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 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.

Figures

Figure 1. Flow of Patients Through Cancer and Leukemia B Group and Southwest Oncology Group 80405 Trial

a The reasons patients with wild-type (wt), indeterminate, or unknown KRAS status were excluded were not captured at the time of exclusion. b Amendment 5 limited trial eligibility to only patients with KRAS wild-type colorectal cancer in November 2008. c This double-biologic treatment group was dropped from the trial and primary analysis based on amendment 6, which was established September 2009. d The primary cohort comprises patients whose KRAS wt colorectal cancer was centrally confirmed by the Southwest Oncology Group and who had consented for the use of their specimens. e Reasons for ineligibility in the primary cohort were not captured. f Forty-nine tumor samples lacked sufficient DNA or analyses were incomplete.

Figure 2. Kaplan-Meier Estimates of Overall Survival Among Patients Randomized to Bevacizumab or Cetuximab

Tick marks on the curves denote the last known follow-up time for patients with no death date reported. The hazard ratio and P value are adjusted for prior adjuvant therapy, prior radiotherapy, protocol chemotherapy, and randomization before and after the amendment restricting eligibility to the KRAS wild-type tumor. Hazard ratio and P value for the RAS analysis are adjusted for prior adjuvant therapy, prior radiotherapy, protocol chemotherapy, and randomization before or after the amendment restricting eligibility to KRAS wild type tumor (KRAS is defined as exon 2 codons 12, 13; exon 4, codons 117, 146; exon3 codons 59, 61 or NRAS: exon 2 codons 12, 13; exon 3 codons 59, 61; exon 4 codons 117, 146).