Andecaliximab plus modified (m)FOLFOX6 first-line therapy for metastatic gastric adenocarcinoma did not improve study outcomes in an unselected study population, but improved efficacy was reported in patients ≥65 years of age.
Advanced gastric cancer generally has a poor prognosis, with a dismal 5-year survival rate. Although in recent years new therapeutic agents have emerged, long-lasting disease control eludes most patients with the disease. Although traditional cytotoxic chemotherapy regimens have been the mainstay of treatment, several recently approved therapeutic agents, including trastuzumab, ramucirumab, pembrolizumab, and trifluridine/tipiracil, have demonstrated slightly improved outcomes. However, a need for effective treatments for advanced gastric cancer remains.
Andecaliximab, a monoclonal antibody, targets matrix metallopeptidase 9, an enzyme that is higher in gastric carcinoma tissue than in healthy tissue. In an early-phase clinical trial, andecaliximab plus chemotherapy was well-tolerated by patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma and demonstrated antitumor activity. Based on the positive results of this trial, a phase 3 randomized multicenter clinical trial, GAMMA-1, was performed on adult patients with HER2-negative gastric or GEJ adenocarcinoma to evaluate the efficacy of andecaliximab plus modified oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) compared with a placebo plus mFOLFOX6.
There were 432 patients randomly assigned to treatment, with 426 patients ultimately treated. On days 1 and 15 of each 28-day treatment cycle, 800 mg of andecaliximab or a placebo was given intravenously for a total of 6 cycles followed by leucovorin and fluorouracil on days 1 and 15. The mFOLFOX6 dosing protocol was oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 or l-leucovorin 200 mg/m2, followed by a bolus of fluorouracil 400 mg/m2 and 2400 mg/m2 fluorouracil infusion over 46 hours. Computed tomography or magnetic resonance imaging scans were performed every 8 weeks to assess tumor response. The median number of administered andecaliximab doses was 14 and the median dose for the placebo group was 12.
The primary study outcome was improved overall survival (OS), with progression-free survival (PFS), objective response rate (ORR), and safety as secondary outcomes. The OS for the group receiving andecaliximab was 12.5 months; for the placebo group, it was 11.8 months. PFS for the group receiving andecaliximab was 7.5 months; for the placebo group, it was 7.1 months. The ORR for the andecaliximab group was 51%; for the placebo group, it was 41%. When OS was analyzed by subgroup, patients ≥65 years of age had increased OS and PFS with andecaliximab versus placebo. There was a trend for improved OS in patients ≥65 years of age. Most patients reported adverse events (AEs), with 47.7% of the andecaliximab group and 51.4% of the placebo group reporting serious AEs. In 4.2% of the andecaliximab group and 6.2% of the placebo group, AEs caused patients to discontinue treatment. The most common grade ≥3 AEs were a decrease in absolute neutrophil number, neutropenia, decreased white blood cell count, and a decrease in lymphocyte counts. There were 339 deaths in the study, with disease progression being the most common cause of death.
Although the unselected study population had no significant results, andecaliximab plus mFOLFOX6 demonstrated efficacy in the elderly patients in this clinical trial.
Source: Shah MA, Bodoky G, Starodub A, et al. Phase III study to evaluate efficacy and safety of andecaliximab with mFOLFOX6 as first-line treatment in patients with advanced gastric or GEJ adenocarcinoma (GAMMA-1). J Clin Oncol. 2021;39:990-1000.
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