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

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. In this randomized phase 2 trial, ziv‐aflibercept does not increase the antitumor activity of first‐line modified folinic acid, fluorouracil, and oxaliplatin 6 (mFOLFOX6) in metastatic esophagogastric cancer. There is increased toxicity observed in the mFOLFOX6/ziv‐aflibercept arm, which results in decreased exposure to mFOLFOX6.