News and Educations

Dear Healthcare Professional Letter on the importance of the wild type RAS status determination (exons 2, 3 and 4 of KRAS and NRAS) prior to Erbitux (cetuximab) treatment


Merck Serono has, in agreement with the Agency for Medicinal Products and Medical Devices (HALMED), sent out a letter to healthcare professionals about the variation in the authorised indication of Erbitux in metastatic colorectal cancer (mCRC).


  • Prior to treatment with Erbitux, it is necessary to confirm the absence of RAS mutations, or confirm the wild type RAS status (exons 2, 3 and 4 of KRAS and NRAS), the RAS mutation status (Exons 2, 3 and 4 KRAS and NRAS) should be determined in an experienced laboratory by means of validated technique
  • It has been necessary to confirm the KRAS mutation status on the exon 2 and confirm the absence of mutations prior the Erbitux treatment. However, additional data suggest that it is also necessary to confirm the absence of RAS mutations, in other words determine the "wild type” RAS status according to the definition above for the activity of Erbitux.
  • In patients with metastatic colorectal carcinoma receiving Erbitux in combination with chemotherapy FOLFOX4 and whose tumours have RAS mutations (exons 2, 3 and 4 KRAS and NRAS) an inferior overall survivor (OS) with progression-free survival (PFS) and objective response rate (ORR) was discovered on the contrary to those who received only the FOLFOX4 protocol.
  • Contraindications for Erbitux in combination with oxaliplatin-containing chemotherapy (i.e. FOLFOX4) encompasses now all patients with colorectal carcinoma, whos tumours have a RAS mutation (exons 2, 3 and 4 of KRAS and RAS) or the RAS mutation status is unknown.

Basic information

Updated information on prescribing and including of additional RAS mutations are based on the retrospective analysis of data in subgroups from a randomised multicentric phase 2 trial of Erbitux and FOLFOX4 protocol vs. FOLFOX4 only in patients with previously untreated mCRC (OPUS study EMR 62202). The OPUS study included 337 patients, out of which 179 patients had a wild type KRAS tumour (on the exon 2). The incidence of additional RAS mutations within the wild type KRAS population on the exon 2 was 30.5 %.

By excluding patients whose tumours had additional mutations on the NRAS exons 2, 3 and 4 and the KRAS exons 3 and 4 from the wild type KRAS population on the exon 2, an improvement of the clinical outcome occurred. On the other side, it was established that patients whose tumours had RAS mutations (including those outside the 2 KRAS exon) and who were treated with Erbitux and FOLFOX4 protocol had an inferior survivor, PFS and ORR with regard to the treatment with the FOLFOX4 protocol only. The authorised therapeutic indications for Erbitux have therefore been changed to delete the risk of a negative influence on the patients with additional RAS mutations alongside the KRAS mutations on the exon 2.

Here you may view the Dear Healthcare professional Letter.

HALMED has not by now received any adverse reaction report associated with the use of Erbitux which would be related to the above mentioned RAS mutations. HALMED will continue to monitor the safe use of cetuximab and will inform the public promptly about any new finding.

We remind healthcare professionals that they should report any adverse reaction to HALMED, as well as quality defect. Patients who have developed any adverse reaction to medicinal product may report it directly to HALMED via form or on-line application, with recommendation regarding any adverse reaction they discover to consult with their doctor or pharmacist about the continuation of their therapy.