Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study
2018
Purpose: Matrix metalloproteinase-9 (MMP9) is implicated in protumorigenic processes. Andecaliximab (GS-5745, a monoclonal antibody targeting MMP9) was evaluated as monotherapy and in combination with mFOLFOX6. Methods: Three dosages of andecaliximab monotherapy [200, 600, and 1800 mg i.v. every 2 weeks (q2w)] were investigated in patients with advanced solid tumors ( n = 13 in a 3+3 design). After determining a recommended dose, patients with advanced HER2-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma ( n = 40) received 800 mg andecaliximab + mFOLFOX6 q2w. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results: Andecaliximab monotherapy demonstrated no dose-limiting toxicity (DLT) in any cohort, displaying target-mediated drug disposition at the lowest dose (200 mg) and linear pharmacokinetics at higher doses. Based on target engagement, recommended doses for further study are 800 mg q2w or 1,200 mg q3w. Maximal andecaliximab target binding, defined as undetectable andecaliximab-free MMP9 in plasma, was observed in the gastric/GEJ adenocarcinoma cohort. We observed no unusual toxicity, although there were four deaths on study not attributed to andecaliximab treatment. In first-line patients ( n = 36), median progression-free survival (PFS) was 9.9 months [95% confidence interval (CI), 5–13.9 months], and the overall response rate (ORR) was 50%. Among all patients ( n = 40), median PFS was 7.8 (90% CI, 5.5–13.9) months, and ORR was 48%, with a median duration of response of 8.4 months. Conclusions: Andecaliximab monotherapy achieved target engagement without DLT. Andecaliximab + mFOLFOX6 showed encouraging clinical activity without additional toxicity in patients with HER2-negative gastric/GEJ adenocarcinoma. A phase III study evaluating mFOLFOX6 ± andecaliximab in this setting is ongoing. Significance: MMP9, a member of the MMP family, is involved in multiple protumorigenic processes. Targeting the tumor microenvironment through MMP9 inhibition with andecaliximab (a recombinant chimeric immunoglobulin G 4 monoclonal antibody) represents a novel strategy for drug development. This phase I study demonstrates promising efficacy without increased toxicity for the combination of andecaliximab and mFOLFOX6 in advanced gastric/GEJ adenocarcinoma and provides the rationale for phase III investigation. Clin Cancer Res; 1–9. ©2018 AACR.
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