Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial

Background The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. Methods BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteriain Solid Tumours (1.0) at1year, 3years, and 5years from the start oftreatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. Findings Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235<middle dot>2 months (IQR 128<middle dot>8-236<middle dot>6) after the 1-year randomisation, 200<middle dot>9 months (190<middle dot>2-208<middle dot>4) after the 3-year randomisation, and 164<middle dot>5 months (134<middle dot>4-176<middle dot>4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6<middle dot>1 months (95% CI 2<middle dot>5-10<middle dot>1) versus 27<middle dot>8 months (19<middle dot>5-37<middle dot>9; hazard ratio [HR] 0<middle dot>36 [95% CI 0<middle dot>20-0<middle dot>64], log-rank p=0<middle dot>0003), after 3 years of imatinib was 7<middle dot>0 months (3<middle dot>5-11<middle dot>7) versus 67<middle dot>0 months (48<middle dot>8-85<middle dot>6; 0<middle dot>15 [0<middle dot>07-0<middle dot>32], log-rank p<0<middle dot>0001), and after 5 years of imatinib was 12<middle dot>0 months (9<middle dot>0-16<middle dot>6) versus not reached (NR; NR-NR; 0<middle dot>13 [0<middle dot>03-0<middle dot>58], log-rank p=0<middle dot>0016). The median time to imatinib resistance after 1 year of imatinib was 28<middle dot>7 months (95% CI 18<middle dot>1-39<middle dot>1) versus 90<middle dot>6 months (25<middle dot>3-156<middle dot>1; HR 0<middle dot>93 [95% CI 0<middle dot>51-1<middle dot>71], log-rank p=0<middle dot>82), after 3 years was 66<middle dot>2 months (43<middle dot>0-89<middle dot>6) versus 127<middle dot>3 months (15<middle dot>0-239<middle dot>7; 0<middle dot>35 [0<middle dot>17-0<middle dot>72, log-rank p=0<middle dot>0028), and after 5 years was 58<middle dot>6 months (0 center dot 0-167<middle dot>4) versus NR (NR-NR; 0<middle dot>24 [0<middle dot>05-1<middle dot>12], log-rank p=0<middle dot>049). Median overall survival after 1 year of imatinib was 56<middle dot>0 months (95% CI 30<middle dot>3-82<middle dot>9) versus 105<middle dot>0 months (20<middle dot>6-189<middle dot>6; HR 0<middle dot>84 [95% CI 0<middle dot>46-1<middle dot>54], log-rank p=0<middle dot>57), after 3 years was 104<middle dot>0 months (90<middle dot>7-118<middle dot>7) versus 134<middle dot>0 months (89<middle dot>7-178<middle dot>3; 0<middle dot>40 [0<middle dot>20-0<middle dot>82], log-rank p=0<middle dot>0096), and after 5 years was NR (NR-NR) versus 110<middle dot>4 months (82<middle dot>7-154<middle dot>1; 1<middle dot>28 [0<middle dot>41-3<middle dot>99]; log-rank p=0<middle dot>67). Interpretation Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.