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Getting the GIST

With significantly improved survival rates, GIST is no longer a death sentence

PillsGastrointestinal Stromal Tumour (GIST) has only recently been recognised as a distinct clinical entity and was initially considered untreatable. A mere 10 years ago, a diagnosis of GIST was akin to a death sentence, carrying with it less than a 5 per cent success rate with chemotherapy and a predicted survival time of only a few years from diagnosis. However, recent advances in treatment options mean that today patients can make long-term plans after diagnosis.

In the US, about 15 per million people are diagnosed with GIST every year, making the disease the most common sarcoma of the GI tract. The tumours most frequently originate from interstitial cells of Cajal (ICCs) in the stomach or small intestine and metastasise predominantly to the liver and peritoneum.

When initially identified as a distinct clinical entity, GIST showed notorious resistance to pharmacotherapy and radiation, a high recurrence rate after primary resection and an ultimately bleak prognosis: a five-year survival rate of 50 per cent, and a median survival rate of six to 18 months for patients with metastatic or recurrent GIST (about 30 per cent of total GIST cases).

A major breakthrough came in 1998 when gain-of-function mutations in the c-kit proto-oncogene (leading to activation of the KIT receptor tyrosine kinase) or occasionally mutations in the platelet-derived growth factor receptor alpha polypetide (PDGFRA) were identified as hallmarks of GISTs; a finding that not only revolutionised the therapeutic approach to the disease, but also differentiated GIST from smooth muscle tumours and made it a unique pathological entity.

Current options
Tyrosine kinase inhibitors (TKI) are the current mainstay pharmacotherapy for GIST.

Novartis's Bcr-Abl protein TKI imatinib mesylate (Glivec/Gleevec), the first effective pharmacological therapy for GIST, has since become the standard-of-care in advanced disease. Imatinib selectively inhibits specific tyrosine kinases, including KIT and PDGFRA, and is generally well tolerated. In 2000, the first patient with treatment-refractory metastatic GIST achieved a major response after imatinib therapy. The product gained FDA approval for metastatic or unresectable GIST in 2002, and was approved for adjuvant treatment in 2008.

Response rates were 40→70 per cent, and 75-80 per cent of patients with metastatic or unresectable GIST were alive two years after starting treatment. Additionally, imatinib's high specificity, targeting only KIT and PDGFRA, led to good tolerance and a low likelihood to elicit systemic side effects.

However, for every up there is also a down, and secondary gain-of-function mutations frequently lead to imatinib resistance within the first two years of therapy; the median progression-free survival in imatinib-treated patients with advanced GIST is 20–24 months. While therapy can still be continued when only focal resistance develops (that is, when only one tumour begins to grow), multifocal resistance calls for a change in therapy. About 70 per cent of imatinib-resistant tumours have secondary mutations, and recent studies suggest that the location of these mutations should direct subsequent treatments.

Sunitinib maleate (Sutent) was one such drug whose development was driven by the quest to find an agent capable of treating patients with imatinib-resistant cancer. Manufactured by Pfizer, sunitinib targets PDGFRA, c-kit and vascular endothelial growth factor (VEGF) receptor among others, providing a double benefit by not only reducing tumour activity but also cutting off its blood supply. The drug has shown efficacy in GIST patients with acquired imatinib resistance and has been available as second-line therapy in the EU, Canada and the US since 2006 and in Japan since 2008.

A second generation TKI manufactured by Novartis, nilotinib (Tasigna), is still in clinical trials for the treatment of GIST. In contrast to first-generation TKIs, this drug uses a different transport mechanism, which leads to higher intracellular concentrations. Nilotinib had shown antiproliferative activity against imatinib-sensitive and imatinib-resistant cell lines in vitro, and early findings from a phase I study showed substantial clinical benefit; however, a second phase I study was terminated because of lack of efficacy in patients previously treated with imatinib and sunitinib; this study showed that the response was related to the location of the secondary mutation, with exon 17 mutations most sensitive to treatment.

In the ENESTg3 phase III trial in GIST patients who failed to improve with imatinib and sunitinib, no statistical differences between progression-free survival or overall survival between active and control groups were found, and the primary endpoint was not met. However, the investigators think the drug might still have benefit as third-line therapy in patients with specific mutations.

Other TKIs, such as dasatinib (Sprycel, Bristol Myers-Squibb), sorafenib (Nexavar, Bayer) and vatalinib (under development by Bayer Schering and Novartis), are also being investigated for their clinical potential in GIST.

Non-TKI approaches
Apart from TKIs, several other treatment approaches are under investigation.

Phosphatidylinositol 3-kinases (PI3K) are involved in multiple cellular functions through activation of protein kinase B (Akt); the PI3-Akt-mTOR (mammalian target of rapamycin) pathway is a requisite for tumour initiation and maintenance. Mutations of this pathway that lead to constant activation are present in many cancers, a fact that makes it an interesting target for research, as PI3/mTOR inhibition could lead to decreased tumour growth and cell proliferation. Several mTOR antagonists have already been launched for different cancers and could therefore be prescribed as off-label therapy; these include everolimus (Zortress/Certican, Novartis), sirolimus (Rapamune, Wyeth) and temsirolimus (Torisel, Pfizer). Others are still in development.

Another possible treatment approach was presented at the American Society of Clinical Oncology (ASCO) 2010 conference: switch pocket kinase inhibitors (SPKIs), which competitively bind the KIT/PDGFRA switch pocket domain, are currently under pre-clinical investigation.

The idea is that these treatments prevent mutations of the ABL kinase domains that confer imatinib resistance in leukaemia patients. In vitro studies on three SPKIs (DP-2976, DP-3636 and DP-4444) showed higher potency of SPKIs than imatinib or sunitinib in drug-resistant GIST cell lines, and against relevant GIST mutant kinases in enzyme assays. It will still be a while before these make it into human trials, but given the results, it could be well worth the wait.

Inhibitors of heat shock protein 90 (HSP90) are another novel approach in the pipeline. Heat shock proteins act as intracellular chaperones for other proteins, and HSP90 has been linked to chaperoning cancer cells, thereby enabling them to survive and thrive. Inhibition of HSP90 could therefore induce selective tumour apoptosis.

At the moment, several HSP90 inhibitors are in clinical development with varying degrees of success. One HSP90 inhibitor, retaspimycin (IPI-504, Infinity Pharmaceuticals), advanced into phase III clinical trials in GIST patients pre-treated with at least imatinib and sunitinib; however, this trial (RING trial) had to be prematurely terminated due to increased mortality in retaspimycin recipients.

Other HSP-90 inhibitors are still in phase I or II, or development has been stopped. However, second-generation HSP-90 inhibitors are in development. One of these, STA-9090, an agent with a broader activity profile than imatinib or sunitinib, and 10–100 times greater potency than first-generation HSP-90 inhibitors, has shown promising efficacy in pre-clinical trials and is currently in phase II for metastatic and/or unresectable GIST.

The future
The initiation of imatinib therapy made GIST manageable and delayed recurrence in a disease that was previously thought to be untreatable. The next stage, the discovery that sensitivity to subsequent therapy might depend on the locations of secondary mutations, has invited further investigations into patient-specific therapy.

Many hopeful therapies are in the making, whether as mono- or combination therapies, and it seems likely that further breakthroughs in GIST management can be expected in the not too distant future.

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The Author
Pipeline was written by Annika Brün of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought.
For information on Adis services, contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

3rd February 2011

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