Post-Surgery Preventive Imatinib (Adjuvant Gleevec)
On December 19, 2008 the US FDA announced approval of the use of imatinib (Gleevec) as adjuvant treatment (prescribed after complete surgical resection) to prevent recurrence of primary GIST. LINK HERE to the brief announcement. Subsequently the European Union and many other countries have also approved this use.
On January 31, 2012 the FDA issued a news release approving longer adjuvant use of imatinib (Gleevec) based on a trial showing an extended duration of progression-free survival or patients who took imatinib for 3 yeas post-surgery compared to those who took it for one year post-surgery. See the FDA news release and the Novartis press release.
Adjuvant imatinib (Gleevec) means taking the drug after complete resection of a primary gastrointestinal stromal tumor (GIST). Trials are underway to determine whether administering imatinib (Gleevec) for some period of time (1, 2, 3, or 5 years) after complete resection of a primary tumor will reduce the percentage of patients who develop recurrences or metastases of GIST. (Note that once GIST has developed metastases, then even if all visible disease has been surgically removed, Gleevec is approved by the FDA and this is not considered adjuvant treatment.)
Data are fairly clear that, after complete resection of a primary tumor, patients in the very-low and low-risk groups do not need adjuvant Gleevec. The question is whether patients with intermediate-risk or high-risk GISTs will benefit.
For two experts' comments about adjuvant imatinib, link to a Q&A piece by Dr. Blay and Dr. Trent on our page Adjuvant Imatinib Opinions.
Ongoing trials include the following:
Z9000 trial: Recruitment into this trial is complete, and an interim analysis has been reported (see below).
Z9001 trial: In the USA the ACOSOG has completed recruitment of patients for this trial studying one year of adjuvant imatinib (Gleevec). An interim analysis was done in spring 2007; please link here to our summary by the principal investigator, Ronald DeMatteo, MD.
RTOG 0132 trial: This trial assessed neoadjuvant plus adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST). This trial has completed recruitment and a preliminary analysis has been published (see below) but follow-up is ongoing.
Adjuvant Imatinib in High-Risk GIST With c-Kit Mutation, Asan Medical Center, South Korea
Five Year Adjuvant Imatinib Mesylate (Gleevec®) in Gastrointestinal Stromal Tumor (GIST) , a new trial that just opened for recruitment in August 2009
Z9000 Trial Interim Results
At the ASCO GI Cancers Symposium in January 2008 Ronald DeMatteo, M.D. presented early results for the Z9000 trial of adjuvant Gleevec for high-risk tumors. Click the presentation title below to link to the abstract. After linking to the abstract on the ASCO site, you can click the icons shown below the abstract to either hear a webcast and see the slides (video icon) or to see the slides only (slides icon).
Title: Efficacy of adjuvant imatinib mesylate following complete resection of localized, primary gastrointestinal stromal tumor (GIST) at high risk of recurrence: The U.S. Intergroup phase II trial ACOSOG Z9000.
Authors: R. P. DeMatteo, K. Owzar, C. R. Antonescu, R. Maki, G. D. Demetri, M. McCarter, M. von Mehren, P. Pisters, M. F. Brennan, K. V. Ballman
The Z9000 trial included GIST patients with high-risk tumors: either large tumors (>10 cm), tumors that had ruptured, or those with no more then 4 peritoneal metastases present at surgery. Between 2001 and 2003 a total of 107 evaluable patients were accrued. Subjects began taking imatinib (Gleevec) within 84 days of surgery and continued taking it for one year at a dose of 400 mg/day. The outcome measures of the study, designed to be compared to historical controls, were overall survival, recurrence-free survival, and toxicity. Dr. DeMatteo previously presented the toxicity data, and this interim analysis focused on the overall and recurrence-free survival results after 4 years of follow-up.
Historically, patients with GISTs over 10 cm had a median overall survival of about 2 years, and about 40% survived for 3 years. The Z9000 trial asked whether 1 year of imatinib taken post-resection would improve these statistics. The trial subjects fell mostly into the large-tumor category (84%) but 17% had tumor rupture and 13% had peritoneal metastases. Half the subjects had gastric GISTs, while 42% had GISTs of the small intestine.
