Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer

Jean Yves Douillard, Kelly S. Oliner, Salvatore Siena, Josep Tabernero, Ronald Burkes, Mario Barugel, Yves Humblet, G. Bodoky, David Cunningham, Jacek Jassem, Fernando Rivera, Ilona Kocákova, Paul Ruff, Maria Błasińska-Morawiec, Martin Šmakal, Jean Luc Canon, Mark Rother, Richard Williams, Alan Rong, Jeffrey Wiezorek & 2 others Roger Sidhu, Scott D. Patterson

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Abstract

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 non-mutated 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.

Original languageEnglish
Pages (from-to)1023-1034
Number of pages12
JournalNew England Journal of Medicine
Volume369
Issue number11
DOIs
Publication statusPublished - 2013

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Colorectal Neoplasms
Mutation
Exons
Therapeutics
oxaliplatin
Epidermal Growth Factor Receptor
Disease-Free Survival
Survival
panitumumab
Confidence Intervals
Safety
Leucovorin
Fluorouracil
Biomarkers

ASJC Scopus subject areas

  • Medicine(all)

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Douillard, J. Y., Oliner, K. S., Siena, S., Tabernero, J., Burkes, R., Barugel, M., ... Patterson, S. D. (2013). Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. New England Journal of Medicine, 369(11), 1023-1034. https://doi.org/10.1056/NEJMoa1305275

Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. / Douillard, Jean Yves; Oliner, Kelly S.; Siena, Salvatore; Tabernero, Josep; Burkes, Ronald; Barugel, Mario; Humblet, Yves; Bodoky, G.; Cunningham, David; Jassem, Jacek; Rivera, Fernando; Kocákova, Ilona; Ruff, Paul; Błasińska-Morawiec, Maria; Šmakal, Martin; Canon, Jean Luc; Rother, Mark; Williams, Richard; Rong, Alan; Wiezorek, Jeffrey; Sidhu, Roger; Patterson, Scott D.

In: New England Journal of Medicine, Vol. 369, No. 11, 2013, p. 1023-1034.

Research output: Contribution to journalArticle

Douillard, JY, Oliner, KS, Siena, S, Tabernero, J, Burkes, R, Barugel, M, Humblet, Y, Bodoky, G, Cunningham, D, Jassem, J, Rivera, F, Kocákova, I, Ruff, P, Błasińska-Morawiec, M, Šmakal, M, Canon, JL, Rother, M, Williams, R, Rong, A, Wiezorek, J, Sidhu, R & Patterson, SD 2013, 'Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer', New England Journal of Medicine, vol. 369, no. 11, pp. 1023-1034. https://doi.org/10.1056/NEJMoa1305275
Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. New England Journal of Medicine. 2013;369(11):1023-1034. https://doi.org/10.1056/NEJMoa1305275
Douillard, Jean Yves ; Oliner, Kelly S. ; Siena, Salvatore ; Tabernero, Josep ; Burkes, Ronald ; Barugel, Mario ; Humblet, Yves ; Bodoky, G. ; Cunningham, David ; Jassem, Jacek ; Rivera, Fernando ; Kocákova, Ilona ; Ruff, Paul ; Błasińska-Morawiec, Maria ; Šmakal, Martin ; Canon, Jean Luc ; Rother, Mark ; Williams, Richard ; Rong, Alan ; Wiezorek, Jeffrey ; Sidhu, Roger ; Patterson, Scott D. / Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 11. pp. 1023-1034.
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abstract = "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 non-mutated 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.",
author = "Douillard, {Jean Yves} and Oliner, {Kelly S.} and Salvatore Siena and Josep Tabernero and Ronald Burkes and Mario Barugel and Yves Humblet and G. Bodoky and David Cunningham and Jacek Jassem and Fernando Rivera and Ilona Koc{\'a}kova and Paul Ruff and Maria Błasińska-Morawiec and Martin Šmakal and Canon, {Jean Luc} and Mark Rother and Richard Williams and Alan Rong and Jeffrey Wiezorek and Roger Sidhu and Patterson, {Scott D.}",
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AU - Douillard, Jean Yves

AU - Oliner, Kelly S.

AU - Siena, Salvatore

AU - Tabernero, Josep

AU - Burkes, Ronald

AU - Barugel, Mario

AU - Humblet, Yves

AU - Bodoky, G.

AU - Cunningham, David

AU - Jassem, Jacek

AU - Rivera, Fernando

AU - Kocákova, Ilona

AU - Ruff, Paul

AU - Błasińska-Morawiec, Maria

AU - Šmakal, Martin

AU - Canon, Jean Luc

AU - Rother, Mark

AU - Williams, Richard

AU - Rong, Alan

AU - Wiezorek, Jeffrey

AU - Sidhu, Roger

AU - Patterson, Scott D.

PY - 2013

Y1 - 2013

N2 - 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 non-mutated 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.

AB - 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 non-mutated 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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