CETUXIMAB NOT EFFECTIVE WITH FLOX REGIMEN

October 19, 2010 (Milan, Italy) — In an unexpected finding, the addition of cetuximab (Erbitux) to combination chemotherapy did not add a significant benefit in the first-line treatment of metastatic colorectal cancer.

The results of the NORDIC VII study, which were presented at the 35th European Society for Medical Oncology (ESMO) Congress, showed that adding cetuximab to the FLOX regimen (fluorouracil, folinate, and oxaliplatin) did not improve response rate, progression-free survival, or overall survival.

The authors found that there were no statistically significant differences between the treatment groups in any of the end points. This lack of significant benefit also applied to subgroups of patients with mutant and wild-type versions of the KRAS gene.

The survival curves were about the same for all groups, said lead author Kjell Magne Tveit, MD, PhD, who presented the findings. Dr. Tveit is a professor at Oslo University Hospital in Norway

"We found a median overall survival of 20 to 22 months for the wild-type group of patients and also for the mutant group of patients, and we did not see any difference between the curves, with a hazard ratio [HR] close to 1.0," explained Dr. Tveit.

"This was, of course, somewhat unexpected and we have performed an extensive validation of the results," he noted, adding that the results were the same after additional analyses.

Dr. Tveit emphasized that the study confirmed that the FLOX regimen is effective in the first-line treatment of metastatic colorectal cancer. "There was a median progression-free survival of 8 months, an overall survival of 20 months, and a response rate slightly above 40%," he said.

BRAF mutation was found to be a strong negative prognostic factor (median overall survival, 7.6 vs 20.4 months), but KRAS status did not appear to be a decisive factor. "KRAS mutation status was not found to be predictive, but we should keep in mind that the study was underpowered to investigate KRAS subpopulations," Dr. Tveit explained.

Mixed Results

The results of the NORDIC VII trial come in the wake of mixed findings from other large trials in which cetuximab was combined with standard chemotherapy regimens as first-line treatment in colorectal cancer.

At the 2010 annual meeting of the American Society of Clinical Oncology, the addition of cetuximab to FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) did not improve survival in patients with stage III colon cancer. As reported by Medscape Medical News at that time, there was no additional benefit, even though the study population included patients with wild-type KRAS.

In the phase 3 CRYSTAL study, cetuximab combined with FOLFIRI (irinotecan, fluorouracil, and leucovorin) reduced the risk for progression of metastatic colorectal cancer, compared with FOLFIRI alone, in patients with wild-type KRAS tumors.

Similarly, results from the phase 2 OPUS study demonstrated that cetuximab plus FOLFOX4 (5-flurorouracil, leucovorin, and oxaliplatin) led to improved survival and reduced disease progression in metastatic colorectal cancer patients with wild-type KRAS.

Dr. Tveit noted, however, that his study appears to "be in line with the COIN study," and concluded that "oxaliplatin may not be a good match for cetuximab for colorectal cancer treatment."

The COIN study, which was presented at the 2009 joint European CanCer Organization/ESMO Multidisciplinary Congress (abstract 6LBA), evaluated whether the addition of cetuximab to continuous oxaliplatin-based chemotherapy would improve overall survival when given as first-line therapy in advanced colorectal cancer. The median overall survival between the groups was not statistically significant.

No Difference Between Groups

In the current study, 571 patients were randomized to 1 of 3 treatment groups:

* Group A: FLOX twice a week (oxaliplatin 85 mg/m2 on day 1, 5-flurorouracil bolus 500 mg/m2, and folinic acid 60 mg/m2 on day 1–2)
* Group B: FLOX + cetuximab (initial dose 400 mg/m2, then 250 mg/m2 once a week)
* Group C: FLOX for 16 weeks + cetuximab continuously, with FLOX reintroduced at progression.

KRAS mutation status was obtained in 498 (87%) of patients, and BRAF mutation status in 457 patients (81%). Almost half (40%) of tumors had KRAS mutations; 12% had BRAF mutations. The primary end point of the study was progression-free survival.

Overall survival was similar among the 3 groups.

Overall survival for the intent-to-treat group was 20.4 months for group A, 19.7 months for group B, and 20.3 months for group C (HR, 1.06; 95% confidence interval [CI], 0.83 - 1.35; P = .67 for groups B vs A).

Overall survival for the wild-type KRAS group was 22 months for group A, 20.1 months for group B, and 21.4 months for group C (HR, 1.14; 95% CI, 0.80 - 1.61; P = .66 for groups B vs A).

Overall survival for the mutated KRAS group was 20.4 months for group A, 21.1 months for group B, and 20.5 months for group C (HR, 1.03; 95% CI, 0.68 - 1.57; P = .89 for groups B vs A)

Progression-free survival was similar between groups A and B.

For the intent-to-treat group, progression-free survival was 7.9 months in group A and 8.3 months in group B (HR, 0.89; 95% CI, 0.72 - 1.11; P = .31).

For the wild-type KRAS group, progression-free survival was 8.7 and 7.9 months, respectively (HR, 1.07; 95% CI, 0.79 - 1.45; P = .66).

For the mutated KRAS group, progression-free survival was 7.8 and 9.2 months, respectively (HR, 0.71; 95% CI, 0.50 - 1.03; P = .07).

True Interaction?

Alberto F. Sobrero, MD, head of medical oncology, Ospedale San Martino, in Genoa, Italy, and discussant of the paper, noted that the overall survival was similar for patients treated with FLOX intermittently and cetuximab continuously and for patients treated until progression.

"Cetuximab added an 8% response rate and marginal progression-free survival in the intent-to-treat population, and it also added toxicity," said Dr. Sobrero.

But the most unexpected conclusion was that there was no better outcome in the wild-type KRAS population, he added. "As far as KRAS relevance, it didn't have any impact on the outcome."

He pointed out that of 11 trials, this is the only one that showed a lower response rate in wild-type than in mutated KRAS.

Given all factors, Dr. Sobrero reasoned that, in his opinion," it is quite likely that the results are not due to bias or chance, but a true interaction" — the possibility that the treatment schedule or oxaliplatin causes a reaction.

The researchers have disclosed no relevant financial relationships.

35th European Society for Medical Oncology (ESMO) Congress: Abstract LBA20. Presented October 10, 2010.