A phase III clinical trial found that cetuximab (Erbitux) added to standard adjuvant chemotherapy for resected stage III colon cancer did not improve either overall survival or disease-free survival (DFS), even in patients with wild-type KRAS tumors. Results of the study, the North Central Cancer Treatment Group Intergroup trial N0147, were presented at the 2010 ASCO Annual Meeting.

The trial, which enrolled nearly 3,000 adults, terminated early after a futility analysis showed adjuvant cetuximab had no benefit over a modified FOLFOX6 regimen (fluorouracil, leucovorin, and oxaliplatin) alone and had significantly more grade 3/4 adverse effects. The investigators had expected the monoclonal antibody to have benefits when added to FOLFOX based on prior research that found cetuximab extends life for patients with metastatic colon cancer expressing the KRAS wild-type gene.

"What we learned is that [the cetuximab benefit in] metastatic disease does not necessarily apply to the adjuvant setting. This treatment should not be used in patients with resected stage III colon cancer," said lead researcher Steven Alberts, MD, Professor of Oncology at the Mayo Clinic College of Medicine in Rochester, Minnesota.

KRAS Status Important

The trial opened before KRAS mutation status testing became available, and once it did in early 2008, the study was redesigned and researchers enrolled only patients with normal KRAS activity. Dr. Alberts reported the results in 1,864 patients with normal KRAS: 909 who received only FOLFOX therapy and 955 who received cetuximab as well.¹ Richard Goldberg, MD, Professor at the University of North Carolina at Chapel Hill, presented the results of the 717 patients with KRAS mutations who were enrolled before testing was required.2 Of those, 343 patients received cetuximab in addition to FOLFOX, and 374 were in the FOLFOX-only arm.

As in other studies, KRAS status was predictive of response to cetuximab, with patients who had mutations faring worse than those with the wild type, Dr. Goldberg said. Overall 3-year DFS for the cetuximab-plus-FOLFOX group was 62.3% for patients with mutated KRAS tumors vs 73.3% for those with wild-type tumors, according to the investigators. Patients who received FOLFOX alone had a 3-year DFS of 70.3% if they had KRAS mutations, compared with 74.1% for the wild type.

"Clearly, cetuximab treatment of patients with KRAS mutations perturbs the tumor biology, in the opposite fashion of what we had hoped," he said.

Why Didn't Cetuximab Work?

"I find no flaws in study design or execution that would explain these results," said the study's discussant, Louis M. Weiner, MD, Director of the Lombardi Comprehensive Cancer Center, and Chair of the Department of Oncology at Georgetown University Medical Center, Washington, DC. The lack of response to cetuximab is likely to hold true for other epidermal growth factor receptor (EGFR)-directed monoclonal antibodies, he said.

"It is critical to understand why the results were negative," Dr. Alberts said. "It may be that cetuximab acts differently in patients with micrometastatic disease than in established metastatic disease."

Dr. Weiner added, "It is possible that the colon cancer cells transiently lose EGFR dependency during the process of metastasis. This would create new opportunities and challenges for drug development designed for the adjuvant therapy of colon cancer." ■

References

1. Alberts SR, Sargent DJ, Smyrk TC, et al: Adjuvant mFOLFOX6 with or without cetuximab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): Results from NCCTG Intergroup Phase III Trial N0147. 2010 ASCO Annual Meeting. Abstract CRA3507. Presented June 5, 2010.

2. Goldberg RM, Sargent DJ, Thibodeau SN, et al: Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147. 2010 ASCO Annual Meeting. Abstract 3508. Presented June 6, 2010.