One of the major recent advances in the field of colorectal cancer has been the identification of K-Ras mutations. K-Ras mutation determines colorectal cancer’s responsiveness to Erbitux and panitumumab. The discovery that metastatic colon cancer tumors express the KRAS gene in 2 forms — mutated and wild-type — has effectively split colon cancer into 2 separate diseases. About 40% of patients with metastatic colon cancer have tumors with a mutated form of the KRAS gene, and these patients are unlikely to respond to treatment with cetuximab and panitumumab. The other patients with the normal, or wild-type, KRAS genes are likely to respond to these drugs. However, whether erbitux and Vectibix should be used first line was not clear form this data.
According to a recent retrospective analysis of the pivotal Phase 3 CRYSTAL study, ERBITUX® (cetuximab), when added to FOLFIRI, was shown to increase median overall survival to 19.9 months in an intent-to-treat (ITT) population of first-line metastatic colorectal cancer (mCRC) patients compared to 18.6 months in those receiving FOLFIRI alone (hazard ratio [HR] 0.878; 95% CI 0.774 0.995; p=0.042). In a subset of mCRC patients with wild-type K-ras tumors, median overall survival was increased to 23.5 months in patients who received ERBITUX plus FOLFIRI compared to 20 months for those taking FOLFIRI alone (HR 0. 796; 95% CI 0.670 0.946; p=0.0094).
On the other hand, when irinotecan was not the drug used, the results were not good. A second Phase 3 study of ERBITUX plus chemotherapy (primarily capecitabine plus oxaliplatin) in first-line mCRC, known as COIN, was conducted in the UK by the Medical Research Council, a UK-based publicly funded organization. The COIN study did not meet its primary endpoint of overall survival in K-ras wild type patients receiving ERBITUX plus chemotherapy vs. chemotherapy alone (17 months vs. 17.9 months) (HR 1.038; 95% CI 0.90 – 1.20; p=0.68). Patients with K-ras wild type tumors receiving ERBITUX plus chemotherapy experienced an increase in the following Grade 3 or 4 adverse events vs. those taking chemotherapy alone: non-hematological events (77% vs. 62%), diarrhea (24% vs. 14%), hypomagnes-aemia (4% vs. 0%), hand foot syndrome (11% vs. 4%) and skin rash (20% vs. <1%).
At this time, per 2011 NCCN COL-C,1 only Folfiri should be used first line with Erbitux or panitumumab.
Van Cutsem E, Lang I, D’haens G et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 2008; 26(15 suppl):abstract 2.
Lievre A, Bachet JB, Boige V et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008; 26(3):374-9.