CHICAGO – Pairing cetuximab with first-line FOLFIRI chemotherapy significantly extended overall survival by roughly 4 months over bevacizumab plus FOLFIRI among patients with KRAS wild-type metastatic colorectal cancer in the phase III FIRE-3 trial.
Patients in the cetuximab (Erbitux) and bevacizumab (Avastin) arms had similar times to disease progression of 10 and 10.3 months, respectively (Hazard ratio, 1.06; P = .54), but those given cetuximab lived for 28.7 months vs. 25 months with bevacizumab (HR, 0.77; P = .017).
The German AIO (Arbeitsgemeinschaft In-ternistische Onkologie) study group trial is the first to directly compare the two approved targeted agents with FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy.
"Based on our findings, we believe that a substantial gain in survival can be achieved when doctors offer cetuximab-based treatment as first-line to their patients with KRAS wild-type metastatic colorectal cancer," lead author Dr. Volker Heinemann said in a press briefing at the annual meeting of the American Society of Clinical Oncology (ASCO), where the data were presented.
FIRE-3 was a negative trial, however, as the primary end point of objective response rate was statistically similar between the cetuximab and bevacizumab arms at 62% and 57% in an intent-to-treat analysis of all 592 patients (odds ratio, 1.18; P = .18). Response was significantly greater with cetuximab though among the 526 patients assessable for efficacy (72.2% vs. 63.1%; OR, 1.52; P = .17), said Dr. Heinemann, professor of medical oncology at the University of Munich.
The take-home message is that patients with metastatic colorectal cancer have options, but the mixed results also raise questions about the influence of subsequent therapies on overall survival, Dr. Richard Goldberg, physician-in-chief at The Ohio State University’s Comprehensive Cancer Center and an ASCO spokesperson, said at the briefing.
"Really all of the different lines of therapy contributed to this outcome and I would challenge the investigators from the AIO to go back and study their data -- study the second, third and fourth-line treatments that their patients had and help explain this finding, which does seem a bit anomalous," he said.
Dr. Heinemann responded that these data will be presented at a forthcoming meeting in Barcelona, and that data suggest cetuximab-based therapy causes deeper tumor shrinkage than bevacizumab. About 60% of all patients received second-line therapy and about 40% crossed over to the other study arm, he added.
The survival benefit is impressive and will reinforce cetuximab and FOLFIRI in those already using the combination, but is unlikely to result in a profound shift in prescribing habits away from bevacizumab and FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) chemotherapy, the dominant combination in the United States, Dr. Al B. Benson III, said in an interview. Instead, many clinicians are awaiting results from the North American intergroup phase III C80405 trial comparing cetuximab with bevacizumab in some patients on FOLFIRI, but the majority on FOLFOX.
"One of the problems in the U.S. with cetuximab is that many patients really do not want to be exposed to the risk of rash; so, what we’ve found, is that people would rather postpone that decision to receive cetuximab if they’re wild-type," said Dr. Benson, professor of hematology/oncology and associate director for clinical investigations at the Robert Lurie Comprehensive Cancer Center of Northwestern University in Chicago.
Dr. Goldberg agreed that it’s doubtful FIRE-3 will change U.S. practice, and said the 80405 trial investigators have petitioned to have the data released ahead of its expected timeline of next year.
"We’re hoping that the data monitoring committee will respond to the uncertainty that this presentation raises and if there is no compelling reason to keep the data blinded, release the data for public scrutiny sometime this year," he said in an interview.
FOLFOX and FOLFIRI are each recommended first-line treatments in the recently updated 2013 National Comprehensive Cancer Network (NCCN) guidelines for metastatic colon cancer, with the addition of a biologic agent optional. If patients receive a bevacizumab-containing regimen first line, the guidelines now recommend that bevacizumab continuation with a different chemotherapy backbone after progression.
Dr. Benson, who helped pen the 2013 NCCN update and is an 80405 trial investigator, said that subsequent therapies, as well as dose reductions and treatment duration, will influence interpretation of the FIRE-3 survival data.
FIRE-3 randomized 592 patients with wild-type tumors to FOLFIRI every 2 weeks plus cetuximab 400 mg/m2 on day 1, followed by 250 mg/m2 weekly, or bevacizumab 5 mg/kg every 2 weeks. An ECOG performance status of 0-1 was present in 98% of patients, 66% were male, and their median age was 64 years.