Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial.
BACKGROUND
The effect of imatinib discontinuation on progression-free survival and overall survival in long-lasting responders with advanced gastrointestinal stromal tumours (GIST) is unknown. We assessed treatment interruption in patients with non-progressive disease according to the Response Evaluation Criteria In Solid Tumors criteria after 3 years of imatinib in a randomised trial.


METHODS
In this open-label national multicentre phase 3 study in France, patients with GIST free of progression after 3 years of imatinib 400 mg/day were randomly assigned to continue or interrupt imatinib. Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of two and four patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. An interim analysis was planned after the first 50 randomly assigned patients. Analysis was done according to the intention-to-treat principle-ie, all patients randomly assigned to a study group were included. This study is registered with ClinicalTrial.gov, number NCT00367861.


RESULTS
434 patients were enrolled in this trial between May 27, 2002, and May 5, 2009. Between June 13, 2005, and May 30, 2007, 50 patients with non-progressive disease who had received 3 years of treatment with imatinib were randomly assigned to continue or interrupt their treatment, 25 patients in each group. By Dec 7, 2009, after a median follow-up of 35 months (95% CI 33-38) after random assignment, 2-year progression-free survival was 80% (95% CI 58-91) in the continuation group and 16% (5-33) in the interruption group (p < 0·0001). There was no difference in adverse events grade 3 or greater (oedema and asthenia) between the two groups.


CONCLUSIONS
Imatinib interruption after 3 years in responders results in a high risk of rapid progression in patients with advanced GIST. Discontinuation of imatinib is not recommended outside clinical trials unless patients experience significant toxic effects.


BACKGROUND
Conticanet, the Ligue Contre Le Cancer du Rhone, and Novartis.
Le Cesne
Axel
A
Institut Gustave Roussy, Villejuif, France. lecesne@igr.fr
Ray-Coquard
Isabelle
I
Bui
Binh Nguyen
BN
Adenis
Antoine
A
Rios
Maria
M
Bertucci
François
F
Duffaud
Florence
F
Chevreau
Christine
C
Cupissol
Didier
D
Cioffi
Angela
A
Emile
Jean-François
JF
Chabaud
Sylvie
S
Pérol
David
D
Blay
Jean-Yves
JY
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005602:France; D005770:Gastrointestinal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate