Second-Line Bevacizumab Plus FOLFIRI for Advanced Gastroenteropancreatic Neuroendocrine Carcinoma

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In a French noncomparative phase II trial (PRODIGE 41-BEVANEC) reported in The Lancet Oncology, Walter et al found that the addition of bevacizumab to FOLFIRI (irinotecan, leucovorin, and fluorouracil) did not appear to improve overall survival in the second-line treatment of patients with advanced gastroenteropancreatic neuroendocrine carcinoma after failure of first-line platinum/etoposide treatment.

Study Details

In the multicenter open-label trial, 133 patients were randomly assigned between September 2017 and February 2022 to receive bevacizumab plus FOLFIRI (n = 65) or FOLFIRI alone (n = 68). Of these, 59 patients in the bevacizumab/FOLFIRI group and 67 in the FOLFIRI alone group completed at least one cycle of FOLFIRI and constituted the modified intention-to-treat (ITT) population. Treatment consisted of FOLFIRI (irinotecan at 180 mg/m², calcium folinate at 400 mg/m² or levofolinate at 200 mg/m², and fluorouracil at 400 mg/m² bolus then 2,400 mg/m² over 46 hours) and bevacizumab at 5 mg/kg, or FOLFIRI alone every 2 weeks until disease progression or unacceptable toxicity. The primary outcome measure was overall survival at 6 months after random assignment in the modified ITT population.

Overall Survival

Overall survival at 6 months was 53% (80% confidence interval [CI] = 43%–61%) in the bevacizumab/FOLFIRI group and 60% (80% CI = 51%–68%) in the FOLFIRI group.


  • Overall survival at 6 months was 53% with bevacizumab/FOLFIRI and 60% with FOLFIRI.
  • Median overall survival was 6.6 months and 8.9 months.

After a median follow-up of 25.7 months (95% CI = 22.0–38.2 months), median overall survival was 6.6 months (95% CI = 4.5–9.9 months) in the bevacizumab/FOLFIRI group vs 8.9 months (95% CI = 5.7-10.6 months) in the FOLFIRI group. Median progression-free survival was 3.7 months (95% CI = 1.9–5.6 months) vs 3.5 months (95% CI = 1.9–5.1 months). Objective response was observed in 25% and 18% of patients, with median response durations of 7.5 months (interquartile range [IQR] = 5.4–12.6 months) and 5.8 months (IQR = 3.8–5.9 months). Disease control rates were 63% and 57%.

Adverse Events

Grade ≥ 3 treatment-related adverse events occurred in 44% of patients in the bevacizumab/FOLFIRI group and 21% of those in the FOLFIRI group. Those occurring in ≥ 5% of patients were neutropenia (14%), diarrhea (10%), and asthenia (8%) in the bevacizumab/FOLFIRI group and neutropenia (10%) in the FOLFIRI group. Bevacizumab-related adverse events of any grade that occurred in ≥ 5% of patients were arterial hypertension and epistaxis; all were grade 1 or 2, except for grade 3 hypertension that occurred in one patient. Bevacizumab was discontinued due to toxicity in three patients. A treatment-related fatal adverse event (ischemic stroke) occurred in one patient in the bevacizumab/FOLFIRI group.

The investigators concluded, “The addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma.”

Thomas Walter, MD, of Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the French Ministry of Health and Roche SAS. For full disclosures of the study authors, visit

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