Andecaliximab/GS-5745 Alone and Combined with mFOLFOX6 in Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: Results from a Phase I Study

作者：Shah Manish A; Starodub Alexander; Sharma Sunil; Berlin Jordan; Patel Manish; Wainberg Zev A; Chaves Jorge; Gordon Michael; Windsor Kevin; Brachmann Carrie Baker; Huang Xi; Vosganian Greg; Maltzman Julia D; Smith Victoria; Silverman Jeffrey A; Lenz Heinz Josef; Bendell Johanna C

来源：Clinical Cancer Research, 2018, 24(16): 3829-3837.

DOI：10.1158/1078-0432.CCR-17-2469

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.
Patients and 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, patientswith 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 perpendicular to andecaliximab in this setting is ongoing.

• 出版日期2018-8-15