Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib

Montemurro, Michael; Schöffski, Patrick; Reichardt, Peter; Gelderblom, Hans; Schütte, J.; Hartmann, Jörg T.; Moos, Roger von; Seddon, Beatrice; Joensuu, Heikki; Wendtner, C. M.; Weber, Eckhard; Grünwald, Viktor; Roth, Arnaud; Leyvraz, Serge

doi:10.1016/j.ejca.2009.04.030

Cited by 134 publications

(67 citation statements)

References 24 publications

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“…A phase 1 study evaluating the safety and efficacy of nilotinib alone or in combination with imatinib reported clinical activity in imatinib-resistant patients (SD in 72% and 56% of patients, respectively), and this observation was confirmed in a recently reported compassionate use program. 78,79 Nilotinib has been investigated in a prospective multicentric phase 3 randomized clinical trial versus best supportive care, imatinib, or sunitinib in patients failing both agents, the results of which are awaited.…”

Section: High-dose Imatinib In a Neoadjuvant Settingmentioning

confidence: 99%

The role of high‐dose imatinib in the management of patients with gastrointestinal stromal tumor

Gronchi¹,

Blay

Trent

2010

Cancer

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After an era of few treatment options for patients with locally advanced or metastatic gastrointestinal stromal tumor (GIST), imatinib has emerged as the standard of care and first-line treatment for these patients. Although imatinib was initially approved at the doses of 400 and 600 mg daily, results from clinical studies established 400 mg daily as the standard initial dose for the majority of advanced GIST patients. Nevertheless, the use of high-dose imatinib (800 mg daily) has been shown to benefit patients with advanced or metastatic GIST that progresses on the standard-dose, and has been recommended in this setting by the major management guidelines in Europe and the United States. Results from the Meta-GIST meta-analysis showed that patients whose GIST harbors a KIT exon 9 mutation garner a longer progression-free survival time when treated initially with high-dose imatinib (800 mg daily) compared with those patients with KIT exon 11 or no mutations. Thus, the use of high-dose imatinib is recommended by the clinical practice guidelines in these 2 specific clinical situations. In addition, clinicians should weigh the clinical benefit of administering high-dose imatinib against the associated toxicities, as well as the proper management of dose-related side effects. Cancer 2010;116:1847-58. V C 2010 American Cancer Society.KEYWORDS: gastrointestinal stromal tumor, GIST, imatinib, Glivec, Gleevec, high-dose.Gastrointestinal stromal tumors (GISTs) are rare tumors diagnosed in a small percentage of the population (10-20 cases per million).1,2 Nonetheless, GISTs are the most common sarcoma of the gastrointestinal tract, accounting for at least 5% of all sarcomas and 82% of all gastrointestinal mesenchymal tumors.3,4 GISTs may arise anywhere throughout the gastrointestinal tract, including the lower part of the esophagus and the anorectal region. However, GISTs most commonly occur in the stomach (60%), followed by the small intestine (30%), duodenum (4%-5%), rectum (4%), esophagus (<1%) and colon (1%-2%). 5GISTs are most often characterized by strong immunoreactivity to the CD117 antigen, that is, the KIT protein. This strong KIT expression is observed on the interstitial cells of Cajal-pacemaker cells that express high levels of KIT and from which GISTs are thought to derive. 6,7 Besides KIT, 70% to 75% of GISTs stain positive for CD34, 25% to 56% stain for smooth muscle actin, 32% express S100 protein, and 1% to <5% are desmin positive. 8,9 A landmark study by Hirota et al and subsequent reports found that KIT was mutated in approximately 80% of GISTs.10,11 These KIT mutations cause ligand-independent KIT phosphorylation of the mutated protein and constitutive activation of the pathway, leading to cell proliferation and malignant transformation.10 However, KIT mutational status is independent of KIT immunoexpression, as 1) high levels of KIT are a constitutional feature and not a direct consequence of KIT mutation-related autoactivation, 9 and 2) mutant activated KIT proteins are retained within intracellular ...

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Section: High-dose Imatinib In a Neoadjuvant Settingmentioning

confidence: 99%

The role of high‐dose imatinib in the management of patients with gastrointestinal stromal tumor

Gronchi¹,

Blay

Trent

2010

Cancer

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“…Nilotinib is a potent second-generation TKI that targets c-KIT and PDGFR and has demonstrated efficacy in patients with imatinib-refractory GISTs [134]- [137]. In an open phase III trial 248 patients with advanced GIST following prior imatinib and sunitinib failure were randomized to nilotinib or best supportive care [137].…”

Section: Nilotinib and Other Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Gastrointestinal Stromal Tumors in the 21<sup>st</sup> Century

Kanthan¹,

Senger²,

Ahmed³

et al. 2014

JCT

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Gastrointestinal stromal tumours (GISTs) are rare mesenchymal lesions accounting for only 0.2% of all gastrointestinal neoplasms. These tumors arise from the interstitial cells of Cajal, with mutations described in proto-oncogenes such as KIT, PDGFRA, DOG-1, and SDH. The majority of these lesions are asymptomatic, thus the true incidence remains unknown. While patients typically undergo initial endoscopy, CT scan and/or MRI, findings are often nonspecific and require a biopsy to identify the tumor. As such, immunohistochemical evaluation is the gold-standard for the accurate diagnosis of GIST. Though surgical excision remains the gold-standard for curative management, the discovery of imatinib, a tyrosine kinase inhibitor (TKI), has revolutionized the treatment of GIST in the 21 st century as a "prototype" of molecular targeted therapy for solid tumors. Risk assessment for recurrence divides these tumors into low and high-risk categories. In the latter, a role for adjuvant therapy with TKI confers a significantly better prognosis than previously observed. However, secondary mutations conferring drug resistance remain an ongoing challenge for management, as few alternative treatment options are available for patients intolerant/refractory to TKI therapy. In this review, we summarize the epidemiology, molecular pathogenesis, clinical presentation, diagnosis, pathology features, management options, and prognostic features of GISTs.

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“…Second-generation tyrosine-kinase inhibitors (nilotinib, dasatinib), sorafenib (Nexavar) and other similar drugs (AZD 2171, XL-820) are in clinical testing (Dewaele et al, 2009;Montemurro et al, 2009). …”

Section: Unresectable or Metastatic Diseasementioning

confidence: 99%

Small Bowel Stromal Tumors: Approach by Capsule Endoscopy

Trifan¹,

Sîngeap²,

Stanciu³

2011

New Techniques in Gastrointestinal Endoscopy

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Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib

Cited by 134 publications

References 24 publications

The role of high‐dose imatinib in the management of patients with gastrointestinal stromal tumor

The role of high‐dose imatinib in the management of patients with gastrointestinal stromal tumor

Gastrointestinal Stromal Tumors in the 21<sup>st</sup> Century

Small Bowel Stromal Tumors: Approach by Capsule Endoscopy

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Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib

Cited by 134 publications

References 24 publications

The role of high‐dose imatinib in the management of patients with gastrointestinal stromal tumor

The role of high‐dose imatinib in the management of patients with gastrointestinal stromal tumor

Gastrointestinal Stromal Tumors in the 21&lt;sup&gt;st&lt;/sup&gt; Century

Small Bowel Stromal Tumors: Approach by Capsule Endoscopy

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Product

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Gastrointestinal Stromal Tumors in the 21<sup>st</sup> Century