RAS mutations have been shown to confer resistance to anti-EGFR treatment. We assessed here the results of the PETACC8 trial (Cetuximab + FOLFOX vs FOLFOX) in full wild type (WT) patients (pts) (RAS & BRAF). The prognostic impact of individual rare RAS and BRAF mutations has been tested.
Exons 2, 3 and 4 of KRAS and NRAS as well as BRAF exon 11 and 15 have been sequenced, using the ampliseq colon lung cancer panel V2, among the pts who have signed informed consent for translational research. The impact of cetuximab on Time To Recurrence (TTR), Disease Free Survival (DFS) and Overall Survival (OS), has been investigated in pts RAS WT, RAS & BRAF double WT tumors and in pts with rare RAS mutations.
Among the 2559 pts analyzed, 745 (29%) were known to be mutated for KRAS exon 2 and 163 (6.4%) for BRAF V600E. From the remaining 1654 pts 1054 had given informed consent for additional TR analyses and were NGS assessed, with 227 pts (21%) newly diagnosed as KRAS exon 3,4 or NRAS exon 2,3,4 mutated, and 46 (4.4%) as non-V600E BRAF mutated. Cetuximab was not improving significantly TTR, DFS or OS in pts with RAS WT or RAS & BRAF double WT tumors (HR ranging from 0.77 to 1.05, all p > 0.05). FOLFOX + Cetuximab was either not significantly deleterious in RAS mutant pts (HR ranging from 1.13 to 1.29, all p > 0.05). Outcome was not significantly different with and without cetuximab in pts with RAS or BRAF rare mutations (HR ranging from 1.42 to 1.61, all p > 0.05). When pooling both treatment arms, as compared to double WT pts, KRAS and NRAS codon 61 rare mutants were associated with a worse TTR (KRAS, HR : 2.42 [1.40;4.20] p = 0.001 and NRAS, HR : 2.18 [1.21;3.93] p = 0.008) and DFS (KRAS, HR: 1.98 [1.15;3.42] p = 0.01 and NRAS, HR: 1.99 [1.13;3.50] p = 0.015). This was not the case for other RAS or BRAF rare mutations.
In Stage III colon cancer, the addition of cetuximab to standard FOLFOX adjuvant therapy does not improve significantly outcome in RAS and RAS & BRAF double WT pts. No detrimental significant effect was observed in RAS mutant pts. NRAS or KRAS codon 61 seem to be the only rare mutations that has the same pejorative prognostic value than KRAS codon 12 and 13 or BRAF V600E mutations.
Clinical trial identification
EudraCT number 2005-003463-23
Legal entity responsible for the study
Merck and Sanofi
J. Taieb: Honoraria from: Merck Amgen Lilly Sanofi Celgene Roche Glycart. J. Tabernero: Advisory role for Consultant/Advisory role: Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, Sanofi, Symphogen, Takeda and Taiho. G. Folprecht: Advisory role for: Roche Merck KGaA Lilly ImClome Bristol-Myers Squibb He received honoraria from: Merck KGaA He received research funding from Merck KgaA. J-F. Emile: Honoraria from: Merck Serono Roche Glycart He had avisory role for: Merck Serono Roche Glycart. C-B. Levaché: Honoraria from: Amgen Roche Glycart He had advisory role for: Amgen Roche Glycart He was speaker's bureau and expert testimony for: Amgen. J. Thaler: Honoraria and research funding from: Sanofi Merck. L. Nørgård Petersen: Advisory role for Bayer and Roche Glycart. J. Bridgewater: Advisory role for Merck Serono. He received money for travel, accommodatioons, expenses from MSD Oncology and Merck Serono. He received honoraria from Merck Serono. G. Perkins: Advisory role for Sanofi. She received money for travel, accommodations from Sanofi, Celgene, and Roche Glycart. C. Lepage: Money for travel, accommodations and expenses from Ipsen. A. Zaanan: Advisory role for Merck, Amgen, Sanofi, Lilly, and Roche Glycart. P. Laurent-Puig: Advisory role for Sanofi, Merck Serono, Amgen, Genomic Health, Myriad Genetics, Integragen, Prizer, Roche Glycart. All other authors have declared no conflicts of interest.