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    DRUG:

    naporafenib (ERAS-254)

    i
    Other names: ERAS-254, LXH254, LXH 254, LXH-254, ERAS 254, ERAS254
    Company:
    Erasca, Novartis
    Drug class:
    BRAF inhibitor, pan-RAF inhibitor, cRAF inhibitor
    Related drugs:
    7d
    SEACRAFT-1: A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With RAS Q61X Mutations (clinicaltrials.gov)
    P1, N=86, Active, not recruiting, Erasca, Inc. | Trial completion date: Nov 2025 --> Dec 2026
    Trial completion date
    |
    RAS mutation
    |
    Mekinist (trametinib) • naporafenib (ERAS-254)
    7d
    A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2) (clinicaltrials.gov)
    P3, N=78, Active, not recruiting, Erasca, Inc. | Recruiting --> Active, not recruiting | N=470 --> 78
    Enrollment closed • Enrollment change
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation
    |
    Mekinist (trametinib) • temozolomide • dacarbazine • naporafenib (ERAS-254)
    1m
    Insights into RAS-driven melanoma and its therapeutic implications. (PubMed, Cancer Treat Rev)
    Ongoing combination strategies include MEK inhibition with type II RAF inhibitors (naporafenib plus trametinib in phase III trial), ERK1/2 or ERK5 inhibitors, PI3K/mTOR pathway blockade, or CDK4/6 inhibition. Additional investigational approaches include mutation-specific RAS inhibitors (G12C inhibitors already approved for other cancers), NRAS-specific or pan-RAS inhibitors (daraxonrasib in phase III trial for other cancers), targeted protein degradation, RAS-directed peptide and mRNA vaccines (mRNA-4157). NRAS Q61K-derived neoepitopes bound to HLA-A*01:01 have been recognized as immunogenic, suggesting that mutation-specific immunotherapies could represent a promising future strategy. In conclusion, the advent of promising and emerging therapies is set to transform the management of RAS-driven melanoma, making a personalized, biomarker-informed treatment strategy essential for optimizing patient outcomes.
    Review • Journal • PD(L)-1 Biomarker • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • RAS mutation • NRAS Q61
    |
    Mekinist (trametinib) • naporafenib (ERAS-254) • intismeran autogene (mRNA-4157)
    2ms
    Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov)
    P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2026 --> Oct 2026 | Trial primary completion date: Mar 2026 --> Oct 2026
    Trial completion date • Trial primary completion date
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    Mekinist (trametinib) • gefitinib • Kisqali (ribociclib) • Tabrecta (capmatinib) • naporafenib (ERAS-254) • nazartinib (EGF816)
    5ms
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2025 --> Mar 2026 | Trial primary completion date: Oct 2025 --> Mar 2026
    Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    6ms
    Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov)
    P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2025 --> Mar 2026 | Trial primary completion date: Oct 2025 --> Mar 2026
    Trial completion date • Trial primary completion date
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    Mekinist (trametinib) • gefitinib • Kisqali (ribociclib) • Tabrecta (capmatinib) • naporafenib (ERAS-254) • nazartinib (EGF816)
    7ms
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2025 --> Oct 2025 | Trial primary completion date: Jun 2025 --> Oct 2025
    Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    10ms
    SEACRAFT-1: A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With RAS Q61X Mutations (clinicaltrials.gov)
    P1, N=86, Active, not recruiting, Erasca, Inc. | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    RAS mutation
    |
    Mekinist (trametinib) • naporafenib (ERAS-254)
    10ms
    Targeting the MAPK Pathway for NRAS Mutant Melanoma: From Mechanism to Clinic. (PubMed, Br J Dermatol)
    In recent years, significant clinical advancements have been achieved by targeting the NRAS-MAPK pathway, with novel therapies such as the MEK inhibitor tunlametinib and the combination therapy of the pan-RAF inhibitor naporafenib with trametinib leading the way. In this review, we will systematically summarize the recent advances in the direct targeting of mutant NRAS proteins and their downstream RAF and MEK proteins, as well as targeting the MAPK pathway in combination with other therapeutic targets, including the immunotherapy, to treat NRAS mutant melanoma. Additionally, we will further discuss the current issues and emerging countermeasures related to targeted therapy for NRAS mutant melanoma.
    Journal • IO biomarker
    |
    NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation
    |
    Mekinist (trametinib) • Kolupin (tunlametinib) • naporafenib (ERAS-254)
    11ms
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2025 --> Jul 2025 | Trial primary completion date: Feb 2025 --> Jun 2025
    Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    1year
    Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov)
    P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2025 --> Oct 2025 | Trial primary completion date: Apr 2025 --> Oct 2025
    Trial completion date • Trial primary completion date
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    Mekinist (trametinib) • gefitinib • Kisqali (ribociclib) • Tabrecta (capmatinib) • naporafenib (ERAS-254) • nazartinib (EGF816)
    1year
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2024 --> Mar 2025
    Trial completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)