Adjuvant Imatinib Confirmed Beneficial for RFS in High-Risk Gastrointestinal Stromal Tumors

Adjuvant imatinib (Gleevec) has demonstrated significant improvement in relapse-free survival (RFS) over a 2-year period and a mild trend toward long-term improvement in failure-free survival (FFS) as treatment of patients with high-risk gastrointestinal stromal tumors (GIST), according to 9.1-year follow-up results from a randomized phase 3 study conducted in Europe and Singapore.¹

Prior research has shown that treatment with imatinib can achieve a median survival of 5 years or more along with long-term progression-free survival (PFS). The limitation of imatinib in previous studies has been acquired resistance, which can occur after only 2 years of treatment. The randomized, open-label, multicenter phase 3 study of imatinib in patients with high-risk GIST was launched by the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group to demonstrate better outcomes by administering the drug as adjuvant therapy. The study investigators assessed both the prognostic impact of adjuvant imatinib and its impact on minimal residual disease.

The study included 908 patients from 112 sites across 12 countries. At randomization, 454 were entered into the adjuvant imatinib arm and 454 was enrolled into an observation arm. A total of 72 patients were found to be ineligible for and were not dosed or observed. The population treated or observed has a median age of 59 years (interquartile range, [IQR], 49-68), and were 51% male. Most of the patients (86%) had a performance status of 0, and gastric GIST was observed at baseline in 55% of the population.

Assessment of imatinib FFS was the primary end point, and RFS, overall survival (OS), and the incidence of adverse events were the secondary end points. According to the study’s protocol, the FFS of adjuvant imatinib was clinically significant if it achieved at least a 34.5% decrease in the risk of imatinib failure with a hazard ratio (HR) of 0.655 or less.

At a median follow-up of 9 years (IQR, 8-10), 358 patients in the adjuvant treatment arm remained imatinib-failure-free compared with 348 in the observation arm. The difference in FFS between the 2 arms was not considered to be significant (adjusted HR, 0.87; 95.7% CI, 0.65-1.15, P = .307). Sixty-six patients from the adjuvant imatinib arm versus 76 from the observation arm were later switched to another systemic therapy. Of the switch therapies, 99 patients received sunitinib (Sutent), 12 received masitinib (Kinavet), and 9 received nilotinib (Tasigna). It was noted that 6 patients died before receipt of their new systemic therapy.

A total of 326 patients either relapsed or died during the study. The RFS observed with adjuvant imatinib was significantly better than the RFS seen in the observation arm (adjusted HR, 0.71; 95% CI, 0.57-0.89; P = .002). The 5-year RFS rate in the imatinib-treated patients was 70% versus 63% for those in the observation arm, and the 10-year rates were 62.5% versus 61%, respectively. There was no difference in OS between the study arms (HR, 0.88; 95% CI, 0.65-1.21, P = .429), and survival, in general, was not different across the arms. The 10-year survival rate in the adjuvant imatinib arm was 80% versus 78% in the observation arm. Of the patients who relapsed during the study, 299 received salvage imatinib. The results for imatinib FFS and OS were consistent across the intermediate- and the high-risk subgroups evaluated in the study.

The safety of adjuvant imatinib was demonstrated in an earlier phase of the study in 392 patients who were treated for either 12 months or 36 months. It was shown that in all but 2 patients, at least one AE occurred. The most frequently seen AEs were anemia, periorbital edema, and fatigue. AEs led to discontinuation of imatinib in 13.6% of patients who were in the 36-month cohort compared with 7.7% of patients in the 12-month cohort.²

This final analysis of the trial is, therefore, confirmation of the RFS benefit of adjuvant therapy with imatinib in localized GIST.¹

_References:

_{1. Casali PG, Cesne A, Velasco A, et al.Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), Spanish Group for Research on Sarcomas (GEIS). Ann Oncol. Published online January 19, 2021. Accessed February 19, 2021. doi:10.1016/j.annonc.2021.01.004}

_{2. Joensuu H, Eriksson M, Hall KS, et al. Adjuvant imatinib for high-risk gi stromal tumor: Analysis of a randomized trial. J Clin Oncol. 2016;34(3):244-250. doi:10.1200/JCO.2015.62.9170}