Ten-Year Progression-Free and Overall Survival in Patients With Unresectable or Metastatic GI Stromal Tumors: Long-Term Analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup Phase III Randomized Trial on Imatinib at Two Dose Levels

Abstract

Purpose To report on the long-term results of a randomized trial comparing a standard dose (400 mg/d) versus a higher dose (800 mg/d) of imatinib in patients with metastatic or locally advanced GI stromal tumors (GISTs). Patients and Methods Eligible patients with advanced CD117-positive GIST from 56 institutions in 13 countries were randomly assigned to receive either imatinib 400 mg or 800 mg daily. Patients on the 400-mg arm were allowed to cross over to 800 mg upon progression. Results Between February 2001 and February 2002, 946 patients were accrued. Median age was 60 years (range, 18 to 91 years). Median follow-up time was 10.9 years. Median progression-free survival times were 1.7 and 2.0 years in the 400- and 800-mg arms, respectively (hazard ratio, 0.91; P = .18), and median overall survival time was 3.9 years in both treatment arms. The estimated 10-year progression-free survival rates were 9.5% and 9.2% for the 400- and 800-mg arms, respectively, and the estimated 10-year overall survival rates were 19.4% and 21.5%, respectively. At multivariable analysis, age (< 60 years), performance status (0 v ≥ 1), size of the largest lesion (smaller), and KIT mutation (exon 11) were significant prognostic factors for the probability of surviving beyond 10 years. Conclusion This trial was carried out on a worldwide intergroup basis, at the beginning of the learning curve of the use of imatinib, in a large population of patients with advanced GIST. With a long follow-up, 6% of patients are long-term progression free and 13% are survivors. Among clinical prognostic factors, only performance status, KIT mutation, and size of largest lesion predicted long-term outcome, likely pointing to a lower burden of disease. Genomic and/or immune profiling could help understand long-term survivorship. Addressing secondary resistance remains a therapeutic challenge.

Cytoreductive Surgery for Metastatic Gastrointestinal Stromal Tumors Treated With Tyrosine Kinase Inhibitors

“…Subsequently, several clinical trials demonstrated the efficacy of targeting the mutant KIT oncoprotein in patients with metastatic GIST with the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) 5 – 10 . Patients treated with imatinib experienced durable periods of disease control, with a median progression-free survival (PFS) of 2 years, and median overall survival (OS) of 5 years, compared to historical median OS of 9 months 6 .…”

Neoadjuvant Therapy to Downstage the Extent of Resection of Gastrointestinal Stromal Tumors

“…Approximately 80% of GIST tumors have a gain-of-function mutation of the c-kit or PDGF receptor [6,7,8]. Targeted therapy with the small-molecule RTKI imatinib has led to a dramatic improvement of the prognosis of patients with metastatic GIST [9,10,11]. The European Medicines Agency and the Food and Drug Administration did not only approve imatinib for the treatment of metastatic disease but also as an adjuvant therapy for patients with a significant risk of tumor recurrence [12,13].…”

Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib

“…The biological basis is unknown, but, given the similar profile of KIT exon 11 mutations across both groups, it is possible that some steps of the typical cytogenetic progression from microGIST to metastatic GIST are missed during tumor evolution in LTRs . Nonetheless, more studies are warranted to identify molecular biomarkers for LTR at baseline, as few prognostic factors at baseline have emerged from this and prior studies . This is nontrivial, because a priori stratification of patients with GIST according to response could modify management and follow‐up, given the striking differences in PFS and OS.…”

“…In the B2222 study, approximately 30% of the patients remained progression‐free after 5 years on continuous imatinib treatment . Recent updates from the two phase III trials reported a 10‐year PFS estimate of 7%–9%, therefore highlighting that a subgroup of patients with metastatic GIST are exquisitely sensitive to KIT/PDGFRA signaling inhibition with imatinib .…”