FOLFOX plus ziv-aflibercept or placebo in first-line metastatic esophagogastric adenocarcinoma: A double-blind, randomized, multicenter phase 2 trial

Abstract

Background: Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma.

Methods: Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS).

Results: Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort.

Conclusions: Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted.

Keywords: and oxaliplatin (FOLFOX); angiogenesis; esophageal cancer; fluorouracil; folinic acid; gastric cancer; ziv-aflibercept.

Conflict of interest statement

CONFLICT OF INTEREST DISCLOSURES

The other authors made no disclosures.

© 2019 American Cancer Society.

Figures

Figure 1

Consolidated Standards of Reporting Trials diagram.

Figure 2

Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival for patients treated with mFOLFOX6/ziv-aflibercept or mFOLFOX6/placebo. The x-axes are truncated at 24 months from randomization.

Figure 3

Mean chemotherapy relative dose intensity for 5-FU and oxaliplatin over the first 12 and 24 weeks of the trial. The error bars depict the standard error.