BARCELONA – Adding cetuximab to standard adjuvant chemotherapy for resected stage III colon cancer does not benefit patients, according to interim results from a large, phase III, European trial.

In the multicenter randomized study, the combination of FOLFOX4 plus cetuximab (Erbitux) did not prolong disease-free survival compared with FOLFOX4 alone, even in patients with KRAS wild-type tumors. The disease-free survival rate at 3 years was 75.1% in 791 patients given FOLFOX4 with cetuximab and 78% in 811 patients in the control group.

These preliminary results of the PETACC8 cooperative group trial were presented for the first time on June 29 at the European Society for Medical Oncology’s (ESMO’s) 14th World Congress on Gastrointestinal Cancer. The disappointing outcome follows a negative report from the North Central Cancer Treatment Group (NCCTG) N0147 trial, which also looked at the benefit of cetuximab added to FOLFOX in the adjuvant colorectal cancer setting (JAMA 2012;13:1383-93).

The FOLFOX regimen, a combination of oxaliplatin, leucovorin, and 5-fluorouracil (5-FU), has been the standard of care since the MOSAIC trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer) reported its results (Cancer Treat. Rev. 2004;30:711-13), said Dr. Julien Taieb, who presented the current study.

The MOSAIC benefit was confirmed by the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial, with attainable 3-year disease-free survival rates of around 70% (J. Clin. Oncol. 2007;25:2198-204), noted Dr. Taieb of Georges Pompidou European Hospital in Paris.

"When [molecularly] targeted agents came for colorectal cancer, of course everyone was wondering if they were [effective] in the adjuvant setting," he said.

In addition to the U.S. trial of cetuximab, two other trials of the antiangiogenesis inhibitor bevacizumab (Avastin) – the AVANT and NSABP C-08 trials – have also failed to show a benefit in disease-free survival at 3 years in this clinical setting, however.

"It is a little bit disappointing," coinvestigator Dr. Michel Ducreux, head of the gastrointestinal unit at the Institût Gustave Roussy in Villejuif, France, said in an interview.

The current study specifically looked at patients with the KRAS wild type, Dr. Ducreux noted. These are patients who should, in theory, still be able to respond to an epidermal growth factor receptor (EGFR) inhibitor, such as cetuximab. It has been known since 2008 that patients with mutated KRAS tumors do not respond to EGFR inhibition.

"The main point now is to go into the details of the biological samples in that study," Dr. Ducreux suggested, to determine whether any subpopulations of patients might benefit, and if not, to find out why.

The PETACC8 trial was originally designed to compare 12 cycles of FOLFOX4 versus FOLFOX4 plus additional cetuximab. The trial protocol was amended in 2008, when it became possible to select patients for cetuximab therapy based on their KRAS status.

Of the 2,559 patients recruited into the trial at 340 sites in Europe, nearly two-thirds had KRAS wild-type disease and 1,602 of them were randomized. The mean age of the KRAS wild-type patients was 58 years. All had completely resected, pathologically confirmed stage III colon cancer, a good WHO performance status, and a life expectancy of at least 5 years at enrollment.

The primary end point was disease-free survival, defined as the period before recurrence, second colorectal cancer, or death. However, the hazard ratio for disease-free-survival was 1.047 (P = .66). The differences in rates at 1, 2, and 4 years were also not statistically significant for FOLFOX4 with cetuximab (90.4%, 79.7%, and 72.4%, respectively) or without (92%, 81.5%, and 75.5%).

"Disease-free survival was really excellent compared to what has been reported with FOLFOX4 in the literature," Dr. Taieb said.

He noted that while cetuximab appeared to give no extra benefit, there might be subgroup of KRAS wild-type patients that could gain some benefit. There were trends for women; patients 70 years and older; and groups with a WHO performance status of 0, pT1-3 and pN1 tumors, and no bowel obstruction or perforation to do a little better.

Tolerability was as might be expected for the agents tested, but with a higher chance of hypersensitivity reactions, acnelike rash, diarrhea, and mucositis in the cetuximab-containing arm. There was an overall 15% difference in the occurrence of grade 3 and 4 adverse events between the FOLFOX4 with cetuximab and FOLFOX4 arms (80.9% vs. 66.2%, respectively).

"The probability for a positive result in the final analysis is very low," Dr. Taieb said, suggesting that "cetuximab might have a different form of activity on micrometastatic disease compared to that observed in stage IV disease."

Merck Serono and Sanofi-Aventis provided grants to fund the trial. Dr. Taieb has received consultancy and advisory board honoraria from Merck. Dr. Ducreux has received consultancy fees from Merck Serono and Roche.

Adjuvant Cetuximab Fails to Boost FOLFOX in Stage III Colon Cancer