HOTSPOT 25_ V5_SS_24June11

Tutorial slides : 

1 Year vs 3 Years of Adjuvant Imatinib as Treatment of Operable GIST with a High Risk of Recurrence: The SSG XVIII / AIO Study Tutorial slides

Study Design : 

Study Design Phase III, open-label, randomized, prospective, multicenter trial Patients at high risk of recurrence following resection of primary GIST Primary endpoint: 5-year RFS High risk defined according to Fletcher criteria: Tumor diameter >10 cm OR Mitotic rate >10/50 HPFs OR Tumor diameter >5 cm and >5/50 HPFs OR Tumor spillage or rupture Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1 1-year adjuvant treatment with 400 mg/day imatinib (n=200) Follow-up: Every 6 months for a median 54 months following study completion (time required to achieve 110 events) 3-year adjuvant treatment with 400 mg/day imatinib (n=200) Randomization 1:1 randomization stratified by: 1) R0 resection, no tumor rupture; 2) R1 resection or tumor rupture

Study Hypothesis : 

Study Hypothesis 3 years of adjuvant imatinib treatment may result in longer recurrence free survival (RFS) compared with 1 year of adjuvant imatinib treatment Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Endpoints : 

Endpoints Primary endpoint RFS (time from randomization to GIST recurrence or death) Secondary endpoints Safety Overall survival (OS) Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Patient Eligibility Criteria : 

Patient Eligibility Criteria Primary Inclusion Criteria ≥18 years of age KIT+ resectable GIST >50% risk of disease recurrence within 5 years, defined as: GIST (any site) diameter >10 cm and any mitotic rate OR Any GIST diameter with mitotic rate >10/50 HPFs OR Mitotic rate >5/50 HPFs and GIST diameter >5 cm OR Tumor spillage or rupture ECOG performance status 0–2 Adequate organ function Written, voluntary informed consent Exclusion Criteria Metastatic or recurrent GIST <1 week or >12 weeks since surgery Use of any investigational agents ≤28 days prior to start of trial Use of warfarin or any investigational agents within ≤28 days of study Grade III/IV cardiac problems or pregnancy or other uncontrolled medical disease Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Study Analysis Populations : 

Study Analysis Populations Intention-To-Treat Population (ITT) Patients who signed informed consent Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Study Analysis Populations : 

Study Analysis Populations Intention-To-Treat Population (ITT) Patients who signed informed consent Efficacy Population Patients who signed informed consent AND Had GIST at pathology review AND Had no overt metastases at study entry Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Study Analysis Populations : 

Study Analysis Populations Intention-To-Treat Population (ITT) Patients who signed informed consent Efficacy Population Patients who signed informed consent AND Had GIST at pathology review AND Had no overt metastases at study entry Safety Population Patients who took ≥1 dose of imatinib Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Patient Disposition : 

Patient Disposition *3 patients who withdrew consent were excluded Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Baseline Characteristics (ITT) : 

Baseline Characteristics (ITT) *Available for 366 (92%) out of the 397 tumors Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

RFS in the ITT Population : 

RFS in the ITT Population Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

RFS Events and Deaths* : 

RFS Events and Deaths* *ITTpopulation; median follow-up time 54 months Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Predictors of 3- vs 1-year RFS Efficacy: Mutations : 

Predictors of 3- vs 1-year RFS Efficacy: Mutations HR (95% CI) KIT exon 9 26 0.61 (0.22-1.68) 0.34 KIT exon 11 256 0.35 (0.22-0.56) <0.001 Wild type 33 0.41 (0.11-1.51) 0.16 Other 51 0.78 (0.22-2.78) 0.70 3 years better 1 year better 0.1 1.0 10 Subgroup P-Value Patients, n Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1 KIT Exon 11 mutations are a significant predictor of greater RFS benefit from 3- vs 1-Year of imatinib treatment; KIT exon 9, wild type, and other mutations were not significant predictors

Predictors of 3- vs 1-year RFS Efficacy: Baseline Demographics : 

Predictors of 3- vs 1-year RFS Efficacy: Baseline Demographics HR (95% CI) Age ≤65 256 0.47 (0.30-0.74) 0.001 >65 141 0.49 (0.28-0.85) 0.01 Sex Male 201 0.46 (0.28-0.76) 0.002 Female 196 0.46 (0.28-0.76) 0.002 Tumor site Stomach 202 0.42 (0.23-0.78) 0.005 Other 193 0.47 (0.31-0.73) <0.001 Tumor size ≤ 10 cm 219 0.40 (0.23-0.69) <0.001 >10 cm 176 0.47 (0.29-0.76) 0.002 Mitoses/50 HPF (local) ≤ 10 mitoses 209 0.76 (0.43-1.32) 0.33 > 10 mitoses 154 0.29 (0.17-0.49) <0.001 Mitoses/50 HPF (central) ≤ 10 mitoses 256 0.58 (0.34-0.99) 0.04 > 10 mitoses 137 0.37 (0.23-0.61) <0.001 Tumor rupture No 318 0.43 (0.28-0.66) <0.001 Yes 79 0.47 (0.25-0.89) 0.02 0.1 1.0 10.0 3 years better 1 year better Subgroup P-Value Patients, n Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

RFS in the Efficacy Population* : 

RFS in the Efficacy Population* No. at risk (N=358) 3 years of imatinib 177 167 157 121 71 35 7 0 1 year of imatinib 181 163 126 81 46 25 10 0 0 1 2 3 4 5 6 7 0 20 40 60 80 100 Hazard ratio 0.46 (95% CI, 0.31-0.68) P <0.0001 3 years 1 year 62.1% 50.3% 88.1% 67.4% Years *Excluded: Consent withdrawn, no GIST at pathology review, or overt metastases at study entry Recurrence-Free and Alive,% Median follow-up time 54 months Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

OS in the ITT Population : 

OS in the ITT Population No. at risk (n=397) 3 years of imatinib 198 192 184 152 100 56 13 0 1 years of imatinib 199 188 176 140 87 46 20 0 Hazard ratio 0.45 (95% CI, 0.22-0.89) P =0.019 96.3% 92.0% 94.0% 81.7% 3 years 1 year 0 1 2 3 4 5 6 7 0 20 40 60 80 100 Years Alive, % Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1 Median follow-up time 54 months

Treatment Safety : 

Treatment Safety *Lung injury Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Most Frequent Adverse Events : 

Most Frequent Adverse Events *LDH, lactate dehydrogenase Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1

Conclusions : 

Conclusions 3 years of adjuvant imatinib treatment was associated with significantly greater improvements in both RFS (65.6% vs 47.9%) and OS (92.0% vs 81.7%) compared with 1-year of treatment in patients with resected GIST and a high risk of recurrence Given that the study was powered to detect between-treatment differences in RFS rather than OS, the significant OS benefit is particularly noteworthy and may have been underestimated Adjuvant imatinib was relatively well tolerated; severe AEs were infrequent, and no unexpected AEs emerged with 3- versus 1-year treatment The results of the SSGVIII/AIO trial support use of adjuvant imatinIb therapy for at least 3 years as the "standard of care" in patients with resected GIST and a high risk of recurrence The question, therefore, becomes which patient risk group would benefit from adjuvant treatment, rather than how long that treatment should be continued Joensuu H, et al. J Clin Oncol. 2011;29(suppl): Abstract LBA1