Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer — NEJM
Panitumumab–FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer
Jean-Yves Douillard, M.D., Ph.D., Kelly S. Oliner, Ph.D., Salvatore Siena, M.D., Josep Tabernero, M.D., Ronald Burkes, M.D., Mario Barugel, M.D., Yves Humblet, M.D., Ph.D., Gyorgy Bodoky, M.D., Ph.D., David Cunningham, M.D., Jacek Jassem, M.D., Ph.D., Fernando Rivera, M.D., Ph.D., Ilona Kocákova, M.D., Ph.D., Paul Ruff, M.D., Maria Błasińska-Morawiec, M.D., Martin Šmakal, M.D., Jean Luc Canon, M.D., Mark Rother, M.D., Richard Williams, M.B., B.S., Ph.D., Alan Rong, Ph.D., Jeffrey Wiezorek, M.D., Roger Sidhu, M.D., and Scott D. Patterson, Ph.D.
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Background
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. (Funded by Amgen and others; PRIME ClinicalTrials.gov number,
NCT00364013.)
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