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Metastatic GIST: Significance of exon 9 mutations

DR LOVE: Dr Trent, can you discuss the significance of the KIT exon 9 mutation?

DR TRENT: Exon 9 is in the extracellular domain. Nobody is exactly clear as to how it makes KIT active, but it clearly does.

The other peculiar characteristic of the exon 9 mutation is that a dose-response relationship is apparent in the study by Maria Debiec-Rychter comparing 800 to 400 milligrams per day of imatinib (Debiec-Rychter 2006; [1.5]).

What I’ve done with a few patients — and I only have two patients in whom I’ve tried this — is to offer them a third option of increasing the dose of imatinib up to 1,200 milligrams daily. Interestingly, in both patients, I was able to either slow the growth of their disease or actually decrease the density of and slightly shrink the tumor.

I started one patient on 400 milligrams of imatinib. When his disease progressed, I increased the dose to 600 milligrams and his disease stabilized.

When the disease again progressed, the dose of imatinib went up to 800 milligrams and again his disease stabilized. Eventually when the disease progressed, the dose went to 1,200 milligrams and his disease stabilized.

While this patient was receiving 800 milligrams of imatinib, we started testing for KIT mutations and found that he had an exon 9 mutation. He’s now alternating every other day between 1,200 and 1,600 milligrams of imatinib, and he has experienced no growth of his disease.

Some of this is his choice because he doesn’t want to switch drugs or go on a clinical trial. He wants to push imatinib as far as he can, and that’s what we’ve been doing.

DR LOVE: What do we know about efficacy and side effects with this kind of dosing? Has it been reported in the literature?

DR TRENT: I don’t believe so. In the couple of patients with an exon 9 mutation whom I’ve treated, I believe there is some efficacy.

It’s not been a home run in which the patient has had a partial or a complete response, but it has had some activity. In these few patients, the side effects have been manageable.

Metastatic GIST: Mechanisms of resistance to imatinib

DR LOVE: Can you discuss what we know about the mechanisms of resistance to imatinib?

DR DEMETRI: Once imatinib fails, the vast majority of patients will have a second mutation. If the first mutation is exon 11, it’s not uncommon for the next mutation, unfortunately, to show up down in the kinase domain of exon 17, which essentially renders every small molecule useless.

Some secondary mutations show up in exon 13 of the same strand of DNA that encodes the KIT protein.

When this occurs, the ATP-binding site of the protein will have a mutation that excludes imatinib, but sunitinib can still bind. Wonderful structural studies are being conducted to explain this kind of resistance.

Metastatic GIST: Sunitinib as second-line therapy

DR LOVE: Dr Trent, would you talk about what we know about sunitinib in GIST (1.6)?

DR TRENT: Sunitinib is now FDA approved in the second-line setting for the treatment of patients with GIST who have experienced disease progression on or are intolerant to imatinib.

A Phase II study (George 2006) and a large Phase III study (Demetri 2006) demonstrated that sunitinib has activity in this setting.

In the Phase III study, sunitinib was compared to placebo, and patients were randomly assigned in a two-to-one fashion. The patients who were treated with sunitinib had a median progression-free survival of about six months, which was better than the median progression-free survival in the control arm of about six weeks (Demetri 2006; [1.7]).

Additionally, many responses were observed on PET scanning. So sunitinib clearly has activity. I’ve used it a fair amount in my practice. Many patients don’t respond, but it has reasonable efficacy in some patients.

The side-effect profile of sunitinib is a little different from that of imatinib. With imatinib, patients develop a lot of edema and periorbital edema, which can be a big problem.

Patients who are treated with sunitinib don’t tend to develop that same degree of edema, electrolyte imbalances or problems with fluid shift.

Sunitinib, however, does pose a risk for hypothyroidism and hypertension due to its inhibition of the VEGF receptor. Sunitinib clearly has efficacy and is commonly used in the second-line setting.

DR LOVE: What schedules are used with sunitinib?

DR TRENT: The schedule that was approved was 50 milligrams per day, four weeks on and two weeks off. This daily dose is difficult for many patients to tolerate, and they embrace the two weeks off.

In the study, however, during the two weeks off, patients’ PET scans showed flares. If you perform a PET scan after four weeks of sunitinib, you see a great response in some patients. Then they take two weeks off, and by the time they start the drug again, their PET scan shows tumor activity again and their tumor is flaring up.

So many people in the GIST community of medical oncologists are using the 37.5-mg daily dose, which is better tolerated.

The patient takes it daily, and you’re able to avoid the interruption of kinase inhibitor therapy, which we’ve come to realize is not the best approach for this disease.

DR PIZZOLATO: Are you seeing the same kinds of responses with sunitinib that one sees with imatinib? If not, do you think that’s because we’re not using it as first-line therapy?

DR DEMETRI: The small subset of patients who receive sunitinib because they’re imatinib intolerant are the ones, in our experience, who can derive enormous — three-year or four-year — benefit from sunitinib. I believe the sunitinib data are inevitably contaminated by the fact that we are evaluating it in patients of whom the majority started with exon 11 mutations and were imatinib and sunitinib sensitive and then developed a secondary mutation, including the exon 17 mutation. That will make the data with sunitinib or any small molecule as second-line therapy appear inferior to any up-front drug.

One might ask why we have not yet performed an up-front comparison of sunitinib and imatinib. I believe that study will be conducted. The issue will be the trade-off between toxicity and long-term disease control. I suspect that sunitinib will be as effective, if not better, than imatinib, but the toxicity profile of sunitinib will be harsher