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Z9001 Adjuvant Imatinib (Gleevec) Trial:
2007 Interim Analysis

GIST Support International queried Ronald P. Dematteo, MD FACS about the unblinding of the ACOSOG Z99001 trial, for which he is principal investigator. Dr. DeMatteo is a member of the hepatobiliary service in the Department of Surgery at Memorial Sloan-Kettering Cancer Center.  He has published widely about gastrointestinal stromal tumors and has been involved in several clinical trials for GIST.

Background: 

The ACSOG intergroup Z9001 trial is a randomized, double-blinded trial of imatinib (Gleevec) versus placebo administered for one year following complete resection of a primary GIST.  The trial began recruiting patients in 2002.  Patients were stratified by tumor size (3-6, 6-10, or >10 cm) to make sure that each arm of the study had a similar distribution of patients by tumor size.  Note however that patients were not grouped by mitotic rate in addition to tumor size.  Patients have a CT scan every 3 months for 2 years and then every 6 months for 3 years. Yearly followup continues thereafter until 10 years.

The primary endpoint of the study is recurrence-free survival (RFS).  Overall survival is a secondary endpoint.  Accrual to the trial was halted on April 12, 2007. The Data Monitoring Committee found during a planned interim analysis that the patients taking Gleevec had a significantly lower chance of developing recurrence at 1 year after trial entry.

All patients who participated will now be told whether they had been assigned to Placebo or Gleevec. Patients taking placebo as of April 1 may elect to receive one full year of imatinib without charge. 

Questions and Dr. DeMatteo's Answers: 

1.  The interim analysis evaluated results at the 1-year mark.  Does the study now still continue with the planned followup?

Yes, it is still important to follow patients out to 10 years as originally planned.

2.  Explain the result that caused the study to be unblinded:  a difference in RFS of 97% for the imatinib group versus 83% for the placebo arm at the 1-year mark. 

The data show that at 1 year after entering the study the patients who took Gleevec had a significantly lower chance of recurrence.  The 1-year mark is the end of the period during which patients took either placebo or Gleevec.

3.  As the study matures, might it later emerge that taking 1 year of adjuvant imatinib delays recurrence but does not ultimately reduce the risk of recurrence?

This is a slightly different question. What we have learned is that the rate of recurrence at 1 year is lowered by taking adjuvant Gleevec. Whether adjuvant Gleevec prevents some patients from ever developing recurrence is unknown at this time.

4.  Is it known whether overall survival will be affected by 1 year of adjuvant imatinib?  Are recurrence free survival (RFS) and overall survival (OS) correlated or is this unknown?

Overall survival is not different between the 2 study arms at this time. The primary endpoint of the trial was the rate of recurrence. It is unknown whether RFS and OS correlate in GIST.

5.  Will additional information be presented at the 2007 ASCO meeting about the interim analysis?  Will this include a breakdown of results by tumor site, mutation status, size, risk group, or margin status (R0 versus R1)?

Additional information will be presented, but the specifics have not been determined yet. [See link to the June 2007 ASCO presentation at the end of this article.]

6.  What other adjuvant trials are ongoing, and will these be affected by the unblinding of Z9001?

There are 2 adjuvant trials ongoing in Europe. The EORTC is examining overall survival and comparing no treatment to 2 years of Gleevec. A Scandinavian trial is comparing 1 year versus 3 years of adjuvant Gleevec. We are discussing with the leaders of these trials the possible implications of the current findings.

7.  What steps are involved in filing by Novartis for FDA approval of imatinib as adjuvant therapy, and how long is this process likely to take?

There are a number of steps involved in filing for FDA approval of a drug. The length of this process is variable and cannot be predicted at this time. 

8.  Some patients fear that taking adjuvant Gleevec may 'use up' their magic bullet before they need it.  In light of the French studies on interrupting Gleevec and restarting upon progression, and what was learned in that study, what can you say about using up the magic bullet too soon?

The current trial was not designed to assess the answer to this question. Currently there are no data to suggest that patients will lose future benefit from imatinib (Gleevec) if they take it immediately after surgery for 1 year.  Our study may shed some light on this in the future, but not yet.

Additional Information from ACOSOG

The American College of Surgeons Oncology Group (trial leader) has made available an announcement that includes some additional questions, plus a letter to trial participant patients.  The National Cancer Instirute also has made an announcement.  You can link to these materials below.

Announcement by ACOSOG 

Patient Letter from ACOSOG to trial participants

National Cancer Institute announcement

June 2007 ASCO presentation

Dr. DeMatteo presented the interim Z9001 results at the American Society for Clinical Oncology meeting.  Click the presentation title below to link to the abstract.  Then, to hear the webcast and see the slides, click the video icon located underneath the abstract below the words "Associated Presentation."

Adjuvant imatinib mesylate increases recurrence free survival (RFS) in patients with completely resected localized primary gastrointestinal stromal tumor (GIST): North American Intergroup Phase III trial ACOSOG Z9001

If you listen to Dr. DeMatteo's presentation and view the slides he showed during his talk, you will see the data shown in the following table for recurrence-free survival at the 1-year mark for subjects grouped by the size of their resected primary tumors.

Recurrence-free survival at the 1-year markTumor size
3-6 cm6-10 cm > 10 cm
imatinib group100%96%96%
placebo group95%80%67%
significant difference?nop<.01p<.001

In his ASCO presentation Dr. DeMatteo commented that after the 1-year period of taking either imatinib or placebo ended, the curves for recurrence-free survival in the imatinib arm appeared to change slope, beginning to show inceased rates of recurrence by about 18 months (6 months after the year of imatinib ended).  However, this potential trend will have to be analyzed later once the follow-up period is longer.



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