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| Profile Name | NRAS act mut |
| Gene Variant Detail | |
| Relevant Treatment Approaches |
| Molecular Profile | Indication/Tumor Type | Response Type | Relevant Treatment Approaches | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|---|
| NRAS act mut | lung non-small cell carcinoma | predicted - resistant | Osimertinib | Case Reports/Case Series | Actionable | In a retrospective analysis, activating NRAS mutations were identified in 1 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416). | 31839416 | |
| NRAS act mut | Advanced Solid Tumor | no benefit | Selumetinib | Clinical Study - Cohort | Actionable | In a Phase II trial (MATCH), Koselugo (selumetinib) treatment resulted in a 15% (3/20) six-month progression-free survival rate, no objective responses, and did not lead to tumor regression in pediatric patients with advanced solid tumors including high grade glioma (n=8) and rhabdomyosarcoma (n=7) that harbored MAPK pathway alterations including activating NRAS, HRAS, or KRAS mutations, BRAF V600E, or inactivating NF1 mutations (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 10008; NCT03213691, NCT03155620). | detail... | |
| NRAS act mut | melanoma | predicted - sensitive | Binimetinib + Ribociclib | Phase Ib/II | Actionable | In a Phase Ib/II trial, Kisqali (ribociclib) plus Mektovi (binimetinib) was well tolerated in NRAS-mutant melanoma patients and resulted in an overall response rate of 19.5% (8/41; all PR), disease control rate of 70.7% (29/41), median duration of response of 10.3mo, median progression-free survival of 3.7mo, and median overall survival of 11.3mo in phase II, and a response rate of 22.9% (16/70) in patients with an NRAS Q61 mutation, and 12.5% (1/8) with NRAS G12/G13 mutation (PMID: 35294522; NCT01781572). | 35294522 | |
| NRAS act mut | melanoma | predicted - sensitive | Binimetinib + Exarafenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Exarafenib (KIN-2787) and Mektovi (binimetinib) combination treatment inhibited growth of melanoma cell lines harboring NRAS mutations in culture, and resulted in improved tumor growth inhibition and Mapk pathway suppression in cell line xenograft models compared to either agent alone (J Clin Oncol 40, 2022 (suppl 16; abstr e15099)). | detail... | |
| NRAS act mut | melanoma | predicted - sensitive | FCN-159 | Phase I | Actionable | In a Phase I trial (FCN-159-001), FCN-159 treatment was well tolerated in melanoma patients harboring NRAS activating mutations and resulted in an objective response rate (ORR) of 19% (4/21, all partial responses), a clinical benefit rate (CBR) of 52.4% (11/21), and a median progression-free survival (mPFS) of 3.8 mo across all doses tested, and a CBR of 50% (3/6), mPFS of 3.8 mo at the RP2D dose of 12mg (PMID: 36113242; NCT03932253). | 36113242 | |
| NRAS act mut | multiple myeloma | predicted - sensitive | BMF-219 | Preclinical - Cell culture | Actionable | In a preclinical study, BMF-219 inhibited growth of multiple myeloma cell lines harboring NRAS activating mutations in culture (Cancer Res 2022;82(12_Suppl):Abstract nr 2654). | detail... | |
| NRAS act mut | melanoma | predicted - sensitive | HL-085 | Phase I | Actionable | In a Phase I trial, HL-085 treatment demonstrated acceptable tolerability and resulted in an objective response rate (ORR) of 14.3% (6/42; all partial responses), a disease control rate (DCR) of 78.6%, and a median progression-free survival (PFS) of 3.0 months in patients with advanced melanoma harboring NRAS mutations, and an ORR of 26.7% (4/15), a DCR of 86.7%, and median PFS of 3.6 months at the recommended Phase II dose (PMID: 36600247; NCT03973151). | 36600247 | |
| NRAS act mut | neuroblastoma | predicted - sensitive | Navitoclax + Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to Navitoclax (ABT-263), resulting in reduced cell viability in culture, and the combination treatment resulted in tumor regression in cell line xenograft models (6/6 partial responses) (PMID: 36895472). | 36895472 | |
| NRAS act mut | neuroblastoma | predicted - sensitive | Trametinib + Venetoclax | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to Venclexta (venetoclax), resulting in reduced cell viability in culture, and the combination treatment resulted in tumor growth inhibition with 2/6 partial responses and 3/6 with stable disease in cell line xenograft models (PMID: 36895472). | 36895472 | |
| NRAS act mut | neuroblastoma | predicted - sensitive | S63845 + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to S63845 (MIK655), resulting in reduced cell viability in culture (PMID: 36895472). | 36895472 | |
| NRAS act mut | melanoma | predicted - sensitive | Exarafenib | Case Reports/Case Series | Actionable | In a Phase I trial, Exarafenib (KIN-2787) was tolerated and resulted in a partial response in 17.6% (6/34) and stable disease in 23.5% (8/34) of patients with BRAF-driven advanced solid tumors or NRAS-driven melanoma, including a partial response in 1 melanoma patient harboring an NRAS mutation (Cancer Res (2023) 83 (8_Supplement): CT032; NCT04913285). | detail... | |
| NRAS act mut | melanoma | decreased response | Toripalimab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 9 months in melanoma patients harboring activating NRAS mutations in either G12 (29%) or Q61 (67.1%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p<0.0001) (PMID: 37403699). | 37403699 | |
| NRAS act mut | melanoma | decreased response | Pembrolizumab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 9 months in melanoma patients harboring activating NRAS mutations in either G12 (29%) or Q61 (67.1%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p<0.0001) (PMID: 37403699). | 37403699 |