Explosion of GIST information raises questions

By Jerry Call

GIST clinicians and researchers have done a great job in dissecting the biology of GIST. This sarcoma can now be broken down in many different categories: adult GIST, familial GIST, pediatric GIST and GISTs associated with NF1 (neurofibromatosis).

Some of these categories can be broken down further or in different ways, such as by gene mutation (c-kit, PDGFRA or wild-type for both), mutation location within the gene (exon mutation or “genotyping”), and by location of primary tumor (which may cause differences in signaling).

Compared to six years ago, we have an explosion of new information about GIST.

One of the earliest fruits of this extensive GIST research is the approval of Sutent in the United States. On Jan. 26, Sutent was approved for GIST patients with Gleevec-resistant GIST, and those patients who can’t tolerate Gleevec. This approval is great news for GIST patients in the U.S. and, hopefully, approval will soon follow in other countries. Sutent is the first treatment to be approved after failure of a molecularly targeted therapy (Gleevec).

When science advances as fast as it has in GIST, we are often left with as many questions as answers. Even before Sutent was approved, Richard Palmer, editor of  this newsletter, raised the possibility of doctors/patients combining Gleevec with Sutent once it was approved. Palmer suggested that we acknowledge this possibility in the newsletter. I was reluctant to do this for fear that it might be interpreted as tacit approval, and was content to bury my head in the sand. This lasted about a month, then patients began raising the issue (suggested by their doctors) and other questions triggered by the approval of Sutent.

Before we explore some of these new questions, it might be helpful for the reader to look at the short review of current GIST treatment guidelines that begin on page 1 (see article "Standard treatment guidelines for GIST").

The effects of Gleevec as an initial targeted therapy for GIST have been extensively studied in clinical trials. The results are well documented. The most important factor in determining whether a patient is likely to respond to Gleevec appears to be what type of mutation they have.

Patients with exon 11 mutations in KIT typically have the best response rates and the longest time to disease progression. Patients with exon 9 KIT mutations tend to have an intermediate response rate and time-to-progression. Patients with wild-type GIST (no mutations in KIT or PDGFRA) tend to have poor response rates and fairly rapid time-to-progression. Patients with exon 12 mutations in PDGFRA also tend to respond well to Gleevec; while patients with a specific type of exon 18 PDGFRA mutation, D842V, tend to be resistant to Gleevec.

The response rate of Sutent as an initial targeted therapy in GIST has not been well studied. The only results in this setting come from the few patients in the Sutent trials who were unable to tolerate Gleevec as initial therapy. While the response rate in this small group appears to be similar to initial therapy with Gleevec, the numbers are too small to make firm conclusions.

For patients with Gleevec-resistant GIST, the response rate to Sutent has been studied extensively. In this group, patients with an exon 9 KIT mutation tend to have excellent response rates, patients with wild-type GIST tend to have intermediate response rates, and patients with an exon 11 KIT mutation tend to have lower response rates.

Many of the questions about Sutent center on the response rates to exon 9 and wild-type GIST. The problem in comparing Sutent rates to Gleevec rates is that it is not an apples-to-apples comparison. The Gleevec rates are for “untreated” GISTs while the Sutent rates are for “resistant GIST.”

Still there are a number of interesting questions that cannot be answered by clinical data. For example, patients with exon 9 mutations in KIT tend to have a much better chance of having a “response” at higher doses of Gleevec. There are several theoretical possibilities for these patients (as opposed to the proven/standard recommendations) and the optimal treatment has not been defined. These same theoretical options apply to wild-type GISTs and other GISTs with a less-than-optimal history of response.

There is no data to suggest which of these options would produce the greatest benefit and we are not aware of any ongoing trial that would answer this question. It is unlikely that this data will be available in the near future.

The “standard approach” would be to start with Gleevec until disease progression, THEN crossover to Sutent. The big unanswered question would be whether the mechanisms of resistance that occur with Gleevec would be likely to emerge as early if you started with Sutent. Similar types of questions apply to neoadjuvant and adjuvant Gleevec as well; for example, would Sutent be more effective neoadjuvant therapy for exon 9 GIST?

Beyond the issue of initial treatment is the theoretical issue of combining Sutent and Gleevec either for initial treatment or for Gleevec-resistant GIST. The rational for trying this approach is two-fold: broader-spectrum of activity against secondary mutations and additional antiangiogenesis activity due to inhibition of VEFG by Sutent.

While the idea of using Sutent and Gleevec together or with another KIT inhibitor is interesting, the best place to try this would be in the context of a clinical trial. The toxicity profile and possible drug interactions of this combination have not been studied. Other questions, such as dosing schedule, and the optimal setting (initial therapy or resistant GIST) also need answers.

Large numbers of GIST patients have participated in clinical trials. This has been an important factor in the progress that has been made in treating GIST. It has also been beneficial to the patients as it gives them access to the most advanced medicines prior to approval by regulatory agencies. It also gives them access to doctors and nurses who are much more experienced with GIST. We recommend that patients participate in clinical trials whenever possible.

We recognize, however, that not all patients are eligible for participation in clinical trials. Overly stringent exclusion criteria, such as only allowing ECOG status 0 and 1 patients into trials is sometimes to blame, but sometimes patients simply are too sick, can’t afford it (travel adds up!), or can’t participate for one reason or another.

In theory these patients could still access the latest drugs through compassionate use, but with the exception of the expanded “treatment use protocol” for Sutent (which still had exclusion criteria and required travel), the compassionate use program is difficult to navigate, slow, and seldom used successfully.

For GIST patients, there are a few options today that did not exist a few months ago. There are now two drugs approved for GIST; Gleevec for initial treatment of metastatic or unresectable disease, and Sutent for Gleevec-resistant GIST.

For patients who have exhausted all other possibilities, there is another drug, Nexavar (BAY 43-9006), which is approved for kidney cancer and is in phase II trials for GIST. Nexavar is in some ways similar to Sutent. It inhibits KIT and the VEGF receptors (like Sutent) and also adds RAF inhibition. While it is not approved for GIST, Nexavar or possibly some type of drug combination represent a potential treatment of last resort. Off-label treatments such as this have many challenges, including unproven efficacy (especially after use of Sutent, which has many similarities), unknown toxicity (for combinations), and possibly denial of coverage by insurance, but they may represent a last hope for some patients.