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The first step in the current understanding of gastrointestinal stromal tumour (GIST) came in 1987 with the cloning of the human gene KIT. The KIT oncogene, located on chromosome 4, was found to encode a receptor-tyrosine kinase (KIT) capable of self-phosphorylation on tyrosine residues in cancer cells.

In 1998, a team of researchers at Osaka University Medical School, Osaka, Japan, led by Seiichi Hirota, MD, PhD, established the connection between gain-of-function KIT mutations and GIST. These mutations resulted in continuous, ligand-independent activation of the KIT tyrosine kinase.Moreover, transfection of mutant KIT in murine lymphoid cells induced malignant transformation, suggesting that KIT mutations have a pathogenetic role in GIST³⁵.

The year 2000 would be a watershed year in terms of the expanding activity profile of STI571 (Glivec^® [imatinib]), especially as it related to GIST. Results from 2 separate studies found that in addition to selectively inhibiting the ABL and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, STI571 also inhibited KIT. Michael C. Heinrich, MD, and colleagues at the Oregon Health and Science University, Portland, Oregon, USA, treated 2 human cell lines expressing KIT with STI571 and found that it potently inhibited KIT autophosphorylation as well as the activation of downstream proteins involved in cellular proliferation and survival³⁶. Later the same year, the Novartis scientist Elisabeth Buchdunger, PhD, reported similar results showing that STI571 inhibited KIT-mediated signal transduction in vitro³⁷.

Heikki Joensuu, MD, of Helsinki University Central Hospital in Helsinki, Finland, reported the results of Glivec treatment in a 50-year-old woman with GIST who, despite repeated surgeries and multiple cycles of conventional chemotherapy over a 2-year period, continued to have aggressive, metastatic disease, in the gastrointestinal tract as well as in the liver. Dr Joensuu's patient began 400-mg/d Glivec therapy in March 2000, and by the time 2 weeks of therapy for her metastatic GIST were completed, the combined volume of the 8 largest hepatic lesions had shrunk by half; further decrease in size occurred through 8 months of treatment³⁸. Later reports confirmed that she continued to receive treatment at 22 months³⁹.

Several months after the successful single-patient proof of concept in Finland, accrual began for a phase 1 study of Glivec in patients with advanced soft-tissue sarcomas, including GIST⁴⁰. This study was led by Allan T. van Oosterom, MD, PhD, of the Catholic University Hospital in Leuven, Belgium, and conducted in 3 centres of the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group. A range of Glivec doses were tested, including 400 mg once daily, 300 mg twice daily, 400 mg twice daily, and 500 mg twice daily.

Preliminary study results for 40 patients, including 36 GIST patients, demonstrated that Glivec inhibited tumour growth in 89% of patients with advanced GIST; 53% had objective partial responses according to the Response Evaluation Criteria in Solid Tumors (RECIST). Adverse effects associated with Glivec therapy were generally mild to moderate in severity, manageable, and gradually less troublesome over time. Dose-limiting adverse effects, including nausea, vomiting, oedema and dyspnoea, were associated only with the highest dose (500 mg twice daily), and myelosuppression occurred infrequently⁴⁰.

Final results demonstrated that Glivec was well tolerated and demonstrated significant activity, with 82% of patients deriving clinical benefit in the form of partial response (51%) and stable disease (31%). The investigators concluded that the 400-mg twice-daily dose of Glivec offered acceptable safety and tolerability for the treatment of advanced GIST⁴¹.

Even as the EORTC phase 1 study of Glivec in patients with advanced GIST was underway, recruitment was beginning for a larger, open-label, phase 2 study to be conducted at 4 centres in the United States and Europe. By April 2001, 147 patients with KIT-positive metastatic and/or unresectable GIST were recruited for this phase 2 study, referred to as Study B2222 or the US-Finland trial. Patients received either 400 mg or 600 mg of Glivec once daily³⁹. With follow-up of at least 9 months, 54% of patients had a partial response (50%-96% reduction in tumour bulk) and an additional 28% of patients had stable disease. The median time to objective response was 13 weeks. Like the phase 1 trial before it, this larger trial reported unprecedented responses to Glivec in patients with GIST, response to treatment was rapid, and responses were durable.

At 52-month follow-up, results of the pivotal phase 2 B2222 trial have demonstrated that 84% of patients with advanced GIST were able to achieve stable disease or better^4,5 (16% achieved stable disease, 67% achieved a partial response, and 1% achieved a complete response). The median overall survival with Glivec is 4.8 years.

