Preventative Gleevec for GIST

Many GIST patients have surgery to remove a primary tumor and do not have detectable metastases at the time of surgery. Adjuvant therapy refers to additional treatment given after a main mode of therapy (the main treatment is usually surgery). For example, Gleevec given after surgery in hopes of preventing or delaying a recurrence is called adjuvant therapy.

On December 19th, 2008, the Federal Drug Administration (FDA) approved adjuvant treatment for GIST in the United States. U.S. approval of Gleevec for adjuvant therapy was based on the interim results of the Z9001 phase III adjuvant Gleevec trial.

On May 7, 2009, Glivec (International spelling) received approval from the European Commission (EC) for adjuvant treatment of GIST. This approval applies to all 27 EU member states, plus Norway and Iceland and was also based on the Z9001 phase III trial results.

On April 12th 2007, the American College of Surgeons announced that the phase III trial for Gleevec in treating patients with primary GIST that has been completely removed by surgery (the "Z9001" trial) has successfully met its endpoint. The trial began recruiting GIST patients in 2002 and ended in April, 2007.

This was a very large trial, with hundreds of sites in North America participating. The trial was a double-blind, randomized trial that looked at 713 GIST patients that had their primary tumors completely removed by surgery. The primary tumor had to be 3 cm or greater in size. Patients were then randomized to receive either 400 mg of Gleevec for one year or a placebo for one year. The intent was to see if taking Gleevec for one year delayed or prevented the recurrence of GIST.

In April 2007, an independent data-monitoring committee announced that the trial had crossed the previously established boundary for recurrence-free survival and had thus met its primary endpoint with a highly significant hazard ratio of 3.1. The interim analysis showed a 97 percent recurrence-free survival rate for the Gleevec group as opposed to an 83 percent recurrence-free survival rate for those on the placebo. Taking Gleevec for one year after surgery significantly increased the time before a GIST recurrence. At this time no difference in overall survival has been noted between the two groups.

In the phase II Z9000 trial, imatinib was also given for one year, but there was no placebo arm. In this trial with a median follow-up of 4 years, the 1, 2 and 3 year overall survival rates were 99, 97 and 97%, respectively.
Note: Length of follow-up was not given in the Z9001 trial.

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At the 2010 GI ASCO meeting (January, 2010). Dr. Blackstein (Univ. of Toronto) and colleagues reported on maturing data from the Z9001 adjuvant Gleevec trial. At this analysis, data on recurrence by risk category was given. See table below.

Some questions remain about the use of adjuvant Gleevec such as:

• Will Gleevec prevent a recurrence or just delay a recurrence?
• Will longer follow-up reveal a survival benefit?
• What is the optimum duration of adjuvant Gleevec?
• Should patients with exon 9 tumors take higher doses of Gleevec for adjuvant therapy?
• Are there some subsets of patients that might not benefit from adjuvant Gleevec?
• Should patients with low-risk tumors take adjuvant Gleevec?

Readers interested in exploring these questions further are referred to the links at the bottom of this page.

At this time, there appear to be three factors that a doctor and patients can use to determine whether or not to take preventative Gleevec and at least one additional factor after starting Gleevec to help decide whether to continue it. These factors are given below as an example of decision making that might occur but are not intended as a replacement for discussions with your doctor.

1. Risk of recurrence. A very low risk or low risk tumor might suggest not taking Gleevec, an intermediate risk might take Gleevec for a year and a high risk GIST might take Gleevec for longer than a year or indefinitely. See the Diagnosis and Risk Assessment section for a review of the risk of recurrence.
2. How likely a patient is to respond to Gleevec (if mutational testing is available). Patients with less responsive or non-responsive tumor types are probably less likely to receive benefit from Gleevec, especially if they are low risk. See Mutational Testing.
3. The anxiety level of the patient. Patients with a higher level of anxiety might receive some comfort from adjuvant Gleevec.
4. How well a patient is tolerating Gleevec. A patient that is low risk or has a less responsive mutation type might be more inclined to stop taking Gleevec if they were not tolerating it. A patient with a high risk tumor and a responsive mutation type might have more incentive to keep taking the Gleevec even though they were not tolerating it well.

In practice a doctor might consider all of these things when making a recommendation. Adjuvant Gleevec is approved (in the US) for all risk categories without any limits on duration.

In a presentation at 2008 GI ASCO, Dr. Ronald DeMatteo presented data (from the Z9000 phase II trial) that showed that GIST patients with an exon 9 mutation were especially prone to having recurrences soon after the end of the one year trial period on Gleevec. This seems to suggest that exon 9 patients might benefit from longer periods of adjuvant Gleevec; perhaps indefinitely. The optimal dosage for adjuvant therapy for exon 9 patients remains unclear. Exon 9 patients typically require higher doses of Gleevec for treatment for metastatic disease. See 2008 GI ASCO presentation by Dr. DeMatteo (see the second presentation).