All-RAS wild-type colorectal cancer: Cetuximab associated with survival benefit

The FIRE-3 study has 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, has shown 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.

FIRE-3 has 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=0.017 ) in the FOLFIRI / Cetuximab arm.

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=0.011).
No differential benefit was observed when patients with RAS-mutant tumors were treated with FOLFIRI plus Cetuximab as compared to FOLFIRI plus Bevacizumab.

According to researchers 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.

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, versus 25.6 months with FOLFIRI plus Bevacizumab, a statistically significant difference of 7.5 months ( hazard ratio, HR=0.70; P=0.011 ).

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=0.57 ).
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=0.54 ).
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=0.004 ).
Response rates within both the RAS wild-type and RAS-mutant patients were similar between the arms. ( Xagena )

Helwick C, ASCO Post 2013, Volume 4, Issue 19


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