Imatinib
Until 2001, the surgical resection was the only available treatment for GIST. Cytotoxic chemotherapy, while used with varying degrees of success in the treatment of other soft-tissue sarcomas, was almost completely ineffective, with the median survival for patients with GIST being under 2 years.[26]
In 2001, a remarkable case report published in the New England Journal of Medicine described a single patient with metastatic GIST, treated with imatinib(Drug information on imatinib) mesylate (Gleevec), a tyrosine kinase inhibitor previously used and approved for the treatment of chronic myelogenous leukemia (CML).[27] Imatinib is a 2-phenylaminopyrimidine tyrosine kinase inhibitor that affects protein-tyrosine kinases including Bcr-Abl, PDGFR-α, PDGFR-beta (β), c-Fms, c-kit, and receptor encoded by the ret proto-oncogene (RET).[28]
Published Clinical Studies for Advanced Unresectable Gastrointestinal Stromal TumorsThe patient, who had not previously responded to cytotoxic chemotherapy, had widespread metastases, including eight bulky metastases in her liver that in aggregate measured 112.5 cm2. Treatment was initiated with imatinib at a dose of 400 mg daily, based on the safety of imatinib doses used for the treatment of CML. The response was dramatic. By the end of 8 months, the aggregated large liver lesions had shrunk to 28 cm2, and 6 of 28 liver metastases had entirely disappeared. This exciting discovery led to large clinical trials to assess the best treatment regimen for metastatic and/or unresectable GIST (Table 1).
Imatinib is a potent tyrosine kinase inhibitor. Its mechanism of action derives from competitively inhibiting an ATP-binding pocket and preventing downstream KIT signaling that leads to cell proliferation. After the initial case report was published, a pivotal, open-label, randomized controlled trial was conducted at multiple centers, with 147 patients assigned to either 400 or 600 mg of imatinib, administered once daily.[29] Patients on the lower dose of imatinib could dose-escalate if their tumors progressed. The study demonstrated the safety of imatinib, with adverse events limited to edema (74%), nausea (52%), diarrhea (45%), myalgias (40%), fatigue (35%), and dermatitis or rash (31%). Adverse events were generally mild or moderate in severity. The treatment response rate was reported as 54%, with 28% of patients achieving stable disease, for a disease control rate of 82%.
After the safety of imatinib in GIST was established, two studies evaluated the effect of increasing the dosage to 800 mg/d. In the first study, the European Sarcoma Group set out to establish the maximum tolerated dose of imatinib.[30] Accordingly, 8 patients were given 400 mg of imatinib once daily, 8 received 300 mg twice daily, 16 received 400 mg twice daily, and 8 received 500 mg twice daily. The maximum tolerated dose was 400 mg twice a day.
Subsequent trials have further characterized the optimal dosage for treating GIST. In one study, a dose of 400 mg was compared to 800 mg.[31] In this study, 946 patients were randomized to either the 400-mg or 800-mg treatment arm. When analyzed, 56% of patients in the low-dose treatment arm had experienced disease progression compared with 50% of patients in the high-dose treatment arm. Although a longer period of progression-free survival was noted in patients taking 800 mg/d, fewer dose reductions and treatment interruptions were noted in the group receiving 400 mg/d.
The appropriate dose of imatinib to begin therapy in patients with metastatic or unresectable GIST was evaluated in two separate phase III trials.[32,33] Patients were randomized to receiving either 400 or 800 mg of imatinib per day. The outcomes of these trials showed no survival advantage in one arm over the other, while increased toxicities were observed in patients randomized to the high-dose treatment arm. However, a recent analysis suggested that patients with mutations in KIT exon 9 may have improved disease-free survival with initial imatinib dosages of 800 mg instead of 400 mg.[34] This suggestion has yet to be confirmed in any large clinical trial. The responsiveness to imatinib correlates closely with mutational status. GISTs that harbor the KIT exon 11 mutations show an 85% response rate and those that have the KIT exon 9 mutation have a 45% response rate.
Recently published National Comprehensive Cancer Network (NCCN) guidelines recommend starting patients with metastatic or unresectable GIST on a dose of 400 mg of imatinib once a day.[8] For patients with exon 9 mutations, some recommend that patients initially receive 800 mg of imatinib every day. This recommendation, however, was graded 2B (ie, lower-level evidence, nonuniform consensus), as the efficacy of this regimen was not conclusively supported. For patients on 400 mg of imatinib who have progression of disease, the NCCN guidelines suggest that a dose escalation to 800 mg of imatinib per day may benefit some patients. However, as the studies cited above showed that the toxicities of increased dosages were difficult for many patients to endure, dose escalation may be difficult and patients may ultimately need to be switched to an alternative agent.
While the role of imatinib has been established in the metastatic or unresectable (inoperable) setting (Table 1), new data are emerging for its role in the adjuvant setting as well. Adjuvant imatinib in patients with primary high-risk GIST following complete resection was evaluated in a US Intergroup phase II trial, which confirmed the safety and tolerability of imatinib at 400 mg daily for 1 year in this group.[35]
More recently, the interim analysis of a phase III randomized double-blind study of adjuvant imatinib vs placebo in patients following the resection of primary GIST was presented. These preliminary results showed that participants with c-kit–positive GIST treated with imatinib after surgery had a significantly improved time to recurrence. The interim analysis showed no recurrence of GIST in approximately 97% of patients given imatinib for 1 year, compared to approximately 83% of those who underwent surgery but received placebo. The study had met its primary endpoint in terms of the rate of recurrence-free survival.[36]
How the use of tyrosine kinase inhibitors as neoadjuvant therapy prior to surgery fits into the treatment of GIST remains to be explored. The National Cancer Institute is conducting a clinical trial of imatinib before resection of GIST, and results are pending.
