FOLFOXIRI Plus Avastin Superior as Frontline Regimen for Metastatic Colorectal Cancer

Intensifying the chemotherapy component of a standard regimen containing Avastin reduced the risk of death and increased five-year overall survival in newly diagnosed metastatic colorectal cancer. The clinical trial results of the phase 3 TRIBE trial will be announced at the 2015 Gastrointestinal Cancers Symposium in San Francisco.

The FOLFOXIRI chemotherapy regimen in combination with Avastin resulted in a median OS rate of 29.8 months compared with 25.8 months for the FOLFIRI plus Avastin protocol, researchers said during a press conference Monday in advance of the conference. After a median 48.1 months’ follow-up, an estimated one out of four patients in the FOLFOXIRI group was still alive, as opposed to one out of eight patients in the FOLFIRI group.

“FOLFOXIRI plus bevacizumab represents a new valuable option for the upfront treatment of metastatic colorectal cancer patients,” said lead author Chiara Cremolini, a medical oncologist at the Tuscan Tumor Institute in Pisa, Italy. She said the advantage with the more intensive regimen “increases over time.”

However, Cremolini said, not all patients would be considered good candidates for the FOLFOXIRI regimen, which combines three chemotherapy drugs. FOLFOXIRI includes all of the elements of FOLFIRI (folinic acid [leucovorin], fluorouracil [5-FU], and irinotecan) plus oxaliplatin. Overall, 508 patients with mCRC were randomized to receive either FOLFOXIRI plus Avastin or FOLFIRI plus Avastin for up to 12 cycles over 6 months. Some 15 percent of patients in the FOLFOXIRI group and 12 percent in the FOLFIRI cohort were able to undergo radical resection after induction therapy. Patients received follow-up 5-FU/leucovorin plus Avastin as maintenance therapy until disease progression. The TRIBE trial enrolled patients between the ages of 18 years and 75 years, but individuals 70 to 75 years were eligible only with a performance status of 0, said Cremolini.

“It is not recommended to administer this regimen to patients older than 75,” she said. The FOLFOXIRI regimen has been shown to increase the incidence of grade 3/4 diarrhea, mucositis, neuropathy and neutropenia compared with the FOLFIRI regimen, Cremolini said. She noted that participants in the TRIBE trial were generally in good condition but had a poor prognosis; many of the patients had more than one site of metastasis and most were unresectable.

Smitha S. Krishnamurthi, who served as moderator of the presscast, said the TRIBE trial “clearly demonstrates” that the FOLFOXIRI plus Avastin regimen is safe and effective.

“This regimen is not for everyone but for the right patients this is one of the most active regimens with an impressive, almost 25 percent survival rate at 5 years,” said Krishnamurthi, associate professor of Medicine at Case Western Reserve University in Cleveland, Ohio.

The findings presented this week are updated results from the trial, which the Gruppo Oncologico del Nord Ovest (GONO) research group conducted at 34 cancer centers throughout Italy from July 2008 through May 2011. The primary endpoint of the study was progression-free survival (PFS), a milestone that was reached two years ago.

In the updated results, the median PFS was 12.3 months with FOLFOXIRI plus Avastin versus 9.7 months with FOLFIRI plus Avastin. The benefits were evident across all subgroups analyzed, said Cremolini.

Krishnamurthi said clinicians in the United States generally did not start using the FOLFOXIRI regimen based on the earlier results because they already were incorporating chemotherapy and Avastin into treatment plans. FOLFIRI is a widely used frontline therapy in the treatment of patients with mCRC, along with the FOLFOX regimen of folinic acid, 5-FU and oxaliplatin. The GONO group will continue its research with the phase 3 TRIBE-2 trial in which 654 patients will be randomized to receive firstline FOLFOXIRI plus Avastin followed by either reintroduction of FOLFOXIRI plus Avastin at disease progression or FOLFOX plus Avastin followed by FOLFIRI plus Avastin at progression, researchers indicated.

In addition, the phase 2 MACBETH trial is evaluating a shorter duration of FOLFOXIRI (4 months versus 6 months) plus Erbitux (cetuximab) followed by maintenance with Avastin or Erbitux. The MOMA study also seeks to improve upon the maintenance regimen.