Photo Courtesy © ASCO/Todd Buchanan 2013
Fotios Loupakis, MD, PhD
FOLFOXIRI plus bevacizumab improved progression-free survival (PFS) and response rates with a modest increase in side effects compared with FOLFIRI plus bevacizumab in patients with unresectable metastatic colorectal cancer (mCRC). Results from the head-to-head phase III TRIBE study were announced at the 2013 Gastrointestinal Cancers Symposium by Fotios Loupakis, MD, PhD, Department of Oncology, University of Pisa, Italy.
Doublets plus bevacizumab are a standard of care as first-line treatment of mCRC. A previous phase III trial demonstrated superior response rates, PFS, and overall survival with FOLFOXIRI compared with FOLFIRI in this setting (J Clin Oncol
. 2007;25:1670-1676). Further, adding bevacizumab to FOLFOXIRI showed promising activity as a first-line treatment in a phase II study, with a median PFS of 13.1 months, a response rate of 77%, and an acceptable toxicity profile (Lancet Oncol
. 2010;11:845-852), said Loupakis.
“We conducted the [phase III] study to replicate the findings we had with the previous phase II trial,” he said. “We wanted to show that intensive treatment with a triplet is still of value in the bevacizumab era.”
Loupakis et al compared the FOLFOXIRI triplet and the FOLFIRI doublet as first-line treatment in 508 patients with unresectable mCRC. Patients were randomized to:
FOLFOXIRI/bevacizumab (bevacizumab, 5 mg/kg; irinotecan, 165 mg/m2; oxaliplatin, 85 mg/m2; leucovorin, 200 mg/m2; and 5-fluorouracil [5-FU] infusion of 3200 mg/m2 over 48 hours), or
FOLFIRI/bevacizumab (bevacizumab, 5 mg/kg; irinotecan, 180 mg/m2; leucovorin, 200 mg/m2; and 5-FU bolus 400 mg/m2 followed by 5-FU infusion of 2400 mg/m2 over 48 hours).
Treatment was repeated every 2 weeks for a planned maximum of 12 cycles followed by maintenance with bevacizumab and 5-FU until tumor progression. Compared with FOLFIRI/bevacizumab, there were more delayed cycles (6% vs 16%) and more cycles with dose reduction 8% vs 21%) in the FOLFOXIRI/bevacizumab arm. “These did not compromise the overall dose intensity of the treatment plan,” said Dr. Loupakis.
After a median follow-up of 26.6 months, median PFS was 12.2 months with FOLFOXIRI/bevacizumab compared with 9.7 months for FOLFIRI/bevacizumab. The hazard ratio for FOLFOXIRI/bevacizumab was 0.73 (P
= .0012). At 2 years, 20.3% of the FOLFOXIRI/bevacizumab arm were free of progression compared with 11.4% of the FOLFIRI/bevacizumab arm.
“The key finding is that even in the bevacizumab era, FOLFOXIRI extended PFS of patients treated upfront with this regimen,” Loupakis said.
The response rates were 65% with FOLFOXIRI/bevacizumab and 53% with FOLFIRI/bevacizumab (P
“There was no major differences [between groups] in the occurrence of serious adverse events, fatal adverse events, treatment-related deaths, or early deaths,” Loupakis said.
As expected, he added, grade 3/4 toxicities that were more significantly common with FOLFOXIRI/bevacizumab versus FOLFIRI/bevacizumab were diarrhea (19 cases vs 11 cases; P
= .012), stomatitis (9 vs 4; P
= .048), neutropenia (50 vs 20; P
<.001), and neurotoxicity (5 vs 0; P
<.001). There were nine cases of grade 3/4 febrile neutropenia in the FOLFOXIRI/bevacizumab arm compared with six in the FOLFIRI/bevacizumab arm (not significant; P
Early deaths (within 60 days from randomization) occurred in 3.6% and 2.7% of the FOLFOXIRI/bevacizumab and FOLFIRI/bevacizumab arms, respectively.
Loupakis F, Cremolini C, Masi G, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): results of the phase III randomized TRIBE trial. J Clin Oncol 30: 2012 (suppl 34; abstr 336).
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