MMP9 Inhibitor Added to Chemo in Gastric/GEJ Cancer

Roxanne Nelson, RN, BSN

January 21, 2019

SAN FRANCISCO — Adding the investigational agent andecaliximab (ADX, Gilead) to front line chemotherapy did not improve outcomes in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, but an exploratory analysis suggested that survival outcomes were significantly improved in patients ages 65 years or older.

"We were intrigued with this phenomenon with age," said lead author Manish A. Shah, MD, of Weill Cornell Medicine and New York-Presbyterian. "For patients aged 65 or older, andecaliximab was associated with an improvement in both progression free survival and overall survival."

Shah presented the results of the study here at the Gastrointestinal Cancers Symposium (GICS) 2019.

Andecaliximab, developed by Gilead, is a monoclonal antibody that selectively inhibits matrix metalloproteinase 9 (MMP9 )

Proteins in the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiologic processes and can promote cancer cell invasion and metastasis by degrading the extracellular matrix, Shah explained.

"Increased MMP9 expression is associated with poor prognosis in many cancers, particularly in gastric cancer," said Shah. "It is produced by some tumor cells and associated with macrophages and neutrophils, and all gastric tumors tested have MMP9."

The increased expression of MMP9 impacts the tumor immune microenvironment, so this is a potentially important therapeutic target, he explained.

Findings from an early phase I/Ib study of chemotherapy with the mFOLFOX6 regimen (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) together with andecaliximab, which showed encouraging antitumor activity in patients with gastric or GEJ adenocarcinoma. The median progression-free survival in the first line setting was 9.9 months, with an objective response rate of 50%.

No Benefit from Adding Andecaliximab

The phase 3 trial now being presented investigated mFOLFOX6 with or without andecaliximab in 432 patients with untreated HER2-negative gastric or GEJ adenocarcinoma.

Oxaliplatin was administered on days 1 and 15 of each 28-day treatment cycle (total of six cycles), followed by leucovorin and 5-fluorouracil dosing on days 1 and 15 of each 28-day treatment cycle until disease progression. Andecaliximab 800 mg was infused on days 1 and 15 of each 28-day cycle until disease progression.

Shah commented: "We were aggressive with treatment, as we wanted to demonstrate a real improvement in benefit." Their hope was to improve overall survival from 11.5 months to 16.4 months, with a hazard ratio (HR) of 0.70

However, the results were disappointing. Despite the overall response rate being significantly improved with the addition of andecaliximab, survival outcomes did not differ between the two groups.

Median progression-free survival was 7.5 months with andecaliximab and 7.1 months without it, for a stratified hazard ratio of 0.84 (95% confidence interval [CI], 0.67 – 1.04; P = .10). There was a trend favoring the novel agent, but it was not significant.

Median overall survival was 12.5 months with the addition of the MMP inhibitor, and 11.8 months without it, for an HR of 0.93 (P = .56). "Disappointingly, we did not see any improvement with andecaliximab," he noted.

Benefit Seen in Older Patients

However, an exploratory analysis revealed that the addition of andecaliximab appeared to improve outcomes in older patients. In the subset of patients ages 65 or older, the median progression-free survival was 13.9 months with the drug vs 10.5 months without it, for an HR of 0.64 (P = .029).

Median overall survival for older patients was 13.9 months vs 10.5 with chemotherapy alone (HR 0.64).

"The apparent increased response…in patients 65 years and older needs further work and correlative work," Shah concluded.

He added that a combination of andecaliximab with immunotherapy is also being evaluated.

"Intriguing" Finding

In a discussion of the paper, Martine Extermann, MD, PhD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, speculated on why older patients may have responded to andecaliximab.  "What if age increased the level of MMP9?" she said. "This patient may be living with higher levels of MMP9 in the tumor environment."

Experimental studies with mice have shown that serum MMP9 can increase with age, but she noted that she could only find one human study and the data were inconclusive.

There is some literature that the presence of comorbidities can increase MMP9 levels in humans, so more data on comorbidities in this population would be helpful, she commented.

In addition, Extermann said, the investigators should be asked if there are serum samples available for MMP9 testing, to see if the patients who had higher levels had the best response.

"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."

When doing research in precision medicine, she added that "we should stop focusing only on the tumor and look at the broader spectrum of precision medicine."

This would include collecting data on comorbidities and nutrition, as well as collecting blood/serum and nontumor tissue.

The study was funded by Gilead Sciences. Shah has received research funding from Boston Biomedical (Inst), Gilead Sciences (Inst), Merck (Inst), and Oncolys BioPharma (Inst). Several coauthors have also disclosed relationships with industry. Extermann reports research funding from GTX.

Gastrointestinal Cancers Symposium (GICS) 2019: Abstract 4. Presented January 18, 2019.

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