In IMADGIST study, extending the adjuvant treatment with imatinib from the recommended 3 to 6 years resulted in a significant reduction in the risk of recurrence after resection of primary localised gastrointestinal stromal tumour (GIST) in patients at high risk for relapse, similar in magnitude to that observed in the SSGXVIII study which defined the 3 years as standard duration of the adjuvant treatment. This benefit is obtained with a similar adverse events profile in the two arms.
A longer follow-up is required to assess the impact of 3 additional years on survival, as well as on emergence of resistance to imatinib. Given the reduction of the risk of relapse, 6 years of adjuvant treatment with imatinib for localised GIST at high risk of relapse with imatinib sensitive mutations represents a reasonable option according to Prof. Jean-Yves Blay of the Department of Medicine, Centre Leon Berard in Lyon, France, and colleagues, who published the findings on 3 September 2024 in the Annals of Oncology.
The authors wrote in the background that a large proportion of patients with GIST who receive 3 years of adjuvant imatinib will relapse in the years following the interruption of imatinib. A longer duration of adjuvant imatinib, lasting 5 years was tested in the PERSIST-5 study, without a control arm. Relapse-free survival (RFS) was 90% at 5 years; 49% of patients stopped treatment before the scheduled duration of 5 years. Whether a longer duration of imatinib treatment improves disease-free survival (DFS) has not been explored in a randomised setting.
The multicentre open-label, randomised phase III IMADGIST study was initiated in 2014 with the aim to determine whether the maintenance of imatinib for 3 more years (6 years in total arm) improves the outcome in patients with high-risk GIST compared to standard total duration of 3 years of adjuvant treatment. The study was conducted by the French Sarcoma Group. The primary endpoint was intent-to-treat DFS. Secondary endpoints include overall survival (OS), time to imatinib resistance, response after imatinib reintroduction at relapse, and safety.
From December 2014 to April 2023, a total of 136 patients aged ≥18, ECOG performance status ≤2, with a localised GIST with a R0 or R1 surgery, and a risk of tumour recurrence ≥35% according to NCCN risk classification were randomised in 14 centres; of those 65 patients were randomised to the 3 years arm versus 71 in the 6 years arm. Primary sites were gastric and small bowel in 60 (44%) and 64 (47%) patients respectively. A total of 52 (38%) and 71 (52%) of patients had a risk of relapse of 35-70% and >70%.
With a median follow-up of 55 months (IQR 46-59) post randomisation, DFS was significantly superior in the arm receiving 6 years of adjuvant treatment (hazard ratio HR 0.40, 0.20-0.69, p = 0.0008). Time to imatinib resistance, survival, adverse events, and quality-of-life were not different in the two arms.
The DFS of patients in the two risk stratification subgroups was different; within the subgroup with a 35-70% risk of relapse, only one of the 31 patients (3%) in the arm treated with 6 years of adjuvant treatment relapsed in the observation period versus eight of 21 patients (39%) in the arm of the 3 years treatment. This is the stratification subgroup benefiting the most from the 6 years duration of treatment, with a large proportion of patients non progressing after 3 additional years of treatment.
Excluding patients with tumour rupture for the 3 additional year of adjuvant treatment can be debated based on the post hoc analysis. But other patients in the high-risk (>70%) strata (with a cautious note for rupture) derive benefit, in the form of delayed relapse, from 6 years of adjuvant imatinib treatment.
Future research questions include the subsequent analysis of the time to secondary imatinib resistance and OS with a longer follow-up. In view of these results, the researchers intend to explore a longer duration of treatment with imatinib in patients at high risk of relapse (>70%) in a forthcoming IMADGIST10 study.
The authors also wrote that the results of the IMADGIST study have important implications for other cancers in which adjuvant targeted therapies is a standard treatment, such as EGFR-mutated lung cancer, ALK-mutated lung cancer, or BRAF-mutated melanoma. In these more common cancer types, a longer duration of adjuvant treatment may also deserve to be explored in a randomised setting.
The study was supported and funded by academic grants.
Reference
Blay JY, Schiffler C, Bouché O, et al. A randomized study of 6 vs 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse. Annals of Oncology; Published online 3 September 2024. DOI: https://doi.org/10.1016/j.annonc.2024.08.2343