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Metastatic GIST: Salvage surgery for patients with disease progression on imatinib

DR LOVE: Should salvage surgery be attempted on patients whose disease progresses despite treatment with a tyrosine kinase inhibitor (1.8)?

DR BLANKE: Many data have emerged recently on salvage surgery in the setting of tyrosine kinase inhibitor failure, and it doesn’t work very well.

A number of series from a number of different institutions has shown that either the disease rapidly relapses systemically, or the surgery appeared easy preoperatively, but once in surgery, physicians find a lot of disease and realize they were only seeing the tip of the iceberg.

Metastatic GIST: Tolerability and efficacy of sunitinib

DR LOVE: In your experience, how is sunitinib tolerated (1.9)?

DR BLANKE: I’ve used a fair bit of sunitinib and find that patients either tolerate it unbelievably well or they feel poorly and refuse to take it.

Patients may experience severe asthenia in addition to all the classic side effects. However, it is tolerated well enough to make it worth trying for patients without other options.

I have had better luck with and prefer to use the continuous daily dosing of 37.5 milligrams, which Dr Demetri and Dr George’s group showed is probably as effective as the 50-mg dose daily for four weeks then off for two weeks (George 2008; [1.10]).

DR LOVE: What do we know about the antitumor effect of sunitinib?

DR BLANKE: The response rate with sunitinib is seven or eight percent in the original trial (Casali 2006). However, a progression-free survival benefit clearly occurs with this agent, and we know from the imatinib studies that achieving stable disease, in terms of how long the patient will live, is every bit as good as achieving an actual response.

So the fact that sunitinib can stop GISTs from growing actually means something. On the other hand, if a patient is highly symptomatic from bulky disease, sunitinib is not likely to make him or her better because of tumor shrinkage.

Metastatic GIST: Novel therapies

DR LOVE: What new combinations are being explored in the treatment of GIST?

DR BLANKE: A logical combination would be sunitinib and imatinib, but investigators have been hesitant because of the potential toxicity. Jordan Berlin at Vanderbilt has finally “bitten the bullet” and is evaluating this combination in a Phase I trial (VU-VICC-GI-0621; [1.11]).

We have little information on front-line sunitinib for GIST. Probably the drug that is furthest along is nilotinib, or AMN107, which is a kind of “super imatinib.” In the early trials it appeared promising as monotherapy and in combination, so now a randomized Phase III trial is evaluating this agent.

DR LOVE: Do you ever go back to imatinib after a patient fails second-line sunitinib?

DR BLANKE: That is one way in which treating GIST is different from treating colon cancer. If a patient with colon cancer fails FOLFOX, we do not continue to use it considering that it may be slowing the disease, even if it is not stopping it.

However, with GIST, if patients fail secondline sunitinib and for some reason can’t go on a trial, there’s nothing else to offer them, so we often go back to imatinib.

The analogy I’ve heard is that it’s like putting on the parking brake while the car is moving. It won’t stop it, but it will slow it down a bit.

We know that when you take these patients off the tyrosine kinase inhibitors, they die rapidly, but if they go back on imatinib, their disease continues to progress but they may live another few months to a year.

DR LOVE: What is the role of bevacizumab in the treatment of GIST?

DR BLANKE: Recently published data suggest that VEGF is even more important in GIST than we thought five years ago. I will be conducting a Phase III trial evaluating imatinib with or without bevacizumab for patients with metastatic or unresectable GIST (SWOG-S0502; [1.12]).

However, I would not recommend using bevacizumab off study. We know that it is safe, but the concern is with bleeding — that’s pretty much it.

Metastatic GIST: Testing for exon 9 mutations

DR HART: Do you believe that in clinical practice, mutation testing should be conducted for all patients prior to starting treatment?

DR BLANKE: The simple answer is yes, it probably should be (1.13). However, our registry data show that only three percent of physicians obtain mutational testing. It’s difficult to do because only about three labs are performing it reliably right now.

If you have a patient in a low-risk situation — for example, a gastric primary or non-small bowel tumor — I’m not sure you need to do it at all. However, if you have a patient with a small bowel primary or metastatic disease, I would recommend it. But we don’t want to blindly put those patients on the 800-mg dose. It’s much more toxic and occasionally lethal, so we don’t want to use that dose unless it’s necessary.

DR RUBIN: I’ve been telling patients who are at high risk with all sites of disease to get the testing done up front because then they have the data.

DR EISENBERG: Indications have emerged that patients with exon 9 mutations respond to sunitinib. What about the idea of using up-front sunitinib versus imatinib for these patients?

DR BLANKE: It comes down to the toxicity profile of sunitinib versus imatinib at 800 milligrams. All the data we have with sunitinib are on the second line — not to say it would be any different in a primary setting, but it might be.

Therefore, I still prefer to treat those patients with higher-dose imatinib and then use sunitinib for salvage treatment. It is amazing that no one is testing sunitinib up front, but it’s not happening.

DR LOVE: What do you think a trial comparing up-front sunitinib to imatinib would show?

DR BLANKE: I believe they would probably be fairly equivalent, but with different subsets benefiting a lot more from one drug or the other, and obviously with different toxicity profiles.