NRAS Mutation

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Molecular profile	Therapy	Type	Level	Direction · significance	Rating (1–5)	Status	Evidence	Source
Acute Myeloid Leukemia1
NRAS Mutation	(prognostic)	Prognostic	B	Does Not Support N/A	3	accepted	EID56 The presence of NRAS mutation in AML patients does not impact diease prognosis (resistant disease, disease-free survival, complete remission rate, relapse rate, induction death). PMID 15951308 · Bowen et al., 2005 · Open in CIViC	civic
Colorectal Adenocarcinoma1
NRAS Mutation OR KRAS Mutation OR BRAF Mutation	(prognostic)	Prognostic	B	Supports Poor Outcome	4	submitted	EID11061 The Medical Research Council (MRC) COIN trial consisted of patients with histologically confirmed adenocarcinoma of the colon or rectum, inoperable metastatic or locoregional measurable disease, and w… (full text at CIViC) PMID 21641636 · Maughan et al., 2011 ·

Molecular profile

Therapy

Type

Level

Direction · significance

Rating (1–5)

Status

Evidence

Source

Acute Myeloid Leukemia1

NRAS Mutation

(prognostic)

Prognostic

Does Not Support N/A

accepted

EID56

The presence of NRAS mutation in AML patients does not impact diease prognosis (resistant disease, disease-free survival, complete remission rate, relapse rate, induction death).

PMID 15951308 · Bowen et al., 2005 · Open in CIViC

civic

Colorectal Adenocarcinoma1

NRAS Mutation OR KRAS Mutation OR BRAF Mutation

(prognostic)

Prognostic

Supports Poor Outcome

submitted

EID11061

The Medical Research Council (MRC) COIN trial consisted of patients with histologically confirmed adenocarcinoma of the colon or rectum, inoperable metastatic or locoregional measurable disease, and w… (full text at CIViC)

PMID 21641636 · Maughan et al., 2011 ·

Cutaneous Melanoma5
NRAS Mutation	Amuvatinib	Predictive	D	Supports Sensitivity Response	1	accepted	EID1476 Preclinical study in melanoma cell lines. Cell lines (2-5/assay) with NRAS mutation were more sensitive to Amuvatinib (inhibitor targets multiple tyrosine kinases) than BRAF mutant cell lines in growt… (full text at CIViC) PMID 24950457 · Fedorenko et al., 2014 · Open in CIViC	civic
NRAS Mutation	Binimetinib	Predictive	B	Supports Sensitivity Response	2	accepted	EID1472 Phase II study in 71 patients with NRAS or BRAF V600 mutant melanoma treated with MEK162. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed). PMID 23414587 · Ascierto et al., 2013 · Open in CIViC	civic
NRAS Mutation	Binimetinib	Predictive	B	Supports Sensitivity Response	5	accepted	EID2937 NEMO is an ongoing, randomised, open-label phase 3 study of patients with advanced, unresectable, AJCC IIIC/IV NRAS-mutant melanoma. 402 patients that were previously untreated or progressed on or aft… (full text at CIViC) PMID 28284557 · Dummer et al., 2017 · Open in CIViC	civic
NRAS Mutation	Binimetinib + RibociclibCombination	Predictive	B	Supports Sensitivity Response	3	accepted	EID2931 Inhibition of CDK4 and 6, regulators of the G1/S cell cycle checkpoint, arrests the cell cycle in the G1 phase, suppresses DNA synthesis, and inhibits cancer cell growth. There is an ongoing phase 1/2… (full text at CIViC) PMID 26987942 · Vu et al., 2016 · Open in CIViC	civic
NRAS Mutation	Docetaxel + TrametinibCombination	Predictive	B	Supports Sensitivity Response	2	accepted	EID1225 Phase 1 trial of trametinib and docetaxel in patients with advanced melanoma lacking BRAF V600 mutations. 15 patients were enrolled (14 BRAF wt). Six patients had a partial response, including four ou… (full text at CIViC) PMID 25542057 · Coupe et al., 2015 · Open in CIViC	civic

Cutaneous Melanoma5

NRAS Mutation

Amuvatinib

Predictive

Supports Sensitivity Response

accepted

EID1476

Preclinical study in melanoma cell lines. Cell lines (2-5/assay) with NRAS mutation were more sensitive to Amuvatinib (inhibitor targets multiple tyrosine kinases) than BRAF mutant cell lines in growt… (full text at CIViC)

PMID 24950457 · Fedorenko et al., 2014 · Open in CIViC

civic

NRAS Mutation

Binimetinib

Predictive

Supports Sensitivity Response

accepted

EID1472

Phase II study in 71 patients with NRAS or BRAF V600 mutant melanoma treated with MEK162. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed).

