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Mutation status predicted response to panitumumab plus FOLFOX4
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The addition of panitumumab to a standard oxaliplatin, fluorouracil and leucovorin regimen extended survival in patients with metastatic colorectal cancer without RAS mutations, according to results of a prospective-retrospective analysis.
Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy, according to background information in the study. Researchers hypothesized other RAS mutations also may predict response to anti-EGFR therapy.
Jean-Yves Douillard, MD, PhD, professor of medical oncology at the University of Nantes in France, conducted the investigation to compare the efficacy and safety of panitumumab (Vectibix, Amgen) plus oxaliplatin, fluorouracil and leucovorin (FOLFOX4) with FOLFOX4 alone.
The analysis included 639 patients without KRAS mutations in exon 2. All patients did have at least one of the following mutations: KRAS exon 3 or 4; NRAS exon 2, 3 or 4; or BRAF exon 15.
Douillard and colleagues identified 512 patients without RAS mutations.
Among that group, researchers reported longer PFS among those treated with panitumumab plus FOLFOX4 (10.1 months v. 7.9 months. Researchers calculated an HR of 0.72 for progression or death with combination therapy (95% CI, 0.58-0.90). Also, patients assigned to the combination regimen demonstrated longer OS (26 months vs. 20.2 months; HR for death=0.78; 95% CI, 0.62-0.99).
Researchers identified 108 patients who had RAS mutations other than KRAS mutations in exon 2. Among that group, patients assigned to panitumumab plus FOXFOX4 experienced inferior PFS and OS outcomes compared with those assigned to FOLFOX4 alone. That finding was consistent with results observed in prior studies of patients who carry KRAS mutations in exon 2.
Douillard and colleagues did not observe any new safety signals.
“This analysis is important as it furthers our understanding of tumor genetics and allows physicians to more accurately match patients to effective treatments,” Douillard said in a press release.
Disclosure: The research was supported by Amgen. The researchers report research funding, grant support or other remuneration from, as well as advisory board and consultant roles with, Amgen, Bayer, GlaxoSmithKline, Merck, Novartis and Roche.
Perspective
Back to TopAmit Mahipal, MD
The Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) compared the efficacy and safety of panitumumab plus FOLFOX4 with those of FOLFOX4 alone in the first-line treatment of patients with metastatic colorectal cancers. The benefit of the experimental arm was limited to patients who did not harbor KRAS exon 2 mutations.
In this study, Douillard and colleagues systematically evaluate the role of KRAS mutations other than in exon 2, NRAS mutations and BRAF mutations in response to panitumumab therapy. Seventeen percent of the patients without KRAS mutations in exon 2 had mutations in other RAS exons. These patients not only did not derive benefit from addition of panitumumab but actually had worse clinical outcomes. In contrast, BRAF mutations did not predict response to panitumumab but was associated with overall poor prognosis.
If the results of PRIME study are replicated in other clinical trials, testing of other RAS mutations should be incorporated in routing clinical practice.
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