New Therapeutic Options in Gastrointestinal Stromal Tumors

February 1, 2008

Gastrointestinal stromal tumors have until recently had a uniformly poor prognosis with lack of effective drug therapies. These tumors usually have activating mutations in either KIT or PDGFR-α tyrosine kinase receptors. Over the past decade, imatinib (Gleevec), a selective tyrosine kinase inhibitor has become the standard of care for the first-line treatment of patients with unresectable and metastatic disease. For patients with imatinib-resistant disease or intolerant to the side effects of imatinib, sunitinib (Sutent), a multitargeted tyrosine kinase inhibitor was recently approved. For earlier-stage disease, status post–complete surgical excision, preliminary data seem encouraging for the role of adjuvant imatinib in prolonging patients' disease-free interval. The impact of neoadjuvant drug therapy needs to be further classified and explored. With additional evaluation of other tyrosine kinase inhibitors and novel therapies against other molecular markers, the treatment paradigm for this malignancy should continue to evolve.

Gastrointestinal stromal tumors have until recently had a uniformly poor prognosis with lack of effective drug therapies. These tumors usually have activating mutations in either KIT or PDGFR-α tyrosine kinase receptors. Over the past decade, imatinib (Gleevec), a selective tyrosine kinase inhibitor has become the standard of care for the first-line treatment of patients with unresectable and metastatic disease. For patients with imatinib-resistant disease or intolerant to the side effects of imatinib, sunitinib (Sutent), a multitargeted tyrosine kinase inhibitor was recently approved. For earlier-stage disease, status post–complete surgical excision, preliminary data seem encouraging for the role of adjuvant imatinib in prolonging patients' disease-free interval. The impact of neoadjuvant drug therapy needs to be further classified and explored. With additional evaluation of other tyrosine kinase inhibitors and novel therapies against other molecular markers, the treatment paradigm for this malignancy should continue to evolve.

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the gastrointestinal tract, has until recently had a uniformly poor prognosis, with effective treatment options being limited to surgical resection. Conventional cytotoxic chemotherapy has led to minimal clinical responses. Since the initial establishment of GIST as an entity distinct from gastrointestinal (GI) smooth muscle and nerve sheath tumors,[1,2] the understanding of its molecular abnormalities and distinct biology has allowed for an increased accuracy in both diagnosis and treatment.

With the advent of small-molecule tyrosine kinase inhibitors, GIST has transformed from a malignancy with a poor prognosis, to a cancer with new and exciting therapeutic options that delay progression of disease and decrease mortality. This review provides a comprehensive overview of GIST with a focus on established and promising therapies in development for the treatment of this sarcomatous tumor.

Epidemiology

Despite being a relatively uncommon neoplasm, GIST is the most common of the sarcomatous tumors of the gastrointestinal tract, with 3,000 to 6,000 new cases diagnosed each year in the United States.[3,4] That said, GISTs constitute less than 1% of all cancers.[3] Extremely small GISTs have been found in autopsy studies in 22.5% to 35% of individuals older than 50 years of age.[5,6] GISTs are typically neoplasms of older adults and show no sex bias, with the majority of men and women presenting after age 50, with a median age of 58 years.[7]

GISTs show a predilection for specific sites in the gastrointestinal tract, with 50% arising in the stomach, 25% in the small bowel, and 10% in the colon and rectum.[4] The remaining primary sites include the mesentery, omentum, and retroperitoneum. Lymphatic spread of GIST is extremely uncommon-so much so that current guidelines recommend against lymph node biopsy at the time of GIST resection.[8] Metastases typically occur in the abdominal cavity or liver. Extra-abdominal spread outside the abdominal cavity to lungs and bones is unusual and reflects an aggressive, more advanced disease process.[9]

At presentation, nonspecific clinical findings are typical. Bloating, fatigue, early satiety, obstruction, pain, and GI bleeding are all possible presentations for this tumor. A normal physical exam prompts further exploration with both endoscopy and computed tomography (CT) with final diagnosis confirmed by pathology.

