A randomized phase III clinical trial published in Annals of Oncology on September 4, 2024 provides evidence that extending adjuvant imatinib treatment from 3 to 6 years significantly reduces the risk of recurrence in patients with high-risk localized gastrointestinal stromal tumors (GIST).
The IMADGIST study was an open-label, multicenter trial conducted across 14 centers in France. It was funded by academic grants from various French research organizations including Programme Hospitalier de Recherche Clinique (PHRC), Institut National du Cancer (INCA), and others. The study aimed to determine if prolonging adjuvant imatinib therapy for an additional 3 years beyond the standard 3-year course could improve outcomes in high-risk GIST patients.
A total of 136 patients aged 18 years or older with localized GIST were enrolled between December 2014 and April 2023. To be eligible, patients must have undergone R0 or R1 surgical resection of their primary tumor and have a risk of recurrence ≥35% according to National Comprehensive Cancer Network (NCCN) criteria. Patients also had to have completed 3 years of adjuvant imatinib therapy without disease progression. Those with known imatinib-resistant mutations were excluded.
Participants were randomized 1:1 to either stop imatinib after 3 years (standard arm, n=65) or continue for 3 additional years (6-year arm, n=71). The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival, time to imatinib resistance, response after imatinib reintroduction at relapse, and safety.
Demographic data showed the study population was balanced between arms, with a median age of 62-63 years. Primary tumor sites were predominantly gastric (44%) and small bowel (47%). The majority of patients (83%) harbored KIT exon 11 mutations. Importantly, 52 patients (38%) had a relapse risk of 35-70%, while 71 (52%) had a risk >70%.
With a median follow-up of 55 months after randomization, the study found that continuing imatinib for 6 years significantly improved DFS compared to stopping at 3 years (HR 0.40, 95% CI 0.20-0.81, p=0.008). The benefit was particularly pronounced in the 35-70% risk group, where only 1 of 31 patients in the 6-year arm relapsed versus 8 of 21 in the 3-year arm.
Interestingly, in the highest risk group (>70%), the benefit was less clear, with DFS curves converging around 60 months post-randomization. A post-hoc analysis suggested patients with tumor rupture may derive less benefit from extended adjuvant therapy, though the small sample size limits interpretation.
Importantly, the study found no significant differences in overall survival, time to imatinib resistance, or quality of life between the two arms at this point. The safety profile was similar in both groups, with muscle spasms being the only adverse event significantly more common in the 6-year arm.
The authors concluded that 3 additional years of adjuvant imatinib provides a significant reduction in relapse risk for high-risk GIST patients, particularly those in the 35-70% risk category. They suggest a 6-year duration of adjuvant imatinib should be considered a new standard for this population.
However, the study has several limitations. As an open-label trial, it was subject to potential bias. The median follow-up of 55 months is insufficient to draw conclusions about long-term outcomes like overall survival or emergence of drug resistance. The sample size was relatively small, limiting subgroup analyses. Additionally, the study used a 35% risk threshold which may be considered low by current standards, and 13 patients were found to have a risk <35% upon central review.
Despite these limitations, the IMADGIST trial provides important evidence that may change clinical practice. For medical professionals treating GIST, these results suggest that extending adjuvant imatinib to 6 years should be strongly considered for patients with a recurrence risk of 35-70%. For very high-risk patients (>70%), the decision may be less clear and require individualized consideration of risks and benefits.
The study also raises intriguing questions for future research. Longer follow-up will be crucial to determine if extended adjuvant therapy impacts overall survival or time to imatinib resistance. The observation that very high-risk patients may relapse rapidly after stopping imatinib at 6 years suggests even longer durations of therapy may be worth investigating for this group.
More broadly, the IMADGIST results may have implications beyond GIST. The authors note that exploring extended durations of adjuvant targeted therapies could be valuable in other cancers where such approaches are standard, such as HER2-positive breast cancer or BRAF-mutant melanoma.
In conclusion, this landmark study provides compelling evidence for extending the duration of adjuvant imatinib in high-risk GIST patients. While further research is needed to refine patient selection and optimize treatment duration, these results are likely to impact clinical practice in the near term, potentially improving outcomes for many GIST patients.
References
Blay JY, Schiffler C, Bouché O, et al. A randomized study of 6 versus 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse. Ann Oncol. 2024;35(12):1157-1168. doi:10.1016/j.annonc.2024.08.2343
