BIRMINGHAM, United KingdomThe first definitive data supporting
the use of matrix metalloproteinase (MMP) inhibitors in treating
gastric cancer were presented by John Fielding at the ASCO annual
meeting.
Dr. Fielding, of Queen Elizabeth Hospital, Birmingham, UK, said the
data showed a significant improvement in survival and in time to
progression for patients with advanced gastric cancer treated with
the MMP inhibitor marimastat, compared to placebo.
The elevated expression of various MMPs found in gastric cancer is
associated with poor prognosis, Dr. Fielding said. The hope was that
inhibiting MMP would slow progression.
To summarize this study, there was a trend toward survival
benefit, which became statistically significant with follow-up. The
1-year survival was 20% for the marimastat group vs 14% with placebo.
Progression-free survival was improved in the marimastat group.
Patients who had chemotherapy and had just local residual disease
were the particular group who appeared to benefit, Dr. Fielding said.
First Report of Results
This was the first report of the final results from a multicenter
study comparing marimastat with placebo in patients with advanced
gastric adenocarcinoma. In this study by the Eastern Cooperative
Oncology Group (ECOG 0-1), patients who had received first-line
chemotherapy were eligible if they had responded or had stable disease.
Recruitment to this trial was fast. We recruited 369 patients
from centers in Europe and the United Kingdom. The first patient was
entered in October 1996, and the trial was completed in October
1998, Dr. Fielding said.
Inclusion criteria included histologically or cytologically confirmed
gastric adenocarcinoma, with inoperable locally advanced or
metastatic disease. For noncurative surgery, the sites of residual
disease had to be documented.
The protocol called for statistical analysis to take place when 85%
of either group had died or 18 months after the last randomization.
There were to be 180 patients in each group, to provide at least a
90% power.
Survival Differences
The primary endpoint was overall survival. A total of 184 patients
were randomized to placebo and 185 to oral marimastat (10 mg twice
daily for up to 18 months). Sixty-two placebo and 61 marimastat
patients had received prior chemotherapy.
Dr. Fielding reported that median survival was 167 days for
marimastat vs 135 days for placebo, hazard ratio (HR) 1.23, P
= .070 (two-tailed log-rank test). A further 6 months of survival
follow-up showed that the difference between the groups was
maintained (P = .046).
One year survival was 20% for marimastat and 14% for placebo (P
= .12). Progression-free survival was significantly in favor of
marimastat (HR 1.31, P = .015).
Prior Chemotherapy
The survival difference was much more significant in patients
who had received chemotherapy prior to their marimastat (P =
.045), Dr. Fielding said. In the nonchemotherapy
patients, there was no difference between the marimastat group and
the placebo group.
Patients without distant metastases also had better overall survival
with marimastat (HR 1.74, P = .022). The numbers are
small in the group with local residual disease who had previous
chemotherapy, but there was a highly significant benefit to receiving
marimastat in this subgroup, Dr. Fielding said.
No treatment related toxicities were found other than the previously
reported musculoskeletal side effects. In the marimastat group,
there were many more patients who developed either joint stiffness or
arthritis, Dr. Fielding said. Two placebo and 18 marimastat
patients stopped treatment because of adverse events.
The investigators concluded that treatment with marimastat resulted
in a significant survival and time-to-disease-progression advantage
for patients with advanced gastric cancer, compared with placebo.
