COIN: No Benefit Found Adding Cetuximab to FOLFOX or CAPOX in First-Line CRC Treatment

Even in colorectal cancer patients with wild-type KRAS mutations, there was no increase in overall survival time or in the time it took before cancer progressed when Erbitux® (cetuximab) was added to FOLFOX or CAPOX chemotherapy.

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