An international, multi-center investigation has concluded that combining the experimental humanized monoclonal antibody andecaliximab (Gilead Sciences) with modified FOLFOX6 therapy does not improve overall survival in patients with untreated HER2-negative gastric or gastroesophageal junction adenocarcinoma.
The investigators noted that the large, phase-III GAMMA-1 trial (NCT02545504) could not replicate encouraging findings from a previous smaller study.
Presenting here at 2019 Gastrointestinal Cancers Symposium (abstract 4), lead author Manish A. Shah, MD, of Weill Cornell Medicine/New York Presbyterian Hospital in New York City explained that andecaliximab inhibits the extracellular enzyme matrix metalloproteinase 9, which is involved in matrix remodeling, tumor growth, and metastasis.
“A phase I/Ib study of mFOLFOX6 + andecaliximab revealed encouraging antitumor activity in patients with gastric or gastroesophageal junction adenocarcinoma (median first-line, progression-free survival of 9.9 months),” the authors wrote.
In the current multicenter investigation -- a phase-III, randomized, double-blind effort -- the researchers built on these previous findings by turning to a larger patient sample to examine the safety and efficacy of mFOLFOX6 with and without andecaliximab among patients with untreated HER2-negative gastric or gastroesophageal junction adenocarcinoma.
The 432 participants were randomized in a 1:1 fashion to receive either mFOLFOX6 plus andecaliximab (n=218) or mFOLFOX6 plus placebo (n=214). Oxaliplatin was administered on days 1 and 15 of each 28-day treatment cycle for a total of six cycles; leucovorin and 5-fluorouracil were also dosed on days 1 and 15 of each 28-day treatment cycle, and continued until disease progression.
Andecaliximab and/or placebo -- each in 800 mg doses -- were infused on days 1 and 15 of each 28-day cycle, continuing until disease progression.
The primary endpoint of the investigation, which was performed between September 2015 and May 2017, was overall survival; secondary endpoints included progression-free survival, objective response rate using RECIST 1.1, and safety.
As Shah reported, combination therapy improved response rates, which were found to be 50.5% with andecaliximab/chemotherapy and 41.1% with chemotherapy alone. Similarly, complete responses were achieved by 8.3% and 4.7% of patients, respectively (p=0.049).
Nevertheless, the addition of andecaliximab did not significantly improve either overall survival or progression-free survival. Indeed, median overall survival was found to be 12.5 months (95% confidence interval: 11.2-14.0 months) among patients in the andecaliximab-mFOLFOX6 group, compared with 11.8 months (95% CI: 10.3-13.5 months) among those who received placebo and mFOLFOX6 (hazard ratio 0.93; 95% CI: 0.74-1.18, p=0.56).
Similarly, median progression-free survival was 7.5 and 7.1 months in the andecaliximab and placebo groups, respectively (HR 0.84; 95% CI: 0.672-1.038, p=0.10). The median investigator-assessed objective response rate was 50.5% in the andecaliximab-mFOLFOX6 group and 41.1% mFOLFOX6-placebo group (p=0.049).
Interestingly, the investigation also revealed no meaningful differences in safety profiles between the two groups. The most common treatment-emergent adverse events were nausea, diarrhea, neutropenia, and fatigue.
The investigators also performed several exploratory analyses, which largely focused on patient age. These analyses found that among patients at least 65 years old, the median progression-free survival was 8.7 months, compared with 5.6 months for those younger than 65 (HR 0.50; p<0.001). The median overall survival was 13.9 and 10.5 months in the two age groups, respectively (HR 0.64; p=0.029).
Nevertheless, the researchers were quick to point out that these age-related endpoints were exploratory, and solely for the purposes of generating hypotheses.
“To summarize,” Shah said in an associated broadcast, “in a non-selected patient population, andecaliximab did not improve survival in the first-lien setting for gastric cancer when combined with modified FOLFOX6. More research needs to be done to understand some of the subgroups that may benefit.”