Sequential vs Combination Fluoropyrimidine, Irinotecan, and Bevacizumab in Metastatic Colorectal Cancer


Key Points

  • Noninferiority was not demonstrated for the sequential vs upfront combination strategy.
  • Benefit was observed with the upfront combination in patients with RAS/BRAF wild-type disease.

In a German phase III noninferiority trial (XELAVIRI) reported by Modest et al in the Journal of Clinical Oncology, noninferiority of first-line sequential vs combination fluoropyrimidine, irinotecan, and bevacizumab (Avastin) was not demonstrated in metastatic colorectal cancer (CRC). Benefit of upfront combination treatment was observed in RAS/BRAF wild-type disease. 

Study Details

In the trial, 421 patients from 82 sites in Germany were randomly assigned between December 2010 and April 2016 to receive sequential fluoropyrimidine (capecitabine or fluorouracil) plus bevacizumab with irinotecan added at first progression (n = 212) or the upfront combination of the 3 agents (n = 209).

The primary endpoint was time to failure of strategy (TFS), defined as time from randomization to failure of the irinotecan-containing regimen. In the sequential treatment group, this definition presumed that the escalation with irinotecan was performed and resulted in at least stabilization of disease; if there were no escalation or no disease control with irinotecan, TFS was defined as having occurred at first progression. The margin for noninferiority of the sequential strategy was set as a lower limit of the 90% confidence interval (CI) for the hazard ratio (HR) of 0.8. If noninferiority were demonstrated, analysis of symptomatic toxicities would define the superior strategy.

TFS Outcomes

Median TFS in the sequential group was 9.6 months vs 9.9 months in the upfront combination group; the HR was 0.86 with a 90% CI of 0.73–1.02, exceeding the noninferiority margin of 0.8 and thus failing to establish noninferiority.

Subgroup analysis showed that upfront combination was associated with better TFS (median 12.6 vs 9.1 months, HR = 0.61, P = .005) among 158 patients with RAS/BRAF wild-type disease, but not among 194 with RAS-mutant disease (median 9.4 vs 10.0 months, HR = 1.09, P = .58; P = .03 with Cox model for interaction of study group and RAS status).

Similar results were observed for overall survival. In the entire population, median overall survival was 21.9 vs 23.5 months, HR = 0.84, P = .14), with benefit of the upfront combination being observed in the RAS/BRAF wild-type subgroup (median 32.2 vs 25.2 months, HR = 0.58, P = .01) and not in the RAS mutant group (median 23.2 vs 21.3 months, HR = 0.92, P = .62). 

The toxicity score of symptomatic grade 2 to 5 events per treatment cycle was significantly better in the sequential group (arithmetic mean = 0.6 vs 0.7, P = .03). However, there was little difference in incidence of grade ≥ 3 adverse events between groups (80.7% vs 77.1%).

The investigators concluded: “Noninferiority of sequential escalation therapy compared with initial combination chemotherapy could not be demonstrated for TFS. RAS status may be important to guide therapy as treatment of patients with upfront combination therapy was clearly superior in RAS/BRAF wild-type tumors, whereas sequential escalation chemotherapy seems to provide comparable results in patients with RAS mutant tumors.”

The legal funder (sponsor) of the trial was Klinikum Grosshadern, University of Munich. Roche Pharma AG supported the trial with study medication and a research grant.

Dominik Paul Modest, MD, of the Klinikum Grosshadern, Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: See study authors’ full disclosures at

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