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
Author(s): Prof Jean-Yves Blay, MDa,b,c; Quentin Devin, MSca,b,c; Prof Florence Duffaud, MDd; Maud Toulmonde, MDe; Nelly Firmin, MDf; Olivier Collard, MDa,b,c,g; Emmanuelle Bompas, MDh; Benjamin Verret, MDg,i; Prof Isabelle Ray-Coquard, MDa,b,c; Prof Sebastien Salas, MDd; Clemence Henon, MDg,i; Charles Honoré, MDg; Mehdi Brahmi, MDa,b,c; Armelle Dufresne, MDa,b,c; Marc Pracht, MDj; Alice Hervieu, MDk; Prof Nicolas Penel, MDl; Prof Francois Bertucci, MDm; Maria Rios, MDn; Esma Saada-Bouzid, MDo; Pauline Soibinet, MDp; David Perol, MDa,c,q; Sylvie Chabaud, PhDa,c,q; Prof Antoine Italiano, MDe; Axel Le Cesne, MDi
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 Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment 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 235·2 months (IQR 128·8–236·6) after the 1-year randomisation, 200·9 months (190·2–208·4) after the 3-year randomisation, and 164·5 months (134·4–176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5–10·1) versus 27·8 months (19·5–37·9; hazard ratio [HR] 0·36 [95% CI 0·20–0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5–11·7) versus 67·0 months (48·8–85·6; 0·15 [0·07–0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0–16·6) versus not reached (NR; NR–NR; 0·13 [0·03–0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1–39·1) versus 90·6 months (25·3–156·1; HR 0·93 [95% CI 0·51–1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0–89·6) versus 127·3 months (15·0–239·7; 0·35 [0·17–0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0–167·4) versus NR (NR–NR; 0·24 [0·05–1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3–82·9) versus 105·0 months (20·6–189·6; HR 0·84 [95% CI 0·46–1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7–118·7) versus 134·0 months (89·7–178·3; 0·40 [0·20–0·82], log-rank p=0·0096), and after 5 years was NR (NR–NR) versus 110·4 months (82·7–154·1; 1·28 [0·41–3·99]; log-rank p=0·67),
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.
FUNDING
Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
Author Affiliations
aCentre Léon Bérard, Lyon, France; bUniversité Claude Bernard Lyon I, Lyon, France; cCentre de Recherche en Cancérologie de Lyon, Lyon, France; dHopital La Timone, Marseille, France; eInstitut Bergonié, Bordeaux, France; fInstitut de Cancérologi Val d’Aurelle, Montpellier, France; gHopitaux Privés de la Loire, St Etienne, France; hInstitut de Cancérologie de l’Ouest, Nantes, France; iInstitut Gustave Roussy, Villejuif, France; jCentre Eugene Marquis, Rennes, France; kCentre George-François Leclerc, Dijon, France; lCentre Oscar Lambret, Lille, France; mInstitut Paoli-Calmettes, Marseille, France; nInstitut de Cancérologie de Lorraine-Alexis Vautrin, Vandoeuvre-lès-Nancy, France; oCentre Antoine Lacassagne, Nice, France; pInstitut Jean Godinot, Reims, France; qDirection Recherche Clinique et Innovation, Lyon, Franc;