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Adjuvant Imatinib for GIST
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a multicenter, randomized, placebo-controlled phase III trial, imatinib (400 mg/d) administered for one year was demonstrated to enhance progression-free survival for patients with gastrointestinal stromal tumors. This study was the basis for the FDA approval for such treatment in this setting.
Source: DeMatteo RP, et al. Adjuvant imatinib mesylate after resection of localized primary gastrointestinal stromal tumors: a randomised, double blind, placebo-controlled trial. Lancet. 2009;373:1097-1104.
Prior to the introduction of effective tyrosine kinase inhibitors, the incidence and prevalence of mesenchymal tumors arising within the gastrointestinal tract was neither well-studied nor understood. What was known was that, as a group, such tumors were particularly aggressive with recurrence- and disease-related death rates, approximating 50% despite surgical resection.1,2 With the demonstration of the tyrosine kinase receptor (KIT) within gastrointestinal stromal tumor (GIST) cells3 and the discovery that gain-of-function mutations in the KIT gene are important in the pathogenesis of GIST,4-6 the introduction of targeted inhibition of that gene by imatinib has resulted in a remarkable transformation in the medical approach to this disease.5-7
With the demonstration of the effectiveness and safety of imatinib treatment for patients with metastatic GIST, the question of whether adjuvant treatment after initial surgical resection would be associated with reduced rates of recurrence and improved overall survival was raised. To address this, DeMatteo et al representing the American College of Surgeons Oncology Group (ACOSOG) Inter-group Adjuvant GIST Study Team undertook a randomized, phase III, double-blind, placebo-controlled, multicenter trial. To be eligible, adult patients treated at any of the 230 participating institutions had to have complete gross resection of a primary gastrointestinal stromal tumor of at least 3 cm in size which was immunohistochemically positive for the KIT protein. Patients were randomly assigned to imatinib 400 mg (n = 359) or placebo (n = 354) daily for one year after surgical resection. Patients and investigators were blinded to the treatment. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumor recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival.
All randomized patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had tumor recurrence or died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs. 83% [78-88] at one year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p < 0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs. 0), abdominal pain (12 [3%] vs. six [1%]), and diarrhea (ten [2%] vs. five [1%]) in the imatinib group and hyperglycemia (two [< 1%] vs. seven [2%]) in the placebo group.
This was a randomized, double-blind study of imatinib for patients with GIST at high risk for recurrence after resection. To recap, after 18 months of median follow-up, progression-free survival (PFS) was 97% in the imatinib group vs. 83% in the placebo group. The improvement in PFS was seen across a broad range of tumor sizes. The findings were sufficiently impressive both to warrant early termination of the study based upon demonstrated efficacy and to persuade the FDA to approve imatinib for use in the adjuvant setting for KIT-positive GIST patients.
It is very important for patients with GIST tumors to be correctly identified at the time of initial resection, so that the benefit of adjuvant therapy is not potentially missed. Resected tumors should be tested for the presence of the KIT tyrosine kinase receptor (CD117 stain); however, there have been reports of CD117-negative GISTs. Platelet-derived growth-factor receptor (PDGFR) staining may also prove helpful. Molecular genetic analysis of c-kit and PDGFR may not only help to identify patients with GIST but, because certain mutations in these genes are associated with imatinib resistance, testing may serve to help assess the potential benefit of therapy, as other drugs have been developed that have activity in imatinib-resistant forms of GIST.8
The duration of imatinib therapy continues to be in question. It is notable that six months after completion of adjuvant therapy, recurrences began to increase, raising the question of whether a more prolonged treatment would be associated with even greater PFS. To this end, the European Organization for Research and Treatment of Cancer (EORTC) trial 62024 is testing zero vs. two years of adjuvant imatinib and the Scandinavian Sarcoma Group trial XVIII is testing one vs. three years of treatment.
For now, there is good evidence that one year of adjuvant imatinib therapy is both safe and effective in reducing GIST recurrence. Just how long beyond that year remains unknown, and because the drug is not without some toxicity, and keeping in mind the issue of acquired resistance to this agent, medical oncologists will need to wait for the maturation of current studies before being confident that longer adjuvant treatment is in the patient's best interest.
1. DeMatteo RP, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg. 2000;231:51-58.
2. Nilsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era a population-based study in western Sweden. Cancer. 2005;103: 821-829.
3. Kindblom LG, et al. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152:1259-1269.
4. Hirota S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-580.
5. Lux ML, et al. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol. 2000;156:791-795.
6. Rubin BP, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001; 61:8118-21.
7. Joensuu H, et al. Management of malignant gastrointestinal stromal tumours. Lancet Oncol. 2002;3:655-664.
8. Demetri GD, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet. 2006;368:1329-1338.