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Historical Management of Gastrointestinal Stromal Tumors

Insights From: Brian Van Tine, MD, PhD, Washington University; Jean-Yves Blay, MD, PhD, Centre Leon Berard
Published: Thursday, Oct 31, 2019



Transcript: 

Brian Van Tine, MD, PhD: The treatment for gastrointestinal stromal tumors is a well-thought-out field involving multidisciplinary treatment. You go through multiple lines of oral therapy with imatinib, sunitinib, and regorafenib with multidisciplinary management along the way, watching for the occasional patient who would also benefit from surgery.

Originally the treatment for GISTs [gastrointestinal stromal tumors] came out of the mutations found in C-Kit and PDGFR with imatinib. We found this wonderful inhibitor of C-Kit really transformed untreatable disease to something that in the advanced setting became palatable. As the next step, we found that certain patients who originally failed low dose of imatinib would respond with a higher dose of imatinib. From there we found the next study that was to come out that really changed the landscape, because we actually have a second-line therapy in sunitinib.

A few years ago there was a randomized trial looking at regorafenib. And in regorafenib we then established a third line of therapy. The problem is that molecularly putting pressure on its oncogenic driver allows for new mutations that develop and cause tyrosine kinase inhibition resistance. And so we’ve been looking for new drugs to these new resistance mutations that arise in the hopes that we can actually inhibit those, and then develop the fourth and fifth and sixth lines of therapy so that we can keep pushing overall survival in patients with gastrointestinal stromal tumors.

In terms of toxicity, imatinib for most patients is well tolerated. It does have some problems with fluid retention and some periorbital edema. But in general, we can make imatinib well tolerated. I think the problem is that if you’ve been on a well-tolerated medication for a very long time and then go from that to, say, something like sunitinib, to a gastrointestinal stromal tumor patient, it’s actually a step up in toxicity. In fact, many patients don’t tolerate it well. Because of that we end up either playing around with it, which would lead to earlier point mutation appearance, or they just don’t want to take it. And then they go from that to regorafenib, which has all its problems with hand-foot syndrome, and that’s not well tolerated either. So we’re looking for ways to make these tyrosine kinase inhibitors better tolerated by patients, or just to find better tyrosine kinase inhibitors that are just more tolerable.

Jean-Yves Blay, MD, PhD: The mutation of PDGF receptor and KIT were identified 20 years ago in gastrointestinal stromal tumors. They are actually the active drivers of these tumors. These mutations are mutually exclusive. Actually, the majority of GISTs are equipped with activating mutation of KIT, and about 10% to 15% are equipped with another mutation of PDGF receptor alpha.

About 15% of the GISTs are associated with different mutations on other genes, but the majority of GIST has this mutation on these kinases. This is very important because these mutations are actionable, which means they can be treated by tyrosine kinase inhibitors, and this actually was the driving force for the development of imatinib, sunitinib, and regorafenib for the treatment of GIST in first-, second-, and third-line settings, because these kinase inhibitors block these activated kinases on the tumor.

The problem, of course, is also that resistance may emerge, and what we know from a large number of publications now is that the resistance observed in GISTs comes from the clonal selection, the selection of resistant clones equipped with the same KIT and PDGF receptor alpha-mutated proteins, but with additional mutation and coding for resistance to these tyrosine kinase inhibitors. So KIT, PDGR receptor alpha are mutated. They are the drivers of GISTs, and on top of that, if exposed to a targeted tyrosine kinase inhibitor, they may be further mutated and develop secondary resistance.

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Transcript: 

Brian Van Tine, MD, PhD: The treatment for gastrointestinal stromal tumors is a well-thought-out field involving multidisciplinary treatment. You go through multiple lines of oral therapy with imatinib, sunitinib, and regorafenib with multidisciplinary management along the way, watching for the occasional patient who would also benefit from surgery.

Originally the treatment for GISTs [gastrointestinal stromal tumors] came out of the mutations found in C-Kit and PDGFR with imatinib. We found this wonderful inhibitor of C-Kit really transformed untreatable disease to something that in the advanced setting became palatable. As the next step, we found that certain patients who originally failed low dose of imatinib would respond with a higher dose of imatinib. From there we found the next study that was to come out that really changed the landscape, because we actually have a second-line therapy in sunitinib.

A few years ago there was a randomized trial looking at regorafenib. And in regorafenib we then established a third line of therapy. The problem is that molecularly putting pressure on its oncogenic driver allows for new mutations that develop and cause tyrosine kinase inhibition resistance. And so we’ve been looking for new drugs to these new resistance mutations that arise in the hopes that we can actually inhibit those, and then develop the fourth and fifth and sixth lines of therapy so that we can keep pushing overall survival in patients with gastrointestinal stromal tumors.

In terms of toxicity, imatinib for most patients is well tolerated. It does have some problems with fluid retention and some periorbital edema. But in general, we can make imatinib well tolerated. I think the problem is that if you’ve been on a well-tolerated medication for a very long time and then go from that to, say, something like sunitinib, to a gastrointestinal stromal tumor patient, it’s actually a step up in toxicity. In fact, many patients don’t tolerate it well. Because of that we end up either playing around with it, which would lead to earlier point mutation appearance, or they just don’t want to take it. And then they go from that to regorafenib, which has all its problems with hand-foot syndrome, and that’s not well tolerated either. So we’re looking for ways to make these tyrosine kinase inhibitors better tolerated by patients, or just to find better tyrosine kinase inhibitors that are just more tolerable.

Jean-Yves Blay, MD, PhD: The mutation of PDGF receptor and KIT were identified 20 years ago in gastrointestinal stromal tumors. They are actually the active drivers of these tumors. These mutations are mutually exclusive. Actually, the majority of GISTs are equipped with activating mutation of KIT, and about 10% to 15% are equipped with another mutation of PDGF receptor alpha.

About 15% of the GISTs are associated with different mutations on other genes, but the majority of GIST has this mutation on these kinases. This is very important because these mutations are actionable, which means they can be treated by tyrosine kinase inhibitors, and this actually was the driving force for the development of imatinib, sunitinib, and regorafenib for the treatment of GIST in first-, second-, and third-line settings, because these kinase inhibitors block these activated kinases on the tumor.

The problem, of course, is also that resistance may emerge, and what we know from a large number of publications now is that the resistance observed in GISTs comes from the clonal selection, the selection of resistant clones equipped with the same KIT and PDGF receptor alpha-mutated proteins, but with additional mutation and coding for resistance to these tyrosine kinase inhibitors. So KIT, PDGR receptor alpha are mutated. They are the drivers of GISTs, and on top of that, if exposed to a targeted tyrosine kinase inhibitor, they may be further mutated and develop secondary resistance.

Transcript Edited for Clarity
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