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Gastrointestinal stromal tumor (GIST)

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).

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Gastrointestinal stromal tumor (GIST)

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  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 surgery1-3 1Nilsson B et al. Cancer 2005; 103:821-9; 2Hassan I et al. Ann Surg Oncol 2008; 15:52-9; 3Rutkowski P et al. Ann Surg Oncol 2007; 14:2018-27

  3. Adjuvant imatinib in GIST: Rationale KIT PDGFRA • 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 trial1 Mutated in ~75% of GISTS Mutated in ~10% of GISTs 1DeMatteo 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. SSGXVIII: Study design An open-label Phase III study Imatinib for 12 months Follow-up Random assignment 1:1 Stratification: 1) R0 resection, no tumor rupture 2) R1 resection or tumor rupture Imatinib for 36 months Follow-up

  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 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 Category12 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 Population181 177 Included in Safety Population 194 198 - On treatment at data collection cut-off 0 (0) 19 (10) Discontinued assigned treatment29 (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) *Median follow-up time 54 months ** As reported by investigators

  19. SSGXVIII: Recurrence-free survival (ITT) 100 % 86.6% 36 Months 80 12 Months 65.6% 60 60.1% 47.9% 40 Hazard ratio 0.46 (95% CI, 0.32-0.65) P <.0001 Median follow-up time 54 months 20 0 Years 0 1 2 3 4 5 6 7 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

  20. Subgroup No. of patients Hazard ratio (95% CI), RFS P value 36 mo better 12 mo better Age ≤65 256 0.47 (0.30-0.74) .001 >65 141 0.49 (0.28-0.85) .01 Sex Male 201 0.46 (0.28-0.76) .002 Female 196 0.46 (0.28-0.76) .002 Tumor site Stomach 202 0.42 (0.23-0.78) .005 Other 193 0.47 (0.31-0.73) <.001 Tumor size ≤ 10 cm 219 0.40 (0.23-0.69) <.001 >10 cm 176 0.47 (0.29-0.76) .002 Mitoses/50 HPF (local) ≤ 10 mitoses 209 0.76 (0.43-1.32) .33 > 10 mitoses 154 0.29 (0.17-0.49) <.001 Mitoses/50 HPF (central) ≤ 10 mitoses 256 0.58 (0.34-0.99) .04 > 10 mitoses 137 0.37 (0.23-0.61) <.001 Tumor rupture No 318 0.43 (0.28-0.66) <.001 Yes 79 0.47 (0.25-0.89) .02 Tumor mutation site KIT exon 9 26 0.61 (0.22-1.68) .34 KIT exon 11 256 0.35 (0.22-0.56) <.001 Wild type 33 0.41 (0.11-1.51) .16 Other 51 0.78 (0.22-2.78) .70 0.1 1.0 10 0.1 1.0 10

  21. SSGXVIII: RFS in Efficacy Population* 100 % 88.1% 36 Months 80 67.4% 12 Months 60 62.1% 50.3% 40 Hazard ratio 0.46 (95% CI, 0.31-0.68) P <.0001 20 0 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 Years 0 1 2 3 4 5 6 7 *Excluded: Consent withdrawn, no GIST at pathology review, or overt metastases at study entry

  22. SSGXVIII: Overall survival (ITT) 96.3% 92.0% 100 % 94.0% 80 81.7% 60 36 Months Hazard ratio 0.45 (95% CI, 0.22-0.89) P = .019 12 Months 40 20 0 Years 0 1 2 3 4 5 6 7 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

  23. Treatment safety *Lung injury

  24. Most frequent adverse events *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: FinlandP.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.

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