PMID 23414587 · Ascierto et al., 2013 · Open in CIViC

civic

NRAS Mutation

Binimetinib

Predictive

Supports Sensitivity Response

accepted

EID2937

NEMO is an ongoing, randomised, open-label phase 3 study of patients with advanced, unresectable, AJCC IIIC/IV NRAS-mutant melanoma. 402 patients that were previously untreated or progressed on or aft… (full text at CIViC)

PMID 28284557 · Dummer et al., 2017 · Open in CIViC

civic

NRAS Mutation

Binimetinib + RibociclibCombination

Predictive

Supports Sensitivity Response

accepted

EID2931

Inhibition of CDK4 and 6, regulators of the G1/S cell cycle checkpoint, arrests the cell cycle in the G1 phase, suppresses DNA synthesis, and inhibits cancer cell growth. There is an ongoing phase 1/2… (full text at CIViC)

PMID 26987942 · Vu et al., 2016 · Open in CIViC

civic

NRAS Mutation

Docetaxel + TrametinibCombination

Predictive

Supports Sensitivity Response

accepted

EID1225

Phase 1 trial of trametinib and docetaxel in patients with advanced melanoma lacking BRAF V600 mutations. 15 patients were enrolled (14 BRAF wt). Six patients had a partial response, including four ou… (full text at CIViC)

PMID 25542057 · Coupe et al., 2015 · Open in CIViC

civic

Erdheim-Chester Disease1
NRAS Mutation OR KRAS Mutation OR RAF1 Mutation OR MAP2K1 Mutation OR MAP2K2 Mutation	Cobimetinib	Predictive	B	Supports Sensitivity Response	4	submitted	EID11328 In an open-label, phase II trial, 18 patients with histiocytosis of any mutational status were enrolled. The overall response rate was 89% (90% CI: 73 - 100). Responses were durable, with no acquired … (full text at CIViC) PMID 30867592 · Diamond et al., 2019 · Open in CIViC	civic

Erdheim-Chester Disease1

NRAS Mutation OR KRAS Mutation OR RAF1 Mutation OR MAP2K1 Mutation OR MAP2K2 Mutation

Cobimetinib

Predictive

Supports Sensitivity Response

submitted

EID11328

In an open-label, phase II trial, 18 patients with histiocytosis of any mutational status were enrolled. The overall response rate was 89% (90% CI: 73 - 100). Responses were durable, with no acquired … (full text at CIViC)

PMID 30867592 · Diamond et al., 2019 · Open in CIViC

civic

Langerhans Cell Histiocytosis1
NRAS Mutation OR KRAS Mutation OR RAF1 Mutation OR MAP2K1 Mutation OR MAP2K2 Mutation	Cobimetinib	Predictive	B	Supports Sensitivity Response	4	submitted	EID11329 In an open-label, phase II trial, 18 patients with histiocytosis of any mutational status were enrolled. Patients received cobimetinib at a starting dose of 60 mg daily for 21 days of each 28-day cycl… (full text at CIViC) PMID 30867592 · Diamond et al., 2019 · Open in CIViC	civic

Langerhans Cell Histiocytosis1

NRAS Mutation OR KRAS Mutation OR RAF1 Mutation OR MAP2K1 Mutation OR MAP2K2 Mutation

Cobimetinib

Predictive

Supports Sensitivity Response

submitted

EID11329

In an open-label, phase II trial, 18 patients with histiocytosis of any mutational status were enrolled. Patients received cobimetinib at a starting dose of 60 mg daily for 21 days of each 28-day cycl… (full text at CIViC)

PMID 30867592 · Diamond et al., 2019 · Open in CIViC

civic

Malignant Colorectal Neoplasm4
NRAS Mutation	(prognostic)	Prognostic	B	Supports Poor Outcome	3	accepted	EID27 Patients with colorectal cancer harboring NRAS mutation have poorer survival outcome and worse prognosis than patients with wildtype NRAS. PMID 24666267 · Therkildsen et al., 2014 · Open in CIViC	civic
NRAS Mutation	Cetuximab	Predictive	D	Supports Resistance	2	accepted	EID1703 A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xeno… (full text at CIViC) PMID 22586653 · Bertotti et al., 2011 · Open in CIViC	civic
NRAS Mutation	Cetuximab + ChemotherapyCombination	Predictive	B	Supports Resistance	2	accepted	EID2210 This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients with KRAS wildtype, NRAS assessable tumors, an… (full text at CIViC) PMID 20619739 · De Roock et al., 2010 · Open in CIViC	civic
NRAS Mutation	Cetuximab + PanitumumabSubstitutes	Predictive	A	Supports Resistance	4	accepted	EID5344 NCCN guidelines indicate colorectal cancer patients with NRAS mutations should not be treated with EGFR inhibitors cetuximab or panitumumab. PMID 28275037 · Benson et al., 2017 · Open in CIViC	civic

