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Association details:
| Biomarker: | NRAS mutation |
|---|---|
| Cancer: | Colorectal Cancer |
| Drug: | Erbitux (cetuximab) (EGFR inhibitor) |
| Direction: | Resistant |
Evidence:
Source:
Excerpt:
The panel therefore strongly recommends RAS (KRAS/NRAS) genotyping of tumor tissue (either primary tumor or metastasis) in all patients with mCRC. Patients with known KRAS or NRAS mutations should not be treated with either cetuximab or panitumumab, either alone or in combination with other anticancer agents, because they have virtually no chance of benefit and the exposure to toxicity and expense cannot be justified.
Source:
Title:
Expanded Low Allele Frequency RAS and BRAF V600E Testing in Metastatic Colorectal Cancer as Predictive Biomarkers for Cetuximab in the Randomized CO.17 Trial
Excerpt:
CO.17 trial compared cetuximab versus best supportive care (BSC) in RAS/BRAF-unselected mCRC. 17 trial using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Cetuximab did not improve OS/PFS for KRAS-, NRAS-, or BRAF-mutated tumors...
DOI:
10.1158/1078-0432.CCR-20-2710
Trial ID:
Source:
Title:
Cetuximab as Salvage Therapy in Patients With Neo Wild-type RAS/RAF Metastatic Colorectal Cancer With Liver Metastases.
Excerpt:
...Unresectable metastatic RAS mutant (either KRAS or NRAS tumor gene mutation) colorectal cancer, 5....
Trial ID:
Source:
Title:
Simvastatin + Cetuximab/Irinotecan in K-ras Mutant Colorectal Cancer (CRC)
Excerpt:
......
Trial ID:
More C2 evidence
Source:
Title:
A study to explore the effects of cetuximab alone or in combination with irinotecan in patients with an abnormal gene (KRAS) in their colon cancer cells.
Excerpt:
...Prior confirmation of tumour KRAS status as either KRAS WT (with no mutations or changes in BRAF, NRAS, PIK3CA exon20) OR KRAS G13D mutation,6. ...
Trial ID:
Source:
Title:
Randomised Phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer (CRC) with either KRAS WT or G13D mutation.
Excerpt:
...“All RAS WT”, - that is no mutation or changes in either KRAS NRAS...
Trial ID:
Source:
Title:
Cetuximab as salvage therapy in patients with neo wild-type RAS/RAF metastatic colorectal cancer. A Proof-of-concept study
Excerpt:
...Unresectable metastatic RAS mutant (either KRAS or NRAS tumor gene mutation) colorectal cancer, 5. ...
Trial ID:
Source:
Title:
Cetuximab in Third Line for Mutant APC, TP53 and RAS Patients With Refractory Metastatic Colorectal Cancer
Excerpt:
...All RAS mutations are allowed (KRAS, NRAS, HRAS)....
Trial ID:
Source:
Title:
Multicenter prospective single-arm study investigating the efficacy and safety of second-line cetuximab plus chemotherapy treatment in initially RAS-mt mCRC patients who converted to RAS-wt at the time of first progression Studio di fase II a singolo braccio di terapia di II linea con cetuximab e chemioterapia in pazienti con carcinoma colorettale metastatico KRAS e NRAS mutato alla diagnosi con assenza di mutazioni di KRAS/NRAS su plasma alla progressione da prima linea
Excerpt:
...- KRAS/NRAS-wt status, tested on ctDNA, at the time of progression after first line treatment- Life expectancy of at least 3 months; • Diagnosi istologica di adenocarcinoma del colon-retto• KRAS/NRAS mutato su biopsia tissutale (tumore primitivo /metastasi) al momento della diagnosi• Evidenza radiologica di progressione di malattia dopo prima linea con chemioterapia e bevacizumab• Malattia misurabile secondo criteri RECIST (RECIST criteria, vers.1.1); • Uomo o donna, età > 18 anni • ECOG Performance Status = 2; • Adeguata funzionalità ematologica, epatica e renale valutata entro 14 giorni dall’inizio del trattamento in studio Adequate bone marrow function (without hematopoietic growth factor or transfusion support within 14 days prior to study enrollment), including:a. ...
Trial ID:
Less C2 evidence
Source:
Title:
Chemotherapy (doublet or triplet) plus targeted therapy by RAS status as conversion therapy in colorectal cancer patients with initially unresectable liver-only metastases. The UNICANCER PRODIGE-14 randomised clinical trial
Published date:
01/06/2022
Excerpt:
PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.
