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Original Investigation
June 20, 2017

Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal CancerA Randomized Clinical Trial

Author Affiliations
  • 1University of California, San Francisco
  • 2Department of Biostatistics and Bioinformatics and Alliance Statistics and Data Center, Duke University Medical Center, Durham, North Carolina
  • 3University of Southern California, Los Angeles
  • 4University of North Carolina at Chapel Hill
  • 5Alliance Statistics and Data Center, Mayo Clinic Cancer Center, Rochester, Minnesota
  • 6Dana-Farber/Partners CancerCare, Boston, Massachusetts
  • 7Indiana University, Simon Cancer Center, Indianapolis
  • 8National Surgical Adjuvant Breast and Bowel Project/NRG Oncology, and Southeastern Medical Oncology Center, Goldsboro, North Carolina
  • 9Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada
  • 10University of Chicago Comprehensive Cancer Center, Chicago, Illinois
  • 11Memorial Sloan Kettering Cancer Center, New York, New York
  • 12Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital, Columbus
  • 13Department of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut
  • 14American Society of Clinical Oncology, Alexandria, Virginia
  • 15Brigham and Women's Hospital, Boston, Massachusetts
  • 16Lenoir Memorial Hospital/Kinston Medical Specialists PA, Kinston, North Carolina
  • 17Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois
  • 18University of Wisconsin, Madison
  • 19Southwest Oncology Group Chair’s Office and Knight Cancer Institute, Oregon Health & Science University, Portland
JAMA. 2017;317(23):2392-2401. doi:10.1001/jama.2017.7105
Key Points

Question  Does the addition of cetuximab with a combination chemotherapeutic regimen improve overall survival compared with the addition of bevacizumab with a combination chemotherapeutic regimen as the initial treatment for patients with advanced or metastatic colorectal cancer who have KRAS wild-type tumors?

Findings  In this randomized clinical trial involving 1137 patients, there was no significant difference in overall survival among patients treated with either leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) or leucovorin, fluorouracil, and irinotecan (FOLFIRI) and then randomized to receive cetuximab or bevacizumab.

Meaning  Neither biologic monoclonal antibody demonstrated significantly greater overall survival for initial treatment of advanced or metastatic colorectal cancer.

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 point was 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.

Trial Registration  clinicaltrials.gov identifier: NCT00265850

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