Panitumumab-FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer
abstract
This abstract is available on the publisher's site.
Access this abstract nowBackground: Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti–epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.
Methods: In this prospective–retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.
Results: Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab–FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab–FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab–FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.
Conclusions: Additional RAS mutations predicted a lack of response in patients who received panitumumab–FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab–FOLFOX4 therapy.
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Additional Info
Disclosure statements are available on the authors' profiles:
Over the last 5 years, it has become worldwide standard clinical practice to test for KRAS mutation status before using EGFR monoclonal antibodies (EGFR mAbs) cetuximab and panitumumab in patients with metastatic colorectal cancer. Routine KRAS testing identifies mutations in codons 12 and 13 (exon 2) and thereby eliminates the approximate 40% of patients who should not receive EGFR mAbs. It has been long postulated that testing for low-frequency KRAS mutations beyond exon 2 and NRAS mutations might further refine the patient population that can benefit from EGFR mAbs. The practice-changing analysis of the PRIME study published by Douillard and colleagues in The New England Journal of Medicine confirmed the predictive value of the additional KRAS and NRAS mutations for panitumumab in patients with metastatic colorectal cancer when added to front-line FOLFOX therapy. The expanded RAS mutation test identified an additional 17% of patients (beyond the 40% by standard analysis) who should not receive panitumumab (and, conceivably, cetuximab). Patients with these mutations did not benefit from the addition of panitumumab to FOLFOX; in fact, they experienced a trend toward a detrimental effect with regard to progression-free and overall survival. These data have already led to a label change for panitumumab in Europe. It can only be hoped that the FDA will follow suit in the US and that soon standard mutation tests for “all-RAS” will be available to better select patients with advanced colorectal cancer for the treatment with panitumumab and cetuximab.