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FOLFOXIRI plus bevacizumab improved outcomes, increased toxicity in metastatic colorectal cancer
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Patients with metastatic colorectal cancer who received first-line treatment with bevacizumab plus FOLFOXIRI chemotherapy demonstrated significantly longer PFS than those treated with bevacizumab plus FOLFIRI chemotherapy, according to results of a randomized phase 3 study.
However, bevacizumab plus FOLFOXIRI was associated with higher rates of certain adverse events, results showed.
Fotios Loupakis, MD, PhD, of the Azienda Ospedaliero–Universitaria Pisana and Università di Pisa, and colleagues sought to compare how the choice of chemotherapy regimen affected outcomes of patients with metastatic colorectal cancer who received no prior chemotherapy or biologic therapy.
The open-label, multicenter trial included 508 patients. Researchers assigned 256 patients in the control arm to bevacizumab (Avastin, Genentech) plus FOLFIRI chemotherapy, which includes fluorouracil, leucovorin and irinotecan (Camptosar, Pfizer). The 252 patients in the experimental arm received bevacizumab plus FOLFOXIRI, which includes fluorouracil, leucovorin, irinotecan and oxaliplatin.
Baseline characteristics were comparable between the cohorts, although more patients in the experimental arm had a primary tumor in the right colon (34.9% vs. 23.8%;
Patients assigned FOLFIRI received a median 12 treatment cycles (range, 1-25), and patients assigned FOLFOXIRI received a median 11 cycles (range, 1-21). Patients then received maintenance therapy with fluorouracil plus bevacizumab until disease progression.
Median follow-up was 32.2 months (range, 24.7-40.6).
Patients assigned bevacizumab plus FOLFOXIRI demonstrated significantly longer median PFS (12.1 months vs. 9.7 months; HR=0.75; 95% CI, 0.62-0.9).
Significantly more patients in the FOLFOXIRI arm responded to treatment (65.1% vs. 53.1%; OR=1.64; 95% CI, 1.15-2.35).
Patients assigned FOLFOXIRI also demonstrated longer median OS, but the difference did not reach statistical significance (31 months vs. 25.8 months; HR=0.79; 95% CI, 0.63-1).
The overall incidence of serious adverse events was similar between patients in the FOLFOXIRI and FOLFIRI arms (20.4% vs. 19.7;
“Our findings show that 6 months of induction treatment with FOLFOXIRI plus bevacizumab (as compared with FOLFIRI plus bevacizumab), followed by maintenance therapy, significantly improved the efficacy of first-line therapy,” Loupakis and colleagues concluded. “The cost was an increase in the incidence of adverse events.”
Disclosure: The study was funded by the ARCO Foundation, F. Hoffman-La Roche and the Gruppo Oncologico Nord Ovest. See the study for a list of the researchers’ relevant financial disclosures.
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David H. Ilson, MD, PhD
Loupakis and colleagues report results of the multicenter, phase 3 TRIBE trial, which evaluated triplet chemotherapy, adding oxaliplatin (Eloxatin, Sanofi-Aventis) to standard two-drug FOLFIRI plus bevacizumab (Avastin, Genentech) in advanced colorectal cancer. The primary endpoint, PFS, was improved with FOLFOXIRI plus bevacizumab compared with FOLFIRI plus bevacizumab (12.1 months vs. 9.7 months; HR=0.75; P=.003). Response to therapy (65% vs. 53%; OR=1.65; P=.006) and OS (31 months vs. 26 months; HR=0.79; P=.054) also favored the oxaliplatin arm. Similar numbers of patients were converted to resectable status with or without oxaliplatin (15% vs. 12%; P=.33). Rates of grade 3 and grade 4 toxicities were significantly higher with oxaliplatin, including neutropenia (50% vs. 21%), diarrhea (19% vs. 11%), stomatitis (9% vs. 4%) and neuropathy (5% vs. 0%). Patients with BRAF mutations (5% to 6%) had suggestion of a greater PFS benefit (HR=0.55).This well-conducted phase 3 trial indicated higher rates of response and longer PFS for triplet therapy compared with FOLFIRI plus bevacizumab in metastatic colorectal cancer, with a trend toward improved OS. The TRIBE trial, however, was not powered to demonstrate a survival benefit for FOLFOXIRI. One of the major arguments for chemotherapy intensification in the first-line treatment of metastatic disease is to improve conversion to resectable disease, but this did not occur with triplet therapy. The broader application of triplet therapy is also questioned by the near-doubling of grade 3 and grade 4 toxicities. Although cross-trial comparisons can yield limited conclusions, the recently reported CALGB 80405 trial — in which KRAS wild-type patients were treated with FOLFIRI plus bevacizumab — achieved an OS exceeding 33 months, approaching the survival reported for triplet therapy on the TRIBE trial. How sequencing subsequent therapies impacts outcomes of these different trials, including the use of bevacizumab beyond progression, will complicate comparative analyses. The observation of a potential greater benefit in BRAF-mutant patients, who have a particularly poor prognosis, may warrant further study.
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