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.

Gleevec is approved for adjuvant treatment for GIST in the United States (December 19th, 2008). In 2011, the NCCN guidelines (USA) were updated after the 1 year versus 3 year Scandinavian trial results were presented at 2011 ASCO. According to the updated guidelines; "Adjuvant imatinib (Gleevec) for at least 36 months should be considered for patients with high risk GIST." In January, 2012, the FDA prescribing information for imatinib was updated to recommend 3 years of adjuvant imatinib (for high risk patients as defined in the Scandinavian study), but the prescribing information noted that "The optimal treatment duration with Gleevec is not known".

Glivec (International spelling) is also approved by the European Commission (EC) for adjuvant treatment of GIST (May 7, 2009). This approval applies to all 27 EU member states, plus Norway and Iceland and was also based on the Z9001 phase III trial results. In February, 2012, the EC approved an updated prescribing label to include 36 months of treatment after surgery for adults with KIT (CD117)-positive gastrointestinal stromal tumors (GIST) who met the inclusion criteria of the Scandinavian study. This extended treatment regimen has been shown to improve recurrence-free survival and overall survival for these patients with KIT+ GIST compared to patients who received 12 months of treatment after surgery. The newly updated label also states that treatment with Glivec beyond 36 months may delay the onset of tumor recurrences further, while noting that an effect (of treatment beyond 36 months) on overall survival has not been determined.

ASCO 2011 - Adjuvant Gleevec shows significant overall survival benefit when given for three years

Although early adjuvant Gleeevec trials showed a clear benefit in terms of reducing recurrences, they had not shown an overall survival benefit. On June 5th, 2011, new data from a randomized phase III trial comparing one year of adjuvant Gleevec to three years of adjuvant Gleevec showed, for the first time, a significant overall survival benefit (see table 1). This data was presented by Heikki Joensuu, M.D., Ph.D., Professor, Oncology, University of Helsinki and principal investigator of the study at the plenary session of ASCO. Plenary sessions are reserved for the most important new oncology data; data that is likely to change oncologists practice. The final results of the study were published in JAMA (March, 2012).

"This study confirms the hypothesis that extending the duration of Glivec treatment for patients following surgery improves recurrence-free survival. For the first time, an effect on overall survival was found," said Dr. Joensuu. "Results from this trial may positively impact clinical practice by helping physicians create the optimal treatment plan for patients with operable KIT+ GIST."

"Over the past nine years Glivec has provided KIT+ GIST patients with the first effective drug treatment option in the metastatic setting and later in the adjuvant setting," said Hervé Hoppenot, President, Novartis Oncology. "Now we see exciting new data showing that by extending post-surgical treatment duration to three years, Glivec has significant impact on overall survival in patients with KIT+ GIST. This is important news for GIST patients and the GIST community."

SSGXVIII Study Details

The SSG XVIII clinical trial was conducted by the Scandinavian Sarcoma Group (SSG), and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie (AIO). SSG XVIII is a multicenter, prospective, randomized study for the evaluation of adjuvant treatment with Glivec of histologically verified KIT+ GIST with a greater than 50% risk of GIST recurrence despite complete removal of all macroscopic GIST tissue at surgery.

The primary endpoint of the study was to compare the recurrence-free survival in GIST patients with a greater than 50% estimated risk of disease recurrence within the first five years following the diagnosis and treatment with adjuvant Glivec for 12 or 36 months. The secondary endpoints included overall survival and treatment safety.

Four hundred patients entered the study and the median follow-up was 54 months. Recurrence-free survival was longer in the 36-month group compared to the 12-month group (HR 0.46, 95% CI 0.32-0.65; p<.0001; five-year recurrence-free survival 66% vs. 48%, respectively). Patients assigned to 36 months of Gleevec had longer overall survival (HR 0.45, 95% CI 0.22-0.89; p=.019; five-year overall survival 92% vs. 82%, respectively). Gleevec was generally well tolerated. The proportion of patients who discontinued Gleevec during the assigned treatment period for reasons other than GIST recurrence was 26% in the 36-month group and 13% in the 12-month group.

Duration of Adjuvant Gleevec

In an article written by Roxanne Nelson for Medscape Today, Dr. Charles Blanke, the discussant for the ASCO presentation, noted, "These results clearly demonstrated that 3 years of imatinib are better than 1 for recurrence-free survival and, to date, overall survival. "If you have a patient with a high risk — at least defined by the study — GIST, giving him or her 3 years of imatinib represents the new gold standard," he said.

"For now, with the overall survival benefit demonstrated with immediate postoperative imatinib, it is no longer acceptable to withhold treatment in the adjuvant setting, hoping to 'catch up' when the patient has recurrent metastatic disease," Dr. Blanke said. In the article, Dr. Blanke went on to add, "There are plenty of reasons to think that giving imatinib for a longer period (longer than 3 years) would be better, but that theory remains unproven," he continued. "For now, if I was a patient with high-risk GIST and I had a compliant oncologist, I would request more. As a compliant oncologist, I personally will offer patients treatments to eternity — meaning indefinitely."

Results from Earlier Trials

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 that time no difference in overall survival had been noted between the two groups.

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:

• 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?
  • Note that, in Europe, a panel of GIST experts recommended against adjuvant treatment for GIST patients with a D842V PDGFRA mutation(Reichardt et al, 2012).
• Should patients with low-risk tumors take adjuvant Gleevec?
  • Note that, in Europe, a panel of GIST experts recommended against adjuvant treatment for very low-risk and low-risk GIST patients (Reichardt et al, 2012).
• Should patients with a R1 resection (positive tumor margins) undergo re-excision (see Reichardt et al, 2012)?

Readers interested in exploring these questions further are referred to the links at the bottom of this page. However, please note that these articles (in "Helpful Links") were written prior to the results at 2011 ASCO showing improved survival for 3 years of imatinib.

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. 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. Note that in Europe, adjuvant treatment is not recommended for patients with a PDGFRA D842V mutation (Reichardt et al, 2012).
3. The anxiety level of the patient. Patients with a higher level of anxiety might receive comfort from adjuvant Gleevec.
4. How well a patient is tolerating Gleevec. A patient that is lower 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 Europe, adjuvant treatment is not recommended for patients with a PDGFRA D842V mutation (the most popular exon 18 mutation in PDGFRA) or for low-risk or very-low risk patients (Reichardt et al, 2012).

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).