A second phase 2 study testing a higher dose of Glivec (400 mg twice daily) in patients with either KIT-positive advanced GIST or other soft-tissue sarcomas was conducted by the EORTC Soft Tissue and Bone Sarcoma Group and led by Jaap Verweij, MD, PhD, of the Erasmus University Medical Center in Rotterdam, The Netherlands⁴². Among the 27 GIST patients in the study, 89% achieved clinical benefit in the form of complete response (4%), partial response (67%), or stable disease (19%). No patient in the study discontinued treatment because of toxicity, and most adverse effects, which were mild to moderate in severity, occurred during the first 8 weeks of the study. Responses to Glivec were durable, with nearly three quarters of GIST patients free from progression at 12 months.

As extraordinary results from the phase 2 studies in the United States and Europe became available, they led to speedy approval of Glivec for the treatment of GIST. The US Food and Drug Administration (FDA) approved the new indication in the United States on February 1, 2002. Health authorities in Europe soon followed, with GIST approvals granted in April, May, and July; Glivec was available in Japan by mid 2003. As with CML, Glivec was immediately recognised internationally as a major therapeutic breakthrough in the treatment of advanced GIST.

Glivec has since been established as the standard of care for advanced GIST disease⁵.

The phase 1 and phase 2 (B2222) studies provided evidence that total daily doses of 600 mg or 800 mg could induce responses in GISTs that had progressed at lower Glivec doses. To answer the question of the optimal dose of Glivec in GIST, 2 phase 3 studies were undertaken to compare rates of response and survival achieved with once- or twice-daily dosing of Glivec 400 mg.

The first study (62005), led by Dr Jaap Verweij, was conducted in 56 centres in Europe, Australia, New Zealand, and Singapore⁴³. A total of 946 patients with metastatic and/or unresectable GIST were randomly assigned to receive Glivec 400 mg once (n = 473) or twice (n = 473) daily. Patients in the 400 mg/d group were allowed to cross over to the 800 mg/d arm if their disease progressed. Both doses of Glivec resulted in similar rates of response, with median follow-up exceeding 2 years. However, Glivec 400 mg twice daily resulted in significantly superior progression-free survival (PFS)-the primary end point of the study. Treatment was fairly well tolerated.

The results of study 62005 were similar to those of the identically designed but smaller phase 3 trial (S0033) conducted by the North America Sarcoma Intergroup⁴⁴. The S0033 trial included 746 patients. Overall survival (primary end point) estimates at 2 years in the North American trial were similar for the 2 study arms (78% for the 400 mg/d arm versus 73% for the 800-mg/d arm, P > 0.05). Estimated 2-year PFS showed a trend toward improvement with the 800-mg initial daily dose (53%), compared with the 400-mg dose (50%), but did not reach statistical significance in this study

In 2 clinical studies (B2222 and intergroup study S0033), the daily dose of Glivec was escalated to 800 mg in patients progressing at the lower daily doses of 400 mg or 600 mg. The daily dose was escalated to 800 mg in a total of 103 patients; 6 patients achieved a partial response and 21 achieved a stabilisation of disease after dose escalation, for an overall clinical benefit of 26%. From the safety data available, escalating the dose to 800 mg daily in patients progressing at lower doses of 400 mg or 600 mg daily does not seem to affect the safety profile of Glivec³.

John R. Zalcberg, MD, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues assessed, in the phase 3 study (62005), the outcomes of patients who crossed over from 400 to 800 mg/d of Glivec upon GIST progression on the lower starting dose⁴⁵. At a median follow-up of 25 months from the start of the trial, 29% of patients who crossed over according to study protocol benefited from the dose increase (in the form of either partial response or stable disease) at a median of 112 days after crossover. Overall, adverse effects were manageable, with dose reductions rarely necessary. One year after crossover, 18% of patients were still alive and progression free.

The patients in the S0033 study obtained a similar benefit from dose escalation upon GIST progression. With median follow-up of 307 days after crossover from 400 to 800 mg/d, 7% of patients had partial responses and another 29% achieved stable disease⁴⁴. Both partial response and stable disease have been associated with positive survival outcomes in GIST patients^46,47.

Because of its efficacy in haematological and solid tumour malignancies, Glivec is currently being evaluated as part of a number of clinical research trials.

An active Glivec clinical study programme is continuing for CML and GIST, as well as for a variety of haematological malignancies and solid tumours. Clinicians wishing to obtain information about these trials can consult the international trial registries and Novartis Oncology.

Explore the science of Glivec in Molecular Target.

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