Overall survival: 99% survived to the 1-year point (the year of imatinib). Survival was 97% at 2 years and also at 3 years. This indicates the effectiveness of resuming imatinib after recurrence as a means of extending survival.
Recurrence-free survival: 94% at 1 year (the end of the year of imatinib), 73% at 2 years, and 61% at 3 years. Dr. DeMatteo described that the slope of the graphed line for recurrence-free survival changes after about 18 months, indicating that the protective effect from the 1 year of imatinib diminishes after it is stopped.
Dr. DeMatteo compared these results to those from Z9001, another ongoing trial of adjuvant imatinib (see below). The data for the Z9000 study and the data for the large-tumor group from the Z9001 study fell virtually overlayed on top of each other through the 2-year mark when plotted on the same graph.
Showing Z9000 results grouped by tumor mutation status, Dr. DeMatteo reported that patients with exon 9 mutations of the KIT gene quickly experienced recurrence once imatinib was stopped (0% recurrence-free survival at 2 years). Patients with exon-11 mutations showed about 62% recurrence-free survival at 3 years. PDGFRA-mutant patients had the most favorable results, with about 90% recurrence-free at 3 years. Patients without detectable mutations (wild-type) showed about 77% recurrence-free survival at 3 years.
In conclusion, Dr. DeMatteo repeated that for these GIST patients at high risk of disease recurrence, one year of imatinib prolonged overall survival and recurrence-free survival compared to historical controls.
For another news story on this topic link to MedPage Today .
Z9001 Interim Results
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, and the enrolled patients were unblinded, and all patients were provided with Gleevec. 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.
Dr. DeMatteo answered questions from GIST Support International about the unblinding of the Z9001 trial and the interim results as the following page: Z9001 Adjuvant Gleevec Trial.
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 mark||Tumor size|
|3-6 cm||6-10 cm||> 10 cm|
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 increased 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.
RTOG 0132 Initial Analysis
A preliminary analysis of this trial has been published as follows:
Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, Hoffman JP, Okuno S, Kane JM, von Mehren M.
Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665.
J Surg Oncol. 2009 Jan 1;99(1):42-7. PubMed PMID: 18942073; PubMed Central PMCID:PMC2606912.
This paper will be free-access in PubMed central in January 2010.
This trial selected patients with large and difficult-to-resect primary tumors (Group A, N=30) plus another group of patients with recurrent or metastatic GIST that could be resected (Group B, N=22). Patients took imatinib for 8-12 weeks pre-surgery, then for 2 years post-surgery. This is considered adjuvant therapy ONLY for Group A. Progression-free survival for Group A was 82.7% at the end of the 2-year period of adjuvant imatinib, and the estimated progression-free survival ater one year off the drug (the 3-year mark post-surgery) was 68%.
2008 Analysis Updates and Critiques
At the 2008 ASCO meeting there was a special educational session with summary presentations by Drs. Demetri, DeMatteo, and Blay. The latter two of these presentations are relevant to adjuvant imatinib therapy. The session link is: Gastrointestinal Stromal Tumor (GIST) Comes of Age: Current Management
Once you have linked to the page above, choose Dr. DeMatteo's presentation "Surgical management of GIST including imatinib-refractory disease" (the second one shown) and click either the icon for video or the icon for audio at the right the screen.
Likewise, for Dr. Blay's presentation "Controversy in the adjuvant treatment of GIST," link to the page above and then choose the desired icon (video or slides) for the third presentation shown.
Medscape also offers access to an analysis written by Peter Hohenberger, MD entitled "Should Adjuvant Imatinib Be Used as Primary Treatment for Gastrointestinal Stromal Tumors?" This discussion paper was originally published in the journal Nature Clinical Practice: Oncology. Access to Medscape is free after a registration. To link to the Medscape online reprint, click the title above.
2009 Updates and Commentaries
Exploring the Role of Adjuvant Therapy in GIST: Are We There Yet?
Presenters: Jonathan Fletcher MD, Margaret von Mehren MD, and Ronald DeMatteo MD
This is a Medscape CME webcast plus transcript that you can access after a free registration.
2010 Updates and Commentaries
Optimizing the Management of Resectable Gastrointestinal Stromal Tumors
George D. Demetri, MD; Jean-Yves Blay, MD, PhD; Florence Duffaud, MD PhD
This is a Medscape CME webcast plus transcript that you can access after a free registration.