ORLANDO—A phase II study found improvements in recurrence-free and overall survival with adjuvant imatinib(Drug information on imatinib) (Gleevec) in high-risk GIST patients, compared with historical controls, Ronald P. DeMatteo, MD, reported at the 2008 Gastrointestinal Cancers Symposium (abstract 8).
US Intergroup ACOSOG Z9000 is the first study to evaluate the benefit of imatinib as adjuvant therapy, said Dr. DeMatteo, vice chair, Department of Surgery, Memorial Sloan-Kettering Cancer Center.
Historically, he said, treatment for localized gastrointestinal stromal tumors (GIST) has been determined by whether the disease is resectable, in which case patients undergo surgery, or unresectable, in which case they receive imatinib.
Prior to the availability of imatinib, patients with tumors larger than 10 cm typically recurred after surgery. At Memorial Sloan-Kettering, these patients had a median survival of about 2 years, and a 5-year survival of just 20%, Dr. DeMatteo said.
The single-arm open-label multicenter Z9000 study included 107 evaluable patients who received 1 year of adjuvant imatinib 400 mg initiated within 84 days of surgery. All patients underwent complete resection of a c-KIT-expressing primary GIST that met criteria for high risk of recurrence: tumor size 10 cm or larger (84% of patients), tumor rupture (17%), or multifocal disease (13%). Median tumor size was 13 cm. If patients recurred after the year of treatment, they were allowed to go back on imatinib.
Few died on trial
At a median follow-up time of 4 years, overall survival was 99% at 1 year, 97% at 2 years, and 97% at 3 years, Dr. DeMatteo reported. Recurrence-free survival rates were 94%, 73%, and 61%, respectively.
“At 3 years, 61% of patients are still recurrence free, which is remarkable,” Dr. DeMatteo said.
“There was a very low chance of dying on trial. This is a reflection of how well the drug can rescue patients once they develop a recurrence,” Dr. DeMatteo commented.
Patients with KIT exon 9 mutations (n = 10) had dramatically worse recurrence-free survival—only about 10% at 2 years, he pointed out.
The drug was very well tolerated, Dr. DeMatteo said. The highest toxicity experienced was grade 3 (18% of patients); 83% of patients completed the full year of prescribed therapy.
Phase III trial closed early
Dr. DeMatteo noted that a concurrent randomized phase III trial (ACOSOG Z9001) comparing adjuvant imatinib for 1 year vs placebo in patients with resected GIST
3 cm or larger was terminated early based on significantly higher recurrence-free survival with imatinib: 97% vs 83% for placebo, for a 67% reduction in risk (DeMatteo R et al: ASCO 2007, abstract 10079). Median follow-up for this trial was only 13 months.
When comparing recurrence-free survival for the imatinib-treated patients from the phase III trial who had large tumors (greater than 10 cm in size) with that of the phase II imatinib patients (median tumor size 13 cm), “the curves are virtually superimposable,” Dr. DeMatteo commented.
Ideal duration unknown
Dr. DeMatteo said that the ideal duration of adjuvant therapy in GIST patients has not been determined but is the most important question to answer now that the value of adjuvant imatinib has been established.
Will new trial results satisfy Z9001 skeptics?
Paolo G. Casali, MD—Adjuvant imatinib (Gleevec) yielded substantial value in the Z9000 study of high-risk GIST, although the “obvious limitation” is that this was a phase II trial, commented Dr. Casali, Donald L. Bren Professor of Medicine, Molecular Biology and Biochemistry, and Director of the Center for Immunology, University of California, Irvine.
Considering, however, that the similar phase III Z9001 trial was stopped early due to a highly significant difference in recurrence-free survival in favor of imatinib vs placeo, “the implication is that adjuvant imatinib should become a standard treatment,” he said. “The results of the phase II study are interesting, especially to those who were less enthusiastic about the randomized phase III trial.”
The Z9001 results, presented at ASCO 2007, were nearly identical to those of Z9000, showing improved recurrence-free survival with imatinib. “But it was said that recurrence-free survival at 1 year is too early to say a lot about the drug,” he added.
Dr. Casali, who was formerly with the Istituto Nazionale Tumori, noted that “on the other side of the Atlantic, there is skepticism regarding the meaning of these findings. ESMO recommends keeping imatinib as an investigational agent in the adjuvant setting.”
Dr. Casali is chair of an ongoing international study of adjuvant imatinib vs no further therapy after complete GIST resection, which has overall survival as the primary endpoint.
He said that an improvement in recurrence-free survival at 1 year would be highly meaningful if there is also a decrease in the absolute rate of recurrence. “But if there is only a delay in recurrence, then what?” he asked. “There is the possibility that time to secondary imatinib resistance may be shorter for patients who have already been exposed to imatinib as adjuvant therapy.”