Secondary therapy:
FOLFIRINOX
DOI:
10.1038/s41416-021-01644-y
Source:
Title:
O-6 Gene alterations in ctDNA related to the resistance mechanism of anti-EGFR antibodies and clinical efficacy outcomes of anti-EGFR antibody rechallenge plus trifluridine/tipiracil in metastatic colorectal cancer patients in WJOG8916G trial
Published date:
07/04/2021
Excerpt:
...We conducted a phase II trial (WJOG8916G) to evaluate the efficacy and safety of the combination of trifluridine/tipiracil and cetuximab rechallenge in patients (pts) with metastatic colorectal cancer (mCRC)…RAS, BRAF, and PIK3CA muts in ctDNA were associated with worse clinical efficacy outcomes in mCRC patients receiving anti-EGFR antibody rechallenge plus trifluridine/tipiracil.
Secondary therapy:
trifluridine/tipiracil
DOI:
https://doi.org/10.1016/j.annonc.2021.05.010
Source:
Title:
Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis
Excerpt:
In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013).
DOI:
10.1016/S1470-2045(10)70130-3
Source:
Title:
Circulating tumor DNA sequencing in colorectal cancer patients treated with first-line chemotherapy with anti-EGFR
Excerpt:
Tissue KRAS/NRAS wild-type mCRC patients were enrolled and treated with first-line cetuximab-containing chemotherapy….Among 93 patients, 84 (90.3%) had at least 1 somatic mutation in baseline ctDNA samples (average 2.74). Five patients with KRAS or NRAS hotspot mutation in the ctDNA showed significantly worse progression-free survival (PFS) (p = 0.029).
DOI:
10.1038/s41598-021-95345-4
Source:
Title:
The First-in-class Anti-EGFR Antibody Mixture Sym004 Overcomes Cetuximab Resistance Mediated by EGFR Extracellular Domain Mutations in Colorectal Cancer
Excerpt:
Acquired resistance to cetuximab was associated with the emergence of mutations, which occurred mainly in KRAS, NRAS, and EGFR genes (Table 2).
DOI:
10.1158/1078-0432.CCR-15-2400
Source:
Title:
Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients
Excerpt:
In contrast, BRAF mutations (0% for responders vs. 26.1% for non-responders, p = 0.0044) and KRAS (0% for responders vs. 21.7% for non-responders, p = 0.0117) were observed exclusively in non-responders. Three of the 4 subjects with NRAS mutations were non-responders (p = 0.3053) while both PTEN mutations were detected in responders (p = 0.4993). Collective mutation frequencies of KRAS, NRAS, and BRAF combined were higher in non-responders (p = 0.0001).
DOI:
10.18632/oncotarget.8076
Source:
Title:
A Molecularly Annotated Platform of Patient-Derived Xenografts (“Xenopatients”) Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer
Excerpt:
Because our KRAS (codons 12 and 13) wild-type subpopulation included all these genotypes and additional KRAS rare mutations at codons 61 and 146, we decided to exploit our platform to challenge the predictive value of these emerging biomarkers. Our results prospectively validated observations in patients: none of the 7 NRAS- and 3 BRAF-mutant cases (10.6% and 4.5%, respectively) or the 4 cases with KRAS rare mutations (6.1%) responded to cetuximab with tumor shrinkage or stabilization.
DOI:
10.1158/2159-8290.CD-11-0109
Source:
Title:
FOLFOX4 Plus Cetuximab for Patients With Previously Untreated Metastatic Colorectal Cancer According to Tumor RAS and BRAF Mutation Status: Updated Analysis of the CECOG/CORE 1.2.002 Study
Excerpt:
Compared with patients with RAS wt/BRAF wt tumors (n = 124; median overall survival, 28.5 months), those with RAS mutations (n = 10; median, 16.3 months; hazard ratio, 0.43; 95% confidence interval, 0.20-0.89; P = .020) or BRAF mutations (n = 14; median, 11.7 months; hazard ratio, 0.23; 95% confidence interval, 0.12-0.41; P < .0001) had worse overall survival, which remained significant (P < .04) when adjusting for differences in baseline characteristics among the mutation subgroups.
Secondary therapy:
FOLFOX4
DOI:
10.1016/j.clcc.2014.12.003
Source:
Title:
Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
Excerpt:
We screened 51 colorectal cancer cell lines with a concentration range of the EGFR monoclonal antibody Cetuximab and assessed viability after 6 d...Cetuximab-resistant clones harboring mutations (in KRAS, NRAS, and MAP2K1) that would be predicted to activate MAPK signaling were resensitized when a MEK inhibitor (Trametinib) was combined with Cetuximab.
DOI:
10.1101/gr.213546.116
