Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial

Alan P. Venook*, Donna Niedzwiecki, Heinz Josef Lenz, Federico Innocenti, Briant Fruth, Jeffrey A. Meyerhardt, Deborah Schrag, Claire Greene, Bert H. O'Neil, James Norman Atkins, Scott Berry, Blase N. Polite, Eileen M. O'Reilly, Richard M. Goldberg, Howard S. Hochster, Richard L. Schilsky, Monica M. Bertagnolli, Anthony B. El-Khoueiry, Peter Watson, Al B Benson III & 3 others Daniel L. Mulkerin, Robert J. Mayer, Charles Blanke

*Corresponding author for this work

Research output: Contribution to journalArticle

153 Citations (Scopus)

Abstract

IMPORTANCE Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. OBJECTIVE To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Patients (18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. INTERVENTIONS Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. MAIN OUTCOMES AND MEASURES The primary end pointwas overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. RESULTS Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82%of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95%CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95%CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6%vs 55.2%for cetuximab and bevacizumab, respectively (difference, 4.4%, 95%CI, 1.0%-9.0%, P = .13). CONCLUSIONS AND RELEVANCE Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.

Original languageEnglish (US)
Pages (from-to)2392-2401
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume317
Issue number23
DOIs
StatePublished - Jun 20 2017

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Colorectal Neoplasms
Randomized Controlled Trials
Drug Therapy
Survival
oxaliplatin
irinotecan
Leucovorin
Fluorouracil
Disease-Free Survival
Bevacizumab
Cetuximab
Biological Therapy
Canada
Disease Progression
Monoclonal Antibodies
Clinical Trials
Physicians
Therapeutics
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Venook, Alan P. ; Niedzwiecki, Donna ; Lenz, Heinz Josef ; Innocenti, Federico ; Fruth, Briant ; Meyerhardt, Jeffrey A. ; Schrag, Deborah ; Greene, Claire ; O'Neil, Bert H. ; Atkins, James Norman ; Berry, Scott ; Polite, Blase N. ; O'Reilly, Eileen M. ; Goldberg, Richard M. ; Hochster, Howard S. ; Schilsky, Richard L. ; Bertagnolli, Monica M. ; El-Khoueiry, Anthony B. ; Watson, Peter ; Benson III, Al B ; Mulkerin, Daniel L. ; Mayer, Robert J. ; Blanke, Charles. / Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2017 ; Vol. 317, No. 23. pp. 2392-2401.
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title = "Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial",
abstract = "IMPORTANCE Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. OBJECTIVE To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Patients (18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. INTERVENTIONS Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. MAIN OUTCOMES AND MEASURES The primary end pointwas overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. RESULTS Among 1137 patients (median age, 59 years; 440 [39{\%}] women), 1074 (94{\%}) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82{\%}of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95{\%}CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95{\%}CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6{\%}vs 55.2{\%}for cetuximab and bevacizumab, respectively (difference, 4.4{\%}, 95{\%}CI, 1.0{\%}-9.0{\%}, P = .13). CONCLUSIONS AND RELEVANCE Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.",
author = "Venook, {Alan P.} and Donna Niedzwiecki and Lenz, {Heinz Josef} and Federico Innocenti and Briant Fruth and Meyerhardt, {Jeffrey A.} and Deborah Schrag and Claire Greene and O'Neil, {Bert H.} and Atkins, {James Norman} and Scott Berry and Polite, {Blase N.} and O'Reilly, {Eileen M.} and Goldberg, {Richard M.} and Hochster, {Howard S.} and Schilsky, {Richard L.} and Bertagnolli, {Monica M.} and El-Khoueiry, {Anthony B.} and Peter Watson and {Benson III}, {Al B} and Mulkerin, {Daniel L.} and Mayer, {Robert J.} and Charles Blanke",
year = "2017",
month = "6",
day = "20",
doi = "10.1001/jama.2017.7105",
language = "English (US)",
volume = "317",
pages = "2392--2401",
journal = "JAMA - Journal of the American Medical Association",
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}

Venook, AP, Niedzwiecki, D, Lenz, HJ, Innocenti, F, Fruth, B, Meyerhardt, JA, Schrag, D, Greene, C, O'Neil, BH, Atkins, JN, Berry, S, Polite, BN, O'Reilly, EM, Goldberg, RM, Hochster, HS, Schilsky, RL, Bertagnolli, MM, El-Khoueiry, AB, Watson, P, Benson III, AB, Mulkerin, DL, Mayer, RJ & Blanke, C 2017, 'Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 317, no. 23, pp. 2392-2401. https://doi.org/10.1001/jama.2017.7105

Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial. / Venook, Alan P.; Niedzwiecki, Donna; Lenz, Heinz Josef; Innocenti, Federico; Fruth, Briant; Meyerhardt, Jeffrey A.; Schrag, Deborah; Greene, Claire; O'Neil, Bert H.; Atkins, James Norman; Berry, Scott; Polite, Blase N.; O'Reilly, Eileen M.; Goldberg, Richard M.; Hochster, Howard S.; Schilsky, Richard L.; Bertagnolli, Monica M.; El-Khoueiry, Anthony B.; Watson, Peter; Benson III, Al B; Mulkerin, Daniel L.; Mayer, Robert J.; Blanke, Charles.

In: JAMA - Journal of the American Medical Association, Vol. 317, No. 23, 20.06.2017, p. 2392-2401.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial

AU - Venook, Alan P.

AU - Niedzwiecki, Donna

AU - Lenz, Heinz Josef

AU - Innocenti, Federico

AU - Fruth, Briant

AU - Meyerhardt, Jeffrey A.

AU - Schrag, Deborah

AU - Greene, Claire

AU - O'Neil, Bert H.

AU - Atkins, James Norman

AU - Berry, Scott

AU - Polite, Blase N.

AU - O'Reilly, Eileen M.

AU - Goldberg, Richard M.

AU - Hochster, Howard S.

AU - Schilsky, Richard L.

AU - Bertagnolli, Monica M.

AU - El-Khoueiry, Anthony B.

AU - Watson, Peter

AU - Benson III, Al B

AU - Mulkerin, Daniel L.

AU - Mayer, Robert J.

AU - Blanke, Charles

PY - 2017/6/20

Y1 - 2017/6/20

N2 - IMPORTANCE Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. OBJECTIVE To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Patients (18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. INTERVENTIONS Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. MAIN OUTCOMES AND MEASURES The primary end pointwas overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. RESULTS Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82%of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95%CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95%CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6%vs 55.2%for cetuximab and bevacizumab, respectively (difference, 4.4%, 95%CI, 1.0%-9.0%, P = .13). CONCLUSIONS AND RELEVANCE Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.

AB - IMPORTANCE Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. OBJECTIVE To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Patients (18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. INTERVENTIONS Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. MAIN OUTCOMES AND MEASURES The primary end pointwas overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. RESULTS Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82%of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95%CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95%CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6%vs 55.2%for cetuximab and bevacizumab, respectively (difference, 4.4%, 95%CI, 1.0%-9.0%, P = .13). CONCLUSIONS AND RELEVANCE Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.

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DO - 10.1001/jama.2017.7105

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