FDA Approves Genetic Test for KRAS Mutation in CRC Patients

Roxanne Nelson


July 06, 2012

July 6, 2012 — The US Food and Drug Administration (FDA) has approved the therascreen® KRAS RGQ PCR Kit to be sold as a companion diagnostic test for cetuximab (Erbitux).

In addition, the FDA has simultaneously approved a new indication for cetuximab, to be used in combination with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) as a first-line treatment in patients with metastatic colorectal cancer who have epidermal growth factor (EGFR)-expressing and KRAS wild-type tumors.

The therascreen KRAS assay was developed by QIAGEN Manchester Ltd and is able to detect mutations in the KRAS gene. Its purpose is to help guide therapy and assist physicians in predicting which patients are most likely to benefit from treatment with monoclonal antibody EGFR inhibitors.

"The approval of this new Erbitux indication with the concurrent approval of a genetic test provides clear guidance on selecting patients who will optimally benefit," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research, in a statement.

"Clinical trial data leading to the approval of this new indication supports the recommendation to treat those patients whose colorectal tumors do not have KRAS mutations and to avoid treating those with KRAS mutations," explained Dr. Pazdur.

This is the first therascreen test to receive FDA approval. It offers greater sensitivity by requiring recognition of fewer mutated cells (0.8% - 6.4%) than laboratory developed tests (15% - 25%), according to the company. It also gives results in a mean of 4.5 hours compared with an average of 9 to 11 hours for lab-developed tests, although individual results may vary.

According to the US product information for cetuximab, KRAS status testing should be done using an "FDA-approved diagnostic," and the therascreen KRAS kit is now the only test with this status.

Cetuximab is a recombinant, chimeric monoclonal antibody directed against the EGFR with antineoplastic activity, and it may inhibit EGFR-dependent primary tumor growth and metastasis. It is currently approved to be used alone or in combination with other modalities to treat metastatic colorectal cancer and local or advanced squamous cell carcinoma of the head and neck.

The FDA first approved cetuximab in 2004 to treat EGFR-expressing late-stage colorectal cancer in patients who failed other therapies, and in 2009, the FDA approved updated recommendations for cetuximab, based on studies that found the drug is not effective in patients whose tumors have a mutated KRAS gene.

As previously reported by Medscape Medical News, the results of a large phase 3 trial of cetuximab combined with chemotherapy in colorectal cancer showed that only patients with KRAS wild-type tumors benefited from the targeted therapy. At that time, John Marshall, MD, from the Lombardi Comprehensive Cancer Center, Georgetown University, in Washington, DC, commented, in his Medscape Oncology expert blog, that the KRAS discovery 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 or panitumumab, explained Dr. Marshall.

For the expanded indication of cetuximab, the FDA based its approval on a study that showed that among patients with tumors that did not have 1 of the 7 KRAS mutations, median survival was 23.5 months for those who received cetuximab plus FOLFIRI, vs 19.5 months for those who received FOLFIRI alone. Among patients whose tumors had a KRAS mutation, median survival was similar between the 2 groups.

Cetuximab is manufactured and distributed in North America by Bristol-Myers Squibb and Eli Lilly and Company.


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