Malignant Colorectal Neoplasm4

NRAS Mutation

(prognostic)

Prognostic

Supports Poor Outcome

accepted

EID27

Patients with colorectal cancer harboring NRAS mutation have poorer survival outcome and worse prognosis than patients with wildtype NRAS.

PMID 24666267 · Therkildsen et al., 2014 · Open in CIViC

civic

NRAS Mutation

Cetuximab

Predictive

Supports Resistance

accepted

EID1703

A cohort of patient-derived xenografts (PDX) from 85 patients with metastatic colorectal cancer was created. PDX were treated with cetuximab and mechanisms of resistance investigated. None of the xeno… (full text at CIViC)

PMID 22586653 · Bertotti et al., 2011 · Open in CIViC

civic

NRAS Mutation

Cetuximab + ChemotherapyCombination

Predictive

Supports Resistance

accepted

EID2210

This was a retrospective study of 605 patients with metastatic, chemotherapy refractory colorectal cancer treated with cetuximab + chemotherapy. Patients with KRAS wildtype, NRAS assessable tumors, an… (full text at CIViC)

PMID 20619739 · De Roock et al., 2010 · Open in CIViC

civic

NRAS Mutation

Cetuximab + PanitumumabSubstitutes

Predictive

Supports Resistance

accepted

EID5344

NCCN guidelines indicate colorectal cancer patients with NRAS mutations should not be treated with EGFR inhibitors cetuximab or panitumumab.

PMID 28275037 · Benson et al., 2017 · Open in CIViC

civic

Malignant Neoplasm3
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Inactivating Mutation	Selumetinib	Predictive	B	Does Not Support Sensitivity Response	3	accepted	EID11696 In this Phase II study, 20 patients harboring activating RAS gene mutations (KRAS = 8, NRAS = 3. HRAS = 1), BRAF V600E mutations, and NF1 inactivating mutations (n=7) were treated with Selumetinib. No… (full text at CIViC) PMID 35363510 · Eckstein et al., 2022 · Open in CIViC	civic
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Mutation	Selumetinib	Predictive	B	Does Not Support Sensitivity Response	3	accepted	EID11681 In this phase II study of the arm E of the NCI-COG pediatric MATCH trial, 20 patients (median age: 14) were treated with Selumetinib. High-grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most c… (full text at CIViC) PMID 35363510 · Eckstein et al., 2022 · Open in CIViC	civic
NRAS Mutation	Metformin + TrametinibCombination	Predictive	D	Supports Sensitivity Response	3	accepted	EID1230 Preclinical study in 16 NRAS mutant cell lines (melanoma, lung carcinoma, neuroblastoma with various Q61, G13, G12 mutations). The combination of metformin and trametinib shown synergistic effects in … (full text at CIViC) PMID 25504439 · Vujic et al., 2015 · Open in CIViC	civic

Malignant Neoplasm3

BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Inactivating Mutation

Selumetinib

Predictive

Does Not Support Sensitivity Response

accepted

EID11696

In this Phase II study, 20 patients harboring activating RAS gene mutations (KRAS = 8, NRAS = 3. HRAS = 1), BRAF V600E mutations, and NF1 inactivating mutations (n=7) were treated with Selumetinib. No… (full text at CIViC)

PMID 35363510 · Eckstein et al., 2022 · Open in CIViC

civic

BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Mutation

Selumetinib

Predictive

Does Not Support Sensitivity Response

accepted

EID11681

In this phase II study of the arm E of the NCI-COG pediatric MATCH trial, 20 patients (median age: 14) were treated with Selumetinib. High-grade glioma (n=7) and rhabdomyosarcoma (n=7) were the most c… (full text at CIViC)

PMID 35363510 · Eckstein et al., 2022 · Open in CIViC

civic

NRAS Mutation

Metformin + TrametinibCombination

Predictive

Supports Sensitivity Response

accepted

EID1230

Preclinical study in 16 NRAS mutant cell lines (melanoma, lung carcinoma, neuroblastoma with various Q61, G13, G12 mutations). The combination of metformin and trametinib shown synergistic effects in … (full text at CIViC)