Etiology

Oncogenic mutations play a critical role in the development of sarcomas. KIT is a type III receptor tyrosine kinase that is important for the development of melanocytes, germ cells, mast cells, hematopoietic stem cells, as well as the interstitial cells of Cajal and the pacemaker cells of the GI tract, which GIST cells most closely resemble. GISTs are postulated to arise from either the interstitial cells of Cajal, the pacemaker cells that stimulate gut contraction in the myenteric plexus, or from a common precursor cell that gives rise to the interstitial cells of Cajal.[10,11] Given the intimate relation between GIST and the interstitial cells of Cajal, these tumors can arise only in organs where the interstitial cells of Cajal are located, and as such, further distinguish themselves from smooth muscle and peripheral nerve sheath tumors.

As a tyrosine kinase receptor, KIT (CD117) has cell growth regulatory functions. In normal cells, KIT ligand binds and activates two KIT receptors with subsequent phosphorylation and activation of signaling pathways that lead to cell growth and proliferation. As in other cancers, mutations in KIT lead to constitutive activation of KIT in the absence of ligand, unstoppable cell growth, and tumor formation. Most GISTs contain gain-of-function, an oncogenic mutation in KIT or in platelet-derived growth factor receptor–alpha (PDGFR-α), which appears to be the major initiating event that drives the pathogenesis of GIST. KIT-activating mutations are found in 85% to 90% of GISTs,[12,13] making this a distinguishing feature to further separate this tumor from leiomyomas, leiomyosarcomas, and schwannomas.

GISTs are associated with a KIT mutation that often involves exon 9 or 11, whereas mutations in the split kinase domains (exons 13 or 17) are uncommon (< 5%).[14] These mutations are not monolithic and include deletions, insertions, and missense mutations. Approximately 4% of GISTs completely lack KIT immunoreactivity. Most of these KIT-negative GISTs harbor activating mutations in PDGFR-α.[15,16] Of these mutations in PDGFR-α, 85% occur in the second kinase domain (exon 18), of which almost two-thirds consist of a single-point mutation. Although much less common, exon 12 (juxtamembrane domain) and exon 14 (first kinase domain) mutations have also been detected.[17]

Interestingly, nearly all PDGFR-α mutant GISTs arise in the stomach, omentum, or mesentery and show epithelioid morphology.[18-21] The different KIT or PDGFR-α mutations harbored by GISTs contribute to different molecular signatures at the level of gene expression, which further contributes to the complexity of GIST biology and variable responses to treatment.[22] GISTs with neither KIT nor PDGFR-α mutations are referred to as "wild- type" GISTs. In recent years, KIT mutational status has become important as a predictive marker of how well patients with GIST will respond to biologic therapies to counter their cancer.

Treatment

Treatment options for GIST vary based on whether the tumor is local or metastatic, unresectable or accessible through surgery. For localized lesions that are deemed surgically resectable, treatment consists of complete surgical resection. Lymphatic dissection with lymphadenectomy is not recommended because of the rarity of GIST metastasizing through lymphatics. Complete surgical resection with negative margins is the mainstay of treatment and confers a 5-year survival rate of 20% to 44%.[23]

The prognosis for patients with newly diagnosed GIST has been well characterized and studied. The site and size of the primary tumor, as well as the mitotic index all contribute to risk of recurrent or metstatic disease. Tumors are stratified based on size less than 2 cm, 2 to 5 cm, 5 to 10 cm, or greater than 10 cm. Subsequent breakdowns include a mitotic index of less than or greater than 5 per 50 high-power fields and site of disease broken down to gastric, duodenum, jejunum, and ileum or rectum. The highest risk of recurrence is for large tumors with high mitotic indexes. By location, gastric tumors have the least progressive potential.[24,25]

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 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]

TABLE 1

Published Clinical Studies for Advanced Unresectable Gastrointestinal Stromal Tumors

The 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 (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.

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