Food and Drug Administration approval of cetuximab and a new KRAS genetic test for metastatic colorectal cancer: major advance but just the tip of the biomarker iceberg.

The Food and Drug Administration’s (FDA’s) recent approval of a new indication for cetuximab combined with a new KRAS test for use with the 3-drug combination (folinic Acid/5 fluorouracil/irinotecan [FOLFIRI]) as a first-line treatment for patients with metastatic colorectal cancer (mCRC) that express the epidermal growth factor receptor (EGFR) marks an important advance in the use of biomarkers to select the right treatment for the right patient population with mCRC. KRAS mutation status is confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. Critical to this new expanded indication for cetuximab, already approved for late-stage patients refractory to irinotecan-based chemotherapy, is the proviso that this approval applies to patients not having a KRAS mutation because cetuximab does not appear to work in these patients. Concurrent with the new treatment indication, the FDA approved the therascreen KRAS RGQ PCR kit, which provides a reliable way to identify subsets of patients with 1 of the 7 different mutations detected by this genetic assay developed by Qiagen. The importance of this dual product approval in the management of mCRC is further evidenced by several notable features. First, because as many as 60% of patients with mCRC carry the wild-type variant of KRAS, it is suggested that a majority of patients may be candidates for this approach. Second, the evidence for the improved outcome in patients who do not have KRAS mutations comes from retrospective analyses of subsets of patients from 3 trials including the phase 3 Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) study and 2 supportive trials (OPUS and CA225025). In the randomized, controlled, phase 3 CRYSTAL trial, patients receiving cetuximab plus FOLFIRI with wild-type tumors had an overall survival of 23.5 months compared with 19.5 months with FOLFIRI alone. Median progression-free survival was longer with the combination at 9.5 months versus 8.1 months with the expected safety profile of cetuximab and the chemotherapy regimen. In contrast, no significant differences in progression-free survival or best overall response were observed between the treatment groups with mutant KRAS. In addition, the CRYSTAL study also provides provocative evidence that BRAF tumor mutation (eg, V600E) is a strong indicator of poor prognosis, but it could not definitively establish if it is also a negative predictor of cetuximab efficacy due to the small number of patients with these mutations. The striking results observed in CRYSTAL study are also supported by a substantial body of evidence from retrospective analyses of phase 2 and phase 3 studies of the 2 approved anti-EGFR monoclonal antibodies as either monotherapy or in combination with multiagent chemotherapy for mCRC that the presence of KRAS mutations blunts the therapeutic benefit of these agents. Third, this integrated scientific and regulatory approach for a drug and companion diagnostic test approval is the culmination of several reinforcing initiatives including FDA’s “Critical Path Initiative” to extend the application of biomarkers as a companion diagnostics with predictive/prognostic value as part of product labeling and an American Society of Clinical Oncology provisional clinical opinion recommendation in January 2009 that physicians treating patients with EGFR monoclonal antibodies for mCRC first test the patients for KRAS gene mutations. These key developments paved the way in 2009 for the introduction of KRAS mutation testing and hence the entry of personalized medicine into the US marketplace for Department of Hematology, Oncology and Transplantation, Quintiles, Inc, Rockville, MD. The author has no funding or conflicts to disclose. Address for correspondence: Quintiles, Inc, 1801 Rockville Pike, Rockville, MD 20852. E-mail: ronald.lieberman@quintiles.com American Journal of Therapeutics 19, 395–396 (2012)