PMID 25504439 · Vujic et al., 2015 · Open in CIViC

civic

Melanoma7
BRAF V600E AND NRAS Mutation	Dabrafenib + VemurafenibSubstitutes	Predictive	B	Supports Resistance	2	accepted	EID6263 In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired r… (full text at CIViC) PMID 24265155 · Shi et al., 2014 · Open in CIViC	civic
NRAS Mutation	(prognostic)	Prognostic	B	Supports Poor Outcome	3	accepted	EID71 In patients with stage IV melanoma, NRAS mutation was associated with reduced median survival compared to patients with wildtype NRAS. PMID 22180178 · Jakob et al., 2012 · Open in CIViC	civic
NRAS Mutation	Belvarafenib	Predictive	B	Supports Sensitivity Response	3	submitted	EID7452 In a phase1 trial, patients with advanced solid tumor harboring RAS or RAF mutation were treated with pan-RAF inhibitor Belvarafenib (HM99573/GDC-5573). In the dose-escalation cohort, 4 of 9 patients … (full text at CIViC) Open in CIViC	civic
NRAS Mutation	Binimetinib	Predictive	D	Supports Sensitivity Response	3	accepted	EID1509 In a panel of 7 NRAS mutant melanoma cell lines, all 7 were found to be sensitive to the MEK inhibitor MEK162, whereas 3 of 5 melanoma cell lines that were wild type for BRAF and NRAS were not sensiti… (full text at CIViC) PMID 24588908 · Thumar et al., 2014 · Open in CIViC	civic
NRAS Mutation	MEK Inhibitor RO4987655	Predictive	C	Does Not Support Resistance	2	accepted	EID996 Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655). Among 8 patients with NRAS mutated melanoma, 3 experienced clinical benefit: 2 stable disease and 1 partial… (full text at CIViC) PMID 24947927 · Zimmer et al., 2014 · Open in CIViC	civic
NRAS Mutation	Omipalisib + TrametinibCombination	Predictive	D	Supports Sensitivity Response	4	accepted	EID1429 In six NRAS mutant melanoma cell lines, concomitant use of MEK inhibitor and PI3K/mTOR inhibitor resulted in greater decrease in cell viability than either alone, with the synergistic effect being mar… (full text at CIViC) PMID 23431193 · Posch et al., 2013 · Open in CIViC	civic
NRAS Mutation	Trametinib	Predictive	B	Does Not Support Sensitivity Response	2	accepted	EID1227 Phase 1 trial in 97 patients with melanoma (81 cutaneous or unknown, 16 uveal). Seven patients were found to harbor an NRAS mutation and two of them experienced stable disease (one 48 weeks on treatme… (full text at CIViC) PMID 22805292 · Falchook et al., 2012 · Open in CIViC	civic

Melanoma7

BRAF V600E AND NRAS Mutation

Dabrafenib + VemurafenibSubstitutes

Predictive

Supports Resistance

accepted

EID6263

In a retrospective study of 44 relapsed melanoma patients harboring BRAF V600E or V600K (known BRAF inhibitor sensitizing mutations), MAPK pathway reactivation mechanisms were implicated in acquired r… (full text at CIViC)

PMID 24265155 · Shi et al., 2014 · Open in CIViC

civic

NRAS Mutation

(prognostic)

Prognostic

Supports Poor Outcome

accepted

EID71

In patients with stage IV melanoma, NRAS mutation was associated with reduced median survival compared to patients with wildtype NRAS.

PMID 22180178 · Jakob et al., 2012 · Open in CIViC

civic

NRAS Mutation

Belvarafenib

Predictive

Supports Sensitivity Response

submitted

EID7452

In a phase1 trial, patients with advanced solid tumor harboring RAS or RAF mutation were treated with pan-RAF inhibitor Belvarafenib (HM99573/GDC-5573). In the dose-escalation cohort, 4 of 9 patients … (full text at CIViC)

Open in CIViC

civic

NRAS Mutation

Binimetinib

Predictive

Supports Sensitivity Response

accepted

EID1509

In a panel of 7 NRAS mutant melanoma cell lines, all 7 were found to be sensitive to the MEK inhibitor MEK162, whereas 3 of 5 melanoma cell lines that were wild type for BRAF and NRAS were not sensiti… (full text at CIViC)

PMID 24588908 · Thumar et al., 2014 · Open in CIViC

civic

NRAS Mutation

MEK Inhibitor RO4987655

Predictive

Does Not Support Resistance

accepted

EID996

Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655). Among 8 patients with NRAS mutated melanoma, 3 experienced clinical benefit: 2 stable disease and 1 partial… (full text at CIViC)

