FDA Approves KRAS Mutation Test to Help Determine Colorectal Cancer Treatment

July 17, 2012

The new diagnostic test to detect KRAS gene mutations, will facilitate speedier assessment of the KRAS mutation status of a patient’s tumor to allow for an earlier treatment decision to use cetuximab or to go on with another treatment.

Earlier this month the US Food and Drug Administration (FDA) approved a new genetic test to determine those patients whose tumors will respond to cetuximab (Erbitux). The test, the therascreen KRAS RGQ PCR Kit, can be used to determine whether or not patients with advanced colorectal cancer have a wild-type KRAS gene, indicating eligibility for cetuximab treatment.

Simultaneously, cetuximab was given a new indication for first-line treatment in combination with the chemotherapy regimen FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for patients with metastatic colorectal cancer who have EGFR-expressing, and KRAS wild-type tumors. 

A flat, ulcerated adenocarcinoma

Cetuximab is an antibody that targets the epidermal growth factor receptor (EGFR), expressed on colorectal cancer tumors. The drug was first approved under the FDA’s accelerated drug program for colorectal cancer in 2004 as a combination with the chemotherapy irinotecan for patients who no longer respond to irinotecan alone or as a monotherapy for patients who cannot tolerate irinotecan.

Subsequent analysis showed the antibody therapy does not work in colorectal cancer patients who harbor a KRAS mutation in either codon 12 or 13. KRAS is downstream of EGFR, and activating KRAS mutations constitutively activate the MAP kinase pathway, resulting in uncontrolled tumor growth. In 2009, the FDA changed the product labels for both cetuximab and another anti-EGFR antibody indicated for colorectal cancer patients, panitumumab (Vectibix). It is estimated that about 40% of colorectal cancer tumors harbor a KRAS mutation.

The new diagnostic test to detect KRAS gene mutations, developed by Qiagen, will facilitate speedier assessment of the KRAS mutation status of a patient’s tumor to allow for an earlier treatment decision to use cetuximab or to go on with another treatment. Clinical laboratories already assess KRAS mutation status from patient tumor samples as per the updated FDA label in 2009. However, Qiagen says its test produces a result in less than 5 hours-compared to 9 to 11 hours required for current laboratory tests.

The new first-line treatment indication for cetuximab is based on the open-label phase III CRYSTAL trial conducted outside of the United States. Among patients whose tumors did not harbor KRAS mutations, those treated with cetuximab plus FOLFIRI had a median survival of 23.5 months, compared to 19.5 months for those who received only FOLFIRI.

It is important to note that while an activating KRAS mutation precludes treatment with cetuximab for late-stage colorectal cancer patients, a wild-type KRAS gene does not guarantee a patient will respond to anti-EGFR treatment if they have EGFR-positive colorectal cancer. Other novel predictive biomarkers are currently being evaluated including members of EGFR-downstream PI3K/PTEN/AKT/mTOR pathways.