Advances in the Treatment and Understanding of GISTs: An Expert Interview With Dr. Margaret von Mehren

September 11, 2006

Editor's Note:

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority of GISTs express the KIT receptor (stem cell factor receptor, CD117), as shown by immunohistochemical analysis.[1] Approximately 60% of GISTs occur in the stomach, 25% in the small intestine, and 10% in the colon and rectum. The remainder arise from other sites in the GI tract or rare locations such as the gall bladder, appendix, omentum, or mesentery. GISTs account for approximately 2% of all stomach tumors, 14% of all small intestine tumors, and 0.1% of colon tumors. In the United States, the incidence is approximately 5000 new cases annually.[2] The median age at diagnosis is approximately 58 years.

After years of failed therapies, the advent of imatinib, which targets the Kit mutation, revolutionized treatment of this disease for many patients. Treatment was further advanced with the recent approval of the tyrosine kinase inhibitor sunitinib for second-line treatment. For insight into the latest understanding of the disease and the most recent developments in treatment, Medscape sat down with Dr. Margaret von Mehren, from Fox Chase Cancer Center in Philadelphia, Pennsylvania, at the American Society of Clinical Oncology (ASCO) 2006 annual meeting.

Medscape: What is new in the treatment of metastatic GIST after the failure of imatinib?

Dr. von Mehren: We are becoming more aware that we need to talk with our surgical colleagues to determine whether there is a role for surgery after oral treatment has failed. We would not always proceed to the operating room when tumors progress, but if there is one isolated area and it is resectable, a discussion with the surgeon is warranted.

Still, multiple studies have clearly shown that even when patients with metastatic GIST are completely resected, they will still need to be on some form of therapy that targets KIT because those tumors recur quickly. Data presented at ASCO on the long-term remissions with imatinib were very encouraging because the majority of patients derived benefit.[3]

The next thing to do is to look at newer agents. The one with the most data behind it is sunitinib, which in a large phase 3 study presented in 2005 showed benefit in terms of survival in patients who had failed imatinib and then went on to receive sunitinib.[4] What has been interesting and what was presented at the 2006 ASCO[5] is that there are patients with specific mutation sites who may be more sensitive to sunitinib than to imatinib. In particular, those with exon-9 mutations and potentially those with wild-type KIT -- who don't have any mutation -- may benefit more from sunitinib.

Medscape: Why do patients with small bowel GIST appear to have a poorer prognosis?

Dr. von Mehren: It appears that many more of these patients have unfavorable mutations when it comes to treatment with imatinib. Not only are they less likely to respond to imatinib, but even before imatinib therapy, they did worse. In gene expression studies, we know that if you look at patients who have GIST tumors compared with those with small bowel tumors, they are very different. So biologically, they are different tumors. Exactly what the underlying mechanism is, we don't know at this point, but we do know that they are biologically very different.

Medscape: What about adjuvant therapy -- is there any benefit to oral therapy after resection?

Dr. von Mehren: That is an ongoing question, what is best for patients with primary tumors that are resected? A number of adjuvant clinical trials are being conducted in the United States, Europe, and elsewhere asking questions about dose and duration. All patients who have metastatic disease, however, should be on therapy, even if the tumor has been completely resected.

Medscape: When are the results from the adjuvant trials expected?

Dr. von Mehren: I think it is going to be a while yet, probably another 4 to 5 years. The number of patients for the study ongoing in the United States[6] has been increased, so that study is only about 50% accrued.

Medscape: What do you anticipate in the future with respect to novel approaches for GIST?

Dr. von Mehren: More and more drugs are being tested. One of the approaches described on a poster at ASCO is combining imatinib with nilotinib (AMN107).[7] And, now that we have sunitinib, people may start asking: should we be preselecting which patients get which drug? Should we be looking at what type of mutation patients have? I think these are going to be interesting questions. I anticipate that clinical trials will be developed to look at these questions because KIT and PDGF analyses are not always available locally.

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