52O - Resistance to imatinib induced by treatment interruption in advanced GIST: Long-term outcome of the randomized BFR14 study

Background

The long-term impact of tyrosine kinase inhibitor (TKI) interruption on resistance and survival in patients with advanced GIST is unclear. We report here on the long-term outcome of patients with advanced GIST stopping imatinib in the BFR14 randomized study.

Methods

Patients with advanced GIST (any mutation) aged >=18 with a PS 0-3, adequate renal and hepatic function were eligible in the BFR14 study. Patients in complete or partial response, or stable disease at 3 time periods (1 year, 3 years, 5 years) were proposed for randomisation between treatment discontinuation and restart at progression (STOP arm) or continuation of the treatment until progression (CONT arm). Randomization at 1, 3 and 5 years took place from Feb 2003 to Mar 2004, May 2005 to May 2007, and Nov 2007 to Jul 2010 respectively. The primary objective was to compare progression free survival (PFS) in the two groups. Secondary endpoints included overall survival (OS) and time to imatinib resistance (TTIR), defined as the time between randomisation and progression on imatinib (i.e., after restart in the stop arm). Median follow-up after 1, 3, and 5 years randomisations were 234, 200 and 164 months respectively.

Results

Among the 434 patients included in the BFR14 trial, respectively 58 were randomized in the STOP and CONT arms after 1 year, 50 after 3 years, and 27 after 5 years. Two were lost for follow-up. PFS was significantly improved in the CONT vs STOP arms in the three randomization periods. (p<0.001). The TTIR was significantly shorter for patients randomized in the STOP vs CONT arms after 3-years (66 vs 127 months, p=0.009), and after 5-years of imatinib (58.6 vs NR, p=0.03), while no significant difference was found for those randomised after 1 year. Survival after the randomization at 1 year was not significantly different but median OS were 66 vs 127 months in the STOP and CONT arms. Survival after randomization at 3 years was significantly shorter in the STOP arm after 10 year (logrank p=0.005, 15 year survival 5% vs 42%). Survival after randomization at 5 years was not significantly different.

Conclusions

In this randomized study, matinib interruption in non-progressing GIST patients was associated with faster resistance to imatinib and shorter OS in the long-term.

Clinical trial identification

NCT00367861.

Editorial acknowledgement

none

Legal entity responsible for the study

Centre Léon Bérard.

Funding

Novartis, Ligue contre le Cancer, Fondation ARC, NOT PHRC.

Disclosure

J-Y. Blay: Financial Interests, Institutional, Invited Speaker: MSD, MSD, PharmaMar; Financial Interests, Institutional, Advisory Board: Bayer, GSK, Roche; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Other, member of the supervisory board. No remunerations in 2021 and 2022: Innate Pharma; Financial Interests, Personal, Member of Board of Directors: Transgene; Financial Interests, Institutional, Funding: MSD, BMS, Deciphera; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bayer, GSK, Novartis, OSE pharma. F. Duffaud, M. Toulmonde, N. Firmin, E. Bompas, S. Salas, C. Honoré, M. Pracht, D. Perol, S. Chabaud, A. Le Cesne: Financial Interests, Personal and Institutional, Research Grant: Novartis. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmun, Eisai, Sutro, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. M. Brahmi: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Amgen, PharmaMar, Deciphera. A. Dufresne: Non-Financial Interests, Personal, Project Lead, Translational research project: GSK, Adaptimmune; Non-Financial Interests, Personal, Project Lead, Translational research program: Bayer. N. Penel: Financial Interests, Institutional, Research Grant, Research grant for clinical trials in sarcoma filed: Bayer HealthCare. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Invited Speaker: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. All other authors have declared no conflicts of interest.