KRAS Mutations and Epidermal Growth Factor Receptor Inhibitor Therapy in Metastatic Colorectal Cancer
EXECUTIVE SUMMARY
Background: Cetuximab (Erbitux®, ImClone Systems) and panitumumab (Vectibix®, Amgen) are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.
Cetuximab and panitumumab are approved in the treatment of metastatic colorectal cancer in the refractory disease setting, and ongoing studies are investigating the use of these EGFR inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy. A proportion of patients with colorectal cancer have tumors that harbor a somatic KRAS mutation that may affect tumor response to EGFR inhibitors.
Objective: This Assessment evaluates and summarizes the evidence of using tumor cell KRAS mutational status as a predictor of nonresponse to EGFR-targeted therapy with monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer.
Search strategy: A MEDLINE® search (via PubMed) was performed through October 2008 to obtain references to original reports on anti-EGFR therapy and KRAS mutation analysis in metastatic colorectal cancer, using keywords "EGFR," "epidermal growth factor receptor," "KRAS," "cetuximab," "panitumumab," and "metastatic colorectal cancer." The electronic search was limited to English-language studies of human subjects. Review articles provided background information. The bibliographies of retrieved articles were consulted to identify references that may have been overlooked by the electronic search. The electronic search was supplemented with online abstracts from the 2008 American Society of Clinical Oncology (ASCO) annual meeting. Manufacturers and other vendor websites were consulted for information on commercial laboratory assays and drug package inserts.
Selection criteria: Studies were selected for inclusion in the Assessment if they were full-length, peer-reviewed articles published in an English-language journal and studied metastatic colorectal cancer and patient response to anti-EGFR antibodies in relation to tumor KRAS mutational status. To provide more complete information, data from phase II and III randomized trials presented at the 2008 American Society of Clinical Oncology (ASCO) meeting were included if full presentation slides of the study were available online.
Main results: Four randomized, controlled trials have performed nonconcurrent subgroup analyses of the efficacy of EGFR inhibitors in patients with tumors harboring wild-type versus mutated KRAS in metastatic colorectal cancer. The data from the 4 trials have consistently shown a lack of clinical response to cetuximab and panitumumab in patients with tumors exhibiting mutated KRAS, with tumor response and prolongation of progression-free survival observed only in patients with wild-type KRAS tumors. One of the randomized, controlled trials also showed prolongation of overall survival only in patients with wild-type KRAS tumors.
Five single-arm studies that have retrospectively analyzed tumor KRAS mutation status and tumor response rate in patients with metastatic colorectal cancer have shown a consistent lack of response to cetuximab or panitumumab in patients who have KRAS-mutated tumors. Two of these 5 studies have also shown progression-free and overall survival benefit with the use of EGFR inhibitors is limited to patients who have tumors with wild-type KRAS.
These data are sufficient to show the clinical validity of KRAS mutation testing and its clinical utility in guiding therapy selection for patients with metastatic colorectal cancer. The analytic validity of KRAS mutation testing by polymerase-chain reaction (PCR) methods is established as a commercially available laboratory test in CLIA-licensed laboratories.
Author's Comments and Conclusions: The data show that the clinical benefit of using EGFR inhibitors in treating metastatic colorectal cancer, either as monotherapy or in combination with other treatment regimens, is not seen in patients with KRAS-mutated tumors. This data supports knowing a patient's tumor mutation status before consideration of use of an EGFR inhibitor in the treatment regimen. Identifying patients whose tumors express mutated KRAS will avoid exposing patients to ineffective drugs, avoid exposure to unnecessary drug toxicities, and expedite the use of the best available alternative therapy.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether use of KRAS mutation analysis to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab to treat metastatic colorectal cancer meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
KRAS mutation analysis using PCR methodology is commercially available as a laboratory-developed test. Such tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
The evidence compiled from 4 randomized trials and 5 single-arm studies is sufficient to conclude that patients with mutated KRAS tumors in the setting of metastatic colorectal cancer do not respond to anti-EGFR monoclonal antibody therapy.
3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.
There is sufficient evidence to permit conclusions regarding the use of KRAS mutation analysis when the use of an EGFR inhibitor is a consideration in the management of a patient with metastatic colorectal cancer.
5. The improvement must be attainable outside the investigational settings.
The improvement in health outcomes in testing for a KRAS mutation in a patient with metastatic colorectal cancer prior to treatment with an anti-EGFR monoclonal antibody can be attained outside of the investigational settings.
Based on the above, use of KRAS mutation analysis to predict nonresponse to anti-EGFR monoclonal antibodies cetuximab and panitumumab to treat metastatic colorectal cancer meets the TEC criteria.
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NOTICE OF PURPOSE: TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.
