No PFS Benefit For Higher Second-Line Bevacizumab Dose In Metastatic CRC Patients

Researchers recommend the use of bevacizumab 5 mg/kg rather than 10 mg/kg for metastatic colorectal cancer patients who have failed first-line bevacizumab plus an oxaliplatin-based therapy

medwireNews: A higher dose of bevacizumab together with FOLFIRI chemotherapy does not significantly improve progression-free survival (PFS) compared with a lower dose plus FOLFIRI in the second-line treatment of patients with metastatic colorectal cancer (CRC), a Japanese study finds.

“The results suggest that the higher 10 mg/kg dose offers no clear clinical benefit compared with bevacizumab 5 mg/kg in this setting”, say Shigeyoshi Iwamoto, from Kansai Medical University Hirakata Hospital in Osaka, and colleagues.

The phase III EAGLE trial comprised 369 patients with metastatic CRC who had failed treatment with first-line bevacizumab and an oxaliplatin -based regimen.

After a median follow-up of 394 days, median PFS was 6.4 months for the 188 patients randomly assigned to receive bevacizumab 10 mg/kg plus FOLFIRI. This did not differ significantly from the PFS of 6.1 months in the group treated with bevacizumab 5 mg/kg together with FOLFIRI.

The treatment groups were also comparable with respect to median second PFS, defined as the time to progression from the start of first-line therapy, at 17.6 and 17.4 months for the bevacizumab 10 mg/kg and 5 mg/kg arms, respectively.

Time to treatment failure was identical for patients given either dose of bevacizumab, at 5.2 months. And overall survival (OS) was also similar, at a median of 17.0 months for patients treated with the higher dose and 16.3 months for those who received the lower dose, but “follow-up of OS is ongoing”, say the researchers.

Although it is not clear why the higher bevacizumab dose was not more effective, they speculate: “It has […] been shown that free serum [vascular endothelial growth factor] concentrations drop below detectable limits with bevacizumab doses as low as 0.3 mg/kg, suggesting that higher doses may not be necessary for optimal activity in humans.”

The incidence of adverse events of grade 3 or higher related to bevacizumab was also comparable between the bevacizumab 10 mg/kg and 5 mg/kg groups, with gastrointestinal haemorrhage, nasal haemorrhage and hypertension occurring at rates of 0.0% versus 0.6%, 0.5% versus 0.0% and 1.6% versus 1.1%, respectively.

The adverse events rates in the EAGLE trial are lower than those reported in previous studies, even with the higher bevacizumab dose, say the researchers, noting that the rates are more consistent with Japanese post-marketing surveillance findings.

They conclude in the Annals of Oncology: “If bevacizumab is continued after first-line therapy in metastatic [CRC], our data suggest that a dose of 5 mg/kg is appropriate for use as second-line treatment.”


Iwamoto S, Takahashi T, Tamagawa H,et al. FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study.Ann Oncol 2015; Advance online publication 23 April. doi:10.1093/annonc/mdv197

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