Cetuximab Confers Survival Benefit in All-RAS Wild-Type Colorectal Tumors

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Volker Heinemann, MD, PhD

Josep Tabernero, MD

The FIRE-3 study compared the two epidermal growth factor receptor (EGFR) antibodies, on top of chemotherapy, in the first-line treatment of metastatic colorectal cancer. A preplanned analysis of KRAS wild-type patients without RAS mutations, ie, “all-RAS wild-type,” showed overall survival to be significantly longer with cetuximab (Erbitux) than with bevacizumab (Avastin).

The RAS category includes both KRAS and NRAS genes. The so-called all-RAS wild-type tumors are those lacking mutations not only in KRAS exon 2 but in other KRAS exons and also NRAS.

Key Endpoints

FIRE-3 compared FOLFIRI (fluorouracil, leucovorin, irinotecan) plus cetuximab to FOLFIRI plus bevacizumab as first-line treatment for metastatic colorectal cancer. In the primary analysis, the two regimens were comparable in terms of objective response rate, which was the primary endpoint, and progression-free survival, a secondary endpoint. Overall survival, however, which also was a secondary endpoint, was 3.7 months longer (P = .017) in the FOLFIRI/cetuximab arm.1 Since approximately 40% of patients crossed over to the other treatment arm, the meaningfulness of this secondary endpoint has been debated.

The mutational analysis presented at the 2013 European Cancer Congress found overall survival with FOLFIRI/cetuximab to be “markedly superior” to that achieved with FOLFIRI/bevacizumab—a gain of 7.5 months (P = .011), reported Volker Heinemann, MD, PhD, Professor of Medical Oncology at the University of Munich in Germany.2 No differential benefit was observed when patients with RAS-mutant tumors were treated with FOLFIRI plus cetuximab as compared to FOLFIRI plus bevacizumab.

“The exclusion of patients with RAS mutations identifies a population that is more likely to benefit from cetuximab. Upfront determination of RAS mutation status appears highly recommendable in patients with metastatic disease,” Dr. Heinemann said.

New Mutations Identified

The preplanned analysis presented at the European Cancer Congress examined the effect of various mutations within the KRAS wild-type (exon 2) population, of whom 15% were found to harbor mutations beyond the customary KRAS exon 2 mutations. These included mutations in KRAS (exon 3 [codon 59/61], exon 4 [codon 117/146]), NRAS (exon 2 [codon 12/13], exon 3 [codon 59/61], exon 4 [codon 117/146]), and BRAF (V600E).

The analysis involved 342 RAS wild-type patients and 178 RAS mutant patients, which included the 113 with mutations in KRAS exon 2 mutant plus 65 with newly identified RAS mutations.

RAS wild-type patients had a median overall survival of 33.1 months with FOLFIRI plus cetuximab, vs 25.6 months with FOLFIRI plus bevacizumab, a statistically significant difference of 7.5 months (hazard ratio [HR] = 0.70; P = .011). In RAS-mutant carriers, however, no difference was observed between the regimens: Median overall survival was 16.4 months and 20.6 months, respectively (HR = 1.20; P = .57).

In the RAS wild-type patients, there was also no difference between the arms in median progression-free survival, which was approximately 10 months with either treatment (P = .54). Interestingly, for patients with RAS-mutated tumors, median progression-free survival was longer in the opposite arm—12.2 months with bevacizumab vs 6.1 months with cetuximab (P = .004). Response rates within both the RAS wild-type and RAS-mutant patients were similar between the arms.

Surprising Findings

Commenting on the study, Josep Tabernero, MD, Director of Vall d’Hebron Institute of Oncology in Barcelona, Spain, said that the findings should not change practice right now, especially considering that the other key endpoints were not significantly different between the treatments.

“It is difficult to understand how a treatment that does not increase response rate and progression-free survival in the first-line setting has a big impact on overall survival. This is something surprising in the field of cancer,” he said. “It is difficult to compare these regimens when we don’t completely understand what is happening in latter lines—especially which treatments patients received in the second- and third-line setting. We hope that the upcoming results of the CALGB-80405 study will provide more light in this important setting” ■

Disclosure: Dr. Tabernero is a consultant for Amgen, Boehringer, Bristol-Myers Squibb, Genentech, Imclone, Lilly, Merck KGaA, Millennium, Novartis, Onyx, Pfizer, Roche, Sanofi, and Celgene.  He also received honoraria from Amgen, Merck KGaA, Novartis, Roche, and Sanofi, for presentations.


1. Stintzing S, Jung A, Rossius L, et al: Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. 2013 European Cancer Congress. Abstract 17. Presented September 28, 2013.

2. Heinemann V, von Weikersthal LF, Decker T, et al: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). 2013 ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013.