ASCO 2010-ANOTHER FAILURE OF TARGETED CHEMOTHERAPY FOR ADJUVANT TREATMENT OF COLORECTAL CANCER

June 10, 2010 (Chicago, Illinois) — In a finding that was both unexpected and disappointing, the addition of cetuximab (Erbitux) to standard adjuvant chemotherapy in patients with stage III colon cancer did not improve survival. Even though the study population had wild-type KRAS, the addition of cetuximab did not provide additional benefit.

"Much to our surprise, the trial did show that patients receiving standard therapy, compared with those receiving cetuximab with standard therapy, had no difference in outcomes," said lead researcher Steven Alberts, MD, professor of oncology at the Mayo Clinic College of Medicine in Rochester, Minnesota.

Dr. Alberts presented the results here at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting.

The finding was unexpected because cetuximab has previously been shown to improve survival in patients with metastatic colon cancer whose tumors express wild-type KRAS.

This trial is important in several regards, Dr. Alberts noted. "First, it says that what we learned in the metastatic setting does not always apply to the adjuvant setting. Therefore, it is very important that we continue to conduct trials," he said. "It also indicates that disease in earlier stages may be different than disease in later stages."

Now it is critical to understand why cetuximab did not work in this population, Dr. Albert pointed out, adding that there are a number of potential reasons for these findings. One is that cetuximab increased toxicity and therefore decreased the ability of patients to benefit from therapy, although that was only seen in older patients.

"It could also be that cetuximab acts differently in earlier stage disease than later, and is clearly something that we have to continue to investigate," he added.

Cetuximab Should Not Be Used in This Setting

In a discussion of the paper, Louis M. Weiner, MD, said that "these findings are likely to be true for other anti-EGFR antibodies as well."

"Numerous genes contribute to resistance of EGFR antagonists, and this may underlie components of cetuximab resistance in the metastatic disease and adjuvant setting," said Dr. Weiner, who is director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC.

Colon cancer metastasis might not be dependent on signaling through EGFR, he explained, and a combination strategy might be needed to overcome this resistance.

"A better understanding of colon cancer biology will inevitably lead to better treatments, target the right cells at the right time, and effectively disrupt one or more targets that are required for the function of crucial signaling processes," he said.

For right now, cetuximab does not appear to benefit patients in this setting. "I believe that anti-EGFR monoclonal antibodies should not be used in stage III colon-cancer-directed adjuvant therapy regimens, except perhaps in selected clinical trials," Dr. Weiner said.

Overall Survival Better With FOLFOX Alone

FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin), the standard adjuvant therapy for stage III colon cancer, was used in this study, Dr. Alberts and colleagues randomized 1760 patients with resected stage III colon cancer and wild-type KRAS to receive FOLFOX alone (n = 858) or FOLFOX plus cetuximab (n = 902).

At a median follow-up of 15.9 months (1624 patients), the authors found that the rates of disease-free survival were similar in both groups. In fact, overall survival was slightly better with FOLFOX alone than with FOLFOX plus adjuvant cetuximab, and 3-year disease-free survival favored FOLFOX alone (hazard ratio, 1.18; 95% confidence interval, 0.92 to 1.52; P = 0.33).

Outcomes in Overall Study Population
Survival FOLFOX FOLFOX + Cetuximab P value
3-year disease-free survival 74.1% 73.3% .33
3-year overall survival 87.3% 82.1% .06
On-study mortality 0.58 1.44 .07


Accrual in the trial stopped when 50% of planned events demonstrated that there was no benefit associated with the addition of cetuximab to the regimen. Cetuximab was also not associated with any benefit when an assessment of subgroups was conducted.

Greater Differences in Outcomes for Older Patients

However, the researchers observed that there were greater differences in outcomes in patients 70 years and older (n = 227).

Outcomes in Patients 70 Years and Older
Survival FOLFOX FOLFOX + Cetuximab P value
3-year disease-free survival 78% 64.8% .05
3-year overall survival 83.9% 75.4% .17
On-study mortality 1.87 5.84 .12


Grade 3 and higher adverse events were significantly more frequent among patients who received adjuvant cetuximab; this was particularly true for patients 70 years and older. Overall, grade 3/4 toxicities were 45% in the FOLFOX group and 65.4% in the FOLFOX plus cetuximab group (P > .001), although rates of grade 4 and higher neutropenia were similar (9.0% vs 9.7%; P = .62).

The overall rate of adverse events grade 3 and above among older patients was 53.5% in the FOLFOX group and 80.3% in the FOLFOX plus cetuximab group (P < .001).

The researchers observed that there was significantly more failure to complete 12 cycles of treatment in the cetuximab group. Approximately two thirds of patients treated with FOLFOX plus cetuximab (65.6%) completed the full 12 cycles, whereas 77.3% of those treated with FOLFOX alone did.

"We had hoped that we could treat these patients in a targeted way by preselecting patients with wild-type KRAS, who have a chance of responding to cetuximab," said Jennifer Obel, MD, from the NorthShore University HealthSystem in Evanston, Illinois, who moderated a press conference where the findings were highlighted.

She pointed out that this study "comes on the heels" of data presented at last year's ASCO meeting, in which findings demonstrated that bevacizumab (Avastin) did not improve overall survival in stage II and III colon cancer. These findings "cast doubt on whether biologics will play a role in early-stage colon cancer," she said.

"It makes us want to rethink whether we need to think about disease processes as unique and discover novel pathways in the micrometastatic setting," she concluded.

The study was supported by the National Institutes of Health, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer. Dr. Alberts has disclosed no relevant financial relationships; but several coauthors report relationships with Amgen, Bristol-Meyers Squibb, Celgene, Genentech, ImClone Systems, Pfizer, Sanofi-Aventis, Plexxikon, Idera, Agensys, and Lilly

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract CRA3507. Presented June 6 2010.