Could an MMP9 Inhibitor Offer Greater Benefit to Older Gastric/GEJ Cancer Patients?

Adding andecaliximab (ADX) to the mFOLFOX6 chemotherapy regimen does not improve overall survival in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to a new study. However, an exploratory analysis revealed a possibility that older patients may receive greater benefit.

ADX is an inhibitor of matrix metalloproteinase 9 (MMP9). Increased expression of MMP9 “affects the tumor immune microenvironment,” said Manish A. Shah, MD, of the Weill Cornell School of Medicine in New York. He added that it can promote angiogenesis, and is associated with recruitment of myeloid suppressor cells. Earlier research showed promising activity of ADX in the gastric/GEJ cancer setting.

Shah presented results of a randomized phase III trial comparing mFOLFOX6 alone vs the same regimen along with ADX at the American Society of Clinical Oncology (ASCO) 2019 Gastrointestinal Cancers Symposium, held January 17–19 in San Francisco (Abstract 4). The study included a total of 432 patients (218 ADX group, 214 mFOLFOX6 alone group).

The groups were generally well balanced at baseline; the median age was 61 years with ADX and 63 years without, approximately three-quarters of the cohort was male, and about two-thirds of the patients had gastric tumors.

In the ADX group, 42.2% of patients had a partial response, and 8.3% had a complete response. Without ADX, those rates were 36.4% and 4.7%, respectively, yielding a stratified odds ratio for response of 1.47 (95% CI, 1.0–2.15; P = .049).

Survival outcomes showed no difference between the groups. The median progression-free survival was 7.5 months with ADX and 7.1 months without it, for a stratified hazard ratio (HR) of 0.84 (95% CI, 0.67–1.04; P = .10). The median overall survival was 12.5 months with ADX and 11.8 months without it, for an HR of 0.93 (95% CI, 074–1.18; P = .56).

An exploratory analysis revealed that ADX seemed to increase in efficacy compared with mFOLFOX6 alone as patients got older. For patients aged 65 or older, the median progression-free survival with ADX was 13.9 months, compared with 10.5 months without the agent, for an HR of 0.64 (95% CI, 0.43–0.96; P = .029). Shah concluded that the study failed to meet its endpoints, but that this finding in older patients deserves further study.

Martine Extermann, MD, PhD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, was the discussant for the study, and she described a collection of animal research that provides some biological rationale for why ADX may work better in older patients. “What if age increases levels of MMP9?” she asked. If that is the case, and the MMP9 is exerting influence on the tumor microenvironment through modulating angiogenesis and immune cells, then an inhibitor of MMP9 may well work better in older patients. Mouse studies do show that serum MMP9 can increase with age, though data in humans are limited.

“There is an intriguing potential role of ADX in older gastric cancer patients, but it is not ready for clinic yet,” Extermann said. “But it is certainly worth exploring, because biologically it would make sense.”