MILAN – Cetuximab in combination with a continuous or intermittently administered Nordic FLOX regimen for the first-line treatment of metastatic colorectal cancer conferred no advantage over the chemotherapy regimen alone, the first results of the Nordic VII study show.
Dr. Alberto Sobrero
The addition of cetuximab (Erbitux) did not improve response rates, progression-free survival, or overall survival. No better outcome was seen in patients with wild-type KRAS who received cetuximab, although the study was admittedly not powered to look specifically at KRAS subpopulations.
This is contrary to expectations and comes after a very thorough analysis, study investigator Dr. Kjell Magne Tveit of Oslo University Hospital said at the annual congress of the European Society for Medical Oncology. Investigators did not release data from the trial at the American Society of Clinical Oncology meeting earlier this year because they wanted to be sure of the disappointing results.
“Cetuximab has a documented beneficial effect in the later stages of metastatic colorectal cancer when given alone or together with chemotherapy,” Dr. Tveit said in a press release. “We expected that similar findings would be found in early stage [disease] when given together with the oxaliplatin regimen.”
Patient recruitment into the Nordic VII study began in May 2005 and ended in October 2007, with a total of 571 patients randomized to one of three arms: the standard FLOX (5- fluorouracil [5-FU], folinic acid, oxaliplatin) regimen used in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) at the time; FLOX plus additional cetuximab, with both given until progression or toxicity; or FLOX plus continuous cetuximab, with chemotherapy given for 16 weeks and then stopped and reintroduced at progression.
The Nordic FLOX regimen consists of a 5-FU intravenous bolus dose of 500 mg/m2 plus 60 mg/m2 folinic acid on days 1–2 every second week and oxaliplatin (85 mg/m2) on day 1. Cetuximab was used at a dose of 400 mg/m2 on day 1, then 250 mg/m2 weekly.
The primary end point was progression-free survival, and this did not significantly differ between the standard FLOX, FLOX-cetuximab, and “stop/go” FLOX-cetuximab arms, at a median of 7.9, 8.3, and 7.3 months, respectively (P = .31 comparing FLOX-cetuximab vs. standard FLOX).
Overall response rates in the standard FLOX, FLOX-cetuximab, and “stop/go” FLOX-cetuximab arms were 41%, 49%, and 47%, with an odds ratio of 1.35 (P = .15) comparing the first two arms in the intent-to-treat population of 566 evaluable patients. Overall survival was also similar between the groups, at a median of 20.4, 19.7, and 20.3 months, respectively.
“KRAS mutation status was not found to be predictive for cetuximab effect,” Dr. Tveit said, noting that BRAF mutation was “a strong negative prognostic factor.”
The addition of cetuximab also was associated with more grade 3/4 adverse events than the standard FLOX arm. “The Nordic VII study indicates that oxaliplatin may not be a good match for cetuximab in metastatic colorectal cancer,” he observed.
Commenting on the trial, Dr. Alberto Sobrero from the Ospedale San Martino in Genoa, Italy, said the most unexpected result was that cetuximab was of no benefit in patients with wild-type KRAS. Despite a high level of quality-control measures in the study, “only Nordic VII reported lower response rates and progression-free survival in KRAS wild-type than in mutants out of 11 trials,” he said.
The choice of the Nordic FLOX regimen as the “backbone” of chemotherapy was questionable, as it incorporates one of the least effective 5-FU regimens. “If you want to impact on practice, you really want to have your control arm to be what everybody else is using,” he said.
Furthermore, “data supporting cetuximab in combination with oxaliplatin is “shaky at best,” and “whenever irinotecan [Camptosar] is a partner of cetuximab you have fantastic results,” Dr. Sobrero said. Irinotecan-based regimens should therefore be the chemotherapy backbone when using cetuximab. “There is also another piece of evidence of continuing chemotherapy until progression,” he added.
Merck-Serono and Sanofi-Aventis financially supported the Nordic VII study. All study authors had no conflicts of interest. Dr. Sobrero disclosed that he has acted as an advisory board member and speaker for Sanofi-Aventis, Amgen, AstraZeneca, Roche, Merck-Serono, Pfizer, Onyx, Bayer, and Genentech.