Phase II trial of aflibercept with FOLFIRI as a second‐line treatment for Japanese patients with metastatic colorectal cancer

Abstract

Aflibercept targets vascular endothelial growth factor. The present study involved assessing the efficacy, safety and pharmacokinetics of aflibercept plus 5‐fluorouracil/levofolinate/irinotecan (FOLFIRI) as a second‐line treatment for metastatic colorectal cancer (mCRC) in Japanese patients. Aflibercept (4 mg/kg) plus FOLFIRI was administered every 2 weeks in 62 patients with mCRC until disease progression, unacceptable toxicity or patient withdrawal. Tumors were imaged every 6 weeks. The primary endpoint was objective response rate (ORR); secondary endpoints were progression‐free survival, overall survival, safety, and pharmacokinetics of aflibercept, irinotecan and 5‐fluorouracil. A total of 60 patients were evaluated for ORR; 50 had received prior bevacizumab. The ORR was 8.3% (95% confidence interval [CI]: 1.3%‐15.3%), and the disease control rate (DCR) was 80.0% (69.9%‐90.1%). The median progression‐free survival was 5.42 months (4.14‐6.70 months) and the median overall survival was 15.59 months (11.20‐19.81 months). No treatment‐related deaths were observed, and no significant drug‐drug interactions were found. The most common treatment‐emergent adverse events were neutropenia and decreased appetite. Free aflibercept had a mean maximum concentration (coefficient of variation) of 73.2 μg/mL (15%), clearance of 0.805 L/d (22%) and volume of distribution of 6.2 L (18%); aflibercept bound with vascular endothelial growth factor had a clearance of 0.162 L/d (9%) (N = 62). Aflibercept did not significantly affect the pharmacokinetics of irinotecan or 5‐fluorouracil: The clearance was 11.1 L/h/m2 (28%) for irinotecan and, at steady state, 72.6 L/h/m2 (56%) for 5‐fluorouracil (N = 10). Adding aflibercept to FOLFIRI was shown to be beneficial and well‐tolerated in Japanese patients with mCRC. ClinicalTrials.gov Identifier: NCT01882868.

Safety of Aflibercept in Metastatic Colorectal Cancer: A Literature Review and Expert Perspective on Clinical and Real-World Data

“…Two studies assessing aflibercept plus FOLFIRI in 62 patients and 16 patients with mCRC, respectively, have reported a higher incidence of hematologic AEs compared with other larger studies [25,26].…”

“…The most frequently occurring grade 3/4 AEs were neutropenia (61.3%), hypertension (27.4%), diarrhea (19.4%) and decreased appetite (12.9%). There were no treatment-related deaths [25]. In a separate Japanese study, evaluating aflibercept (2 mg/kg or 4 mg/kg) plus FOLFIRI in 14 patients with previously treated mCRC, the most frequently occurring grade 3/4 AEs were neutropenia (76.9%), leukopenia (61.5%), hypertension (30.8%) and stomatitis (15.4%) [26].…”

Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer

“…As mentioned elsewhere, the present study was conducted in accordance with the principles of the Declaration of Helsinki, and in compliance with all international and Japanese laws, regulations, and guidelines. All aspects of the study were approved by an independent ethics committee and institutional review board.…”

“…This study included Japanese patients with mCRC whose cancer had failed to respond to a prior oxaliplatin treatment regimen. Further inclusion and exclusion criteria have been described in detail elsewhere . All patients gave informed consent.…”

“…Further inclusion and exclusion criteria have been described in detail elsewhere. 7 All patients gave informed consent.…”