Z9000 Trial of Adjuvant Imatinib: 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).
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. 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.