RFS P value Age ≤ ( ).001 > ( ).01 Sex Male ( ).002 Female ( ).002 Tumor site Stomach ( ).005 Other ( )<.001 Tumor size ≤ 10 cm ( )<.001 >10 cm ( ).002 Mitoses/50 HPF (local) ≤ 10 mitoses ( ).33 > 10 mitoses ( )<.001 Mitoses/50 HPF (central) ≤ 10 mitoses ( ).04 > 10 mitoses ( )<.001 Tumor rupture No ( )<.001 Yes ( ).02 Tumor mutation site KIT exon ( ).34 KIT exon ( )<.001 Wild type ( ).16 Other ( ) mo better 12 mo better

SSGXVIII: RFS in Efficacy Population* No. at risk (N=358) 36 Months of imatinib Months of imatinib Hazard ratio 0.46 (95% CI, ) P < 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

No. at risk (n=397) 36 Months of imatinib Months of imatinib SSGXVIII: Overall survival (ITT) Hazard ratio 0.45 (95% CI, ) P = %92.0% 94.0% 81.7% 36 Months 12 Months % Years

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

Most frequent adverse events Adverse event Any GradePGrade 3 or 4P 12 Mo % 36 Mo % 12 Mo % 36 Mo % Anemia Periorbital edema Elevated LDH* Fatigue Nausea Diarrhea Leukopenia Muscle cramps3149< *LDH, lactate dehydrogenase

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.

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.