More tumors got smaller with Erbitux treatment, but there was an increase in both serious gastrointestinal toxicity and severe skin rash when the drug was added.

Patients with tumor mutations in any of three genes — KRAS, BRAF, or NRAS — had poorer survival.

Study Design

The COIN trial enrolled 2,445  patients who had not received previous treatment for advanced colorectal cancer in one of three arms:

• ARM A: Standard chemotherapy with either 5-FU, leucovorin, and oxaliplatin (FOLFOX) or oral Xeloda and oxaliplatin (CAPOX).
• ARM B: FOLFOX or CAPOX plus Erbitux (cetuximab)
• ARM C: Intermittent treatment (results reported in another paper.)

Only the results of Arms A and B and patients with wild-type KRAS are discussed in  The Lancet current article. This included 729 patients — 367 on the standard treatment Arm A and 362 who also received Erbitux on Arm B.

Patients were treated until their cancer progressed.

Results for Arms A and B

At the time results were analyzed 71 percent of patients had died in both groups, more than 90 percent of colorectal cancer.

• Overall survival in the chemo only group was 17.0 months and 17.9 months in the group that got chemo plus cetuximab.
• Progression-free survival was 8.6 months in both groups.
• 57 percent of the chemo only group responded with tumor shrinkage compared to 64 percent of the cetuximab group.

Side effects

• 14 patients in the chemo group had severe skin rash (grades 3 or higher) compared to 114 in the cetuximab arm.
• 67 patients in chemo group had severe gastrointestinal toxicity compared to 97 in the cetuximab arm.

Influence of tumor gene mutations

For the 1,630 patients in Arms A and B

• 43% had KRAS mutations
• 8% had BRAF mutations
• 4% had NRAS mutations

Effects of tumor mutations on survival

• No mutations of BRAF, KRAS, or NRAS:  median survival 20.1 months
• Any mutation of BRAF, KRAS, or NRAS:  median survival 13.6 months
• BRAF mutation: 8.8 months
• KRAS mutation: 14.4 months
• NRAS mutation: 13.8 months

Median progression-Free Survival ranged for 5.6 months for patients with BRAF mutations to 9.0 months for patients whose tumors had none of the mutations.

Professor Timothy S. Maugham and investigators in the Medical Research Council COIN trial concluded,

This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.

SOURCE

Maughan et al., The Lancet, Volume 337, Number 9783, Pages 2103 – 2114, 18 June 2011 doi:10.1016/S0140-6736(11)60613-2

It is important to know that in the UK Avastin is not approved, and Erbitux was only recently approved in patients with organ limited disease based on the chance of curative resections in patients initially deemed not to be resectable. However it is difficult to judge what the COIN results mean. The response rates in the patients with wild-type KRAS was significantly increased to 64%, so far so good. The problem is that the time to tumor progression and overall survival was not improved in patients with wild-type KRAS and Erbitux therapies.

I would caution not to jump quickly to conclusions since these data require a closer look. It is certainly surprising that about 40 percent of patients died in the first year which is much higher than any other study, which is usually about 20 percent, suggesting that these patients were sicker than in other trials.

In the UK, which reflects a pretty frugal health system, CT scans to monitor success of therapy are done every three months, not every six weeks as  in  United States or other parts of Europe. This makes it much more difficult to see a difference in results, particularly when we expect a time to tumor progression between 7 and 9 months. We also have to recognize that the CT findings are not centrally reviewed which means they can change when scans are reviewed by an expert panel (numbers always change from the investigator reading to an independent panel).

However the most interesting data are that the patients who received Erbitux and Xeloda had significant side effects leading to two dose reductions meaning that these patients received much less chemotherapy. This group seemed to have no benefit from Erbitux, but the patients who received FOLFOX did. We don’t know for sure why there are why are there more side effects with Xeloda and Erbitux, but both have overlapping GI and skin toxicities.Whether there is also some biological interaction we don’t know yet.

These data certainly need more evaluation and detailed review to be able to fully understand them.

Disclosure: C3 has accepted funding for projects and educational programs from Bristol-Myers Squibb and ImClone Systems in the form of unrestricted educational grants. C3 has ultimate authority over website content.