Sunitinib
Sunitinib (Sutent, SU11248) is an oral multitargeted receptor tyrosine kinase inhibitor that has shown antiangiogenic and antitumor activities in several in vitro and in vivo tumor models. These effects were associated with the blockade of receptor tyrosine kinase signaling by KIT, PDGFRs, all three isoforms of the vascular endothelial growth factor receptor (VEGFR-1, VEGFR-2, VEGFR-3), Fms-like tyrosine kinase-3 receptor (FLT3), and the RET proto-oncogene.[37-42] Although both sunitinib and imatinib bind within the ATP-binding domain of KIT and PDGFRs, they have different binding characteristics and affinities. Additionally, sunitinib inhibits the VEGFR kinases, which are important in tumor-related angiogenesis—a property not shared by imatinib.
The efficacy and safety of sunitinib in patients with advanced GIST after failure of imatinib has been evaluated in a randomized controlled trial (Table 1).[43] A total of 312 patients were randomized in a 2:1 ratio to receive sunitinib or placebo. A planned interim analysis showed a significantly longer median time to tumor progression with sunitinib vs placebo (27.3 vs 6.4 weeks, respectively). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhea, skin discoloration, and nausea. Sunitinib has since been approved for the treatment of GIST that is refractory to imatinib or for patients with intolerance to the side effects of imatinib.
Unfortunately, suntinib treatment failures have also been described. Recent examination of tumors resistant to suntinib that were subsequently resected, as well as in vitro data where mutant KIT was transfected into a Chinese hamster ovary cell line demonstrated that mutations in the KIT activation loop, as well as a novel mutation in KIT exon 16 confer resistance to sunitinib.
Novel Agents
Other tyrosine kinase inhibitors have been explored as potential treatments for metastatic or unresectable GIST. These include nilotinib(Drug information on nilotinib) (Tasigna) and masatinib.
Nilotinib was recently evaluated in a phase I clinical trial for efficacy.[44] In this trial, 53 patients who had failed prior tyrosine kinase therapies (either imatinib or sunitinib) were randomized to receive nilotinib alone at 400 mg twice a day, nilotinib at 400 mg once a day with imatinib 400 mg twice a day, nilotinib 400 mg twice a day and imatinib 400 mg twice a day, or nilotinib 400 mg twice a day and imatinib 400 mg once a day. The investigators concluded that nilotinib, either in combination with imatinib or alone, was an effective treatment for GIST. Of note, 40% of patients in the combined-treatment groups developed a skin rash. The data presented did not describe the severity of the rash nor whether it led to any treatment interruptions or morbidity such as superinfections of the skin.
Masatinib was evaluated in a phase II study presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2007. Masatinib is reported to have greater activity and selectivity against the wild-type KIT receptor and the mutated form of KIT in the juxtamembrane region. In this study, 26 patients who had not received imatinib therapy were given masatinib at 7.5 mg/kg/ d.[45] After 9 months, only 2 of the 21 patients available for review had disease progression; 11 achieved a partial response and 8 had stable disease. Like other tyrosine kinase inhibitors, the most frequent adverse events were nausea, abdominal pain, and diarrhea.
A separate novel therapy for treatment of GIST refractory to sunitinib and imatinib is IPI-504, a novel agent that inhibits heat-shock protein 90 (HSP90), a molecular chaperone that is important in the stabilization and folding of the KIT tyrosine kinase. Rather than attacking the mutant kinase itself, this novel therapy aims to prevent the mutant kinase from being trafficked to the cell surface. In a phase I investigation presented at the 2007 ASCO meeting, patients treated with IPI-504 demonstrated evidence of disease remission on 18F-fluorodeoxyglucose–positron-emission tomography (FDG-PET), CT, and histology.[46] In addition, the maximum tolerated daily dose of IPI-504 was not reached. Given this, it is possible that further escalations in the dosing of IPI-504 will lead to more dramatic responses in patients who have undergone failed therapies with tyrosine kinase inhibitors.
Conclusions
The evolution of treatment for GIST, especially metastatic and unresectable GIST, has been remarkable—from ineffective cytotoxic chemotherapy to oral tyrosine kinase inhibitors that are quite efficacious. In the course of 7 years, the prognosis, treatment, and understanding of this disease has rapidly escalated. However, the story is certainly not over.
Although a noteworthy improvement has been seen with imatinib, primary and acquired resistance has limited the effectiveness of this agent, and alternative therapies remain of utmost importance. Beyond resistance, intolerance to treatment is a realistic concern as well. With new trials being conducted to identify new therapeutic agents for GIST, further changes and challenges are likely to emerge. The role of sunitinib in the current management of patients with GIST needs further exploration. A phase III trial evaluation is planned to determine whether there is a role for first-line therapy with sunitinib instead of imatinib, and treatment based on genotype information and mutational status needs further exploration.
As treatments are evaluated and validated in the metastatic and recurrent setting, the roles of neoadjuvant and adjuvant therapy with tyrosine kinase inhibitors are being further explored as well. We anticipate that the story of treatment for GIST has just begun to be written.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