PMID 24947927 · Zimmer et al., 2014 · Open in CIViC

civic

NRAS Mutation

Omipalisib + TrametinibCombination

Predictive

Supports Sensitivity Response

accepted

EID1429

In six NRAS mutant melanoma cell lines, concomitant use of MEK inhibitor and PI3K/mTOR inhibitor resulted in greater decrease in cell viability than either alone, with the synergistic effect being mar… (full text at CIViC)

PMID 23431193 · Posch et al., 2013 · Open in CIViC

civic

NRAS Mutation

Trametinib

Predictive

Does Not Support Sensitivity Response

accepted

EID1227

Phase 1 trial in 97 patients with melanoma (81 cutaneous or unknown, 16 uveal). Seven patients were found to harbor an NRAS mutation and two of them experienced stable disease (one 48 weeks on treatme… (full text at CIViC)

PMID 22805292 · Falchook et al., 2012 · Open in CIViC

civic

Multiple Myeloma1
NRAS Mutation	(prognostic)	Prognostic	B	Supports N/A	4	accepted	EID496 In patients with multiple myeloma, the presence of a mutation in NRAS was not significantly associated with progression-free or overall survival. PMID 18528420 · Chng et al., 2008 · Open in CIViC	civic

Multiple Myeloma1

NRAS Mutation

(prognostic)

Prognostic

Supports N/A

accepted

EID496

In patients with multiple myeloma, the presence of a mutation in NRAS was not significantly associated with progression-free or overall survival.

PMID 18528420 · Chng et al., 2008 · Open in CIViC

civic

Solid Neoplasm2
NRAS Mutation	Binimetinib	Predictive	B	Does Not Support Sensitivity Response	3	accepted	EID11674 In this NCI-MATCH trial, 47 patients harboring codon 12, 13, or 61 NRAS mutated refractory solid tumors were treated with binimetinib. Of the 47 patients, >50% of the patients had metastatic colorecta… (full text at CIViC) PMID 33637626 · Cleary et al., 2021 · Open in CIViC	civic
NRAS Mutation OR KRAS Mutation OR BRAF Mutation	Lifirafenib	Predictive	B	Supports Sensitivity Response	2	submitted	EID12641 In a first in human open label phase 1 dose escalation and expansion study of lifirafenib in advanced solid tumors (NCT02610361; n = 131; BRAF-mutated n = 53, KRAS/NRAS-mutated n = 66; biomarker BRAF … (full text at CIViC) PMID 32182156 · Desai et al., 2020 · Open in CIViC	civic

Solid Neoplasm2

NRAS Mutation

Binimetinib

Predictive

Does Not Support Sensitivity Response

accepted

EID11674

In this NCI-MATCH trial, 47 patients harboring codon 12, 13, or 61 NRAS mutated refractory solid tumors were treated with binimetinib. Of the 47 patients, >50% of the patients had metastatic colorecta… (full text at CIViC)

PMID 33637626 · Cleary et al., 2021 · Open in CIViC

civic

NRAS Mutation OR KRAS Mutation OR BRAF Mutation

Lifirafenib

Predictive

Supports Sensitivity Response

submitted

EID12641

In a first in human open label phase 1 dose escalation and expansion study of lifirafenib in advanced solid tumors (NCT02610361; n = 131; BRAF-mutated n = 53, KRAS/NRAS-mutated n = 66; biomarker BRAF … (full text at CIViC)

PMID 32182156 · Desai et al., 2020 · Open in CIViC

civic

Low-grade Serous Ovarian Carcinoma1unmapped disease
NRAS Mutation	Trametinib	Predictive	B	Supports Sensitivity Response	4	submitted	EID13128 GOG-281/LOGS was a multinational, open-label, randomised phase 2/3 study comparing trametinib with established systemic therapies in patients with recurrent low-grade serous carcinoma arising from the… (full text at CIViC) PMID 35123694 · Gershenson et al., 2022 · Open in CIViC	civic

Low-grade Serous Ovarian Carcinoma1unmapped disease

NRAS Mutation

Trametinib

Predictive

Supports Sensitivity Response

submitted

EID13128

GOG-281/LOGS was a multinational, open-label, randomised phase 2/3 study comparing trametinib with established systemic therapies in patients with recurrent low-grade serous carcinoma arising from the… (full text at CIViC)

PMID 35123694 · Gershenson et al., 2022 · Open in CIViC

civic

Evidence by cancer (27 items)

Clinical significance (0)