First Definitive Data Supporting MMP Inhibitors to Treat Advanced Gastric Cancer

BIRMINGHAM, United Kingdom—The 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.