SAN FRANCISCO – according to findings of the GAMMA-1 trial reported at the 2019 GI Cancers Symposium.
Dr. Manish A. Shah
“Increased MMP9 expression is associated with poor prognosis across many malignancies and particularly in gastric cancer. All gastric cancers tested have MMP9 expression,” said lead investigator Manish A. Shah, MD, director of the gastrointestinal oncology program at Weill Cornell Medicine, New York, and chief of the solid tumor service and codirector of the Center for Advanced Digestive Disease at New York–Presbyterian. By activating and inactivating extracellular matrix proteins, MMP9 alters the tumor microenvironment, promoting angiogenesis, invasion, and metastases, and blunting the immune response, he said.
Main results of the phase 3, randomized, controlled GAMMA-1 trial showed that adding andecaliximab to the modified FOLFOX-6 regimen did not significantly improve outcomes among the entire population of 432 patients with untreated locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. However, exploratory analyses suggested that it significantly halved the risk of progression-free survival events and reduced by more than a third the risk of death among those aged 65 years or older.
“The apparent increased activity of the combination of mFOLFOX-6 and andecaliximab in patients aged 65 or older needs further study and correlative analyses,” Dr. Shah commented. “Our GAMMA-1 study was done in a nonselected population. We really don’t have a great biomarker for this [antibody]. … This is the question that we’re going to try to address over the next few months as we look at all the data.”
Because andecaliximab is expected to favorably alter the tumor immune microenvironment, it is also being tested in combination with immunotherapies, according to Dr. Shah. Results of some of those studies were also reported at the symposium.
Biological plausibility
Dr. Martine Extermann
A comprehensive view of precision oncology requires consideration not only of the tumor, but also of the microenvironment and the macroenvironment, agreed invited discussant Martine Extermann, MD, PhD, leader of the senior adult oncology program at the Moffitt Cancer Center in Tampa.
“A treatment which works better in older patients – I don’t hear that very frequently,” she commented. But data provide a biological rationale for selective benefit of andecaliximab in older adults. Specifically, this population may have higher MMP9 levels either from simple aging or from comorbidities that become more common as one grows older, such as atrial fibrillation and obstructive sleep apnea.
“My question to the investigators will be, are there serum samples that are available for MMP9 testing and could we check that to see whether these patients are the ones who had the best response to andecaliximab treatment?” Dr. Extermann said. Also, “it would be very interesting to know more about the comorbidities of the study patients and again correlate that with outcome.
“There is an intriguing potential role of andecaliximab in older gastric cancer patients, but it’s not ready for clinic yet,” she concluded. “It is certainly worth exploring because biologically, it would make sense.”