Better Overall Survival Reported With FOLFIRI Plus Cetuximab vs Plus Bevacizumab in RAS Wild-Type Metastatic Colorectal Cancer


Key Points

  • In the extended RAS wild-type population of patients with metastatic colorectal cancer, the FOLFIRI plus cetuximab group had better overall survival than the FOLFIRI plus bevacizumab group.
  • The difference appeared to reflect differences in alternative measures of tumor response.

In a post hoc analysis of the German phase III FIRE-3 trial reported in The Lancet Oncology, Stintzing et al found that first-line FOLFIRI (fluorouracil, leucovorin, irinotecan) plus cetuximab (Erbitux) was associated with improved overall survival vs FOLFIRI plus bevacizumab (Avastin) in an extended RAS wild-type subgroup of patients with metastatic colorectal cancer. The benefit, observed despite an absence of difference in investigator-assessed RECIST (Response Evaluation Criteria in Solid Tumors) objective response or progression-free survival, may have been associated with differences in tumor dynamics on alternative measures.

Study Details

The phase III trial enrolled patients with KRAS exon 2 wild-type tumors. The post hoc analysis included 400 patients in an extended RAS wild-type (KRAS/NRAS, exons 2–4) subgroup from the trial. Alternative metrics of tumor dynamics were evaluated in a centralized radiologic review, including early tumor shrinkage (≥ 20% reduction in the sum of the longest tumor diameters of lesions followed according to RECIST criteria at first tumor assessment at week 6) and the depth of tumor response (maximum percent change in tumor size compared with baseline).

Survival and Tumor Dynamics

Median overall survival in the subgroup was 33.1 months with FOLFIRI plus cetuximab vs 25.0 months with FOLFIRI plus bevacizumab (hazard ratio [HR] = 0.70, P = .0059). Investigator-assessed objective response and progression-free survival were similar in the two groups. Centralized radiologic review of 330 computed tomography–assessable patients (157 in the cetuximab group, 173 in the bevacizumab group) indicated the objective response rate was higher in the cetuximab group (72.0% vs 56.1%, P = .0029), as were frequency of early tumor shrinkage (68.2% vs 49.1%, P = .0005) and the median depth of response (–48.9% vs –32.3%, P < .0001). No differences in the duration of response or time to response were observed.

The investigators concluded: “This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup.”

The study was funded by Merck KGaA and Pfizer.

Sebastian Stintzing, MD, Klinikum der Universität München, is the corresponding author of The Lancet Oncology article.

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