OncoKB New Data Release - November 24, 2025
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Data Release v5.4
November 24, 2025
What's New
Update to our FDA-Approved Oncology Therapies page
Update to our FDA Cleared or Approved Companion Diagnostic Devices (CDx) page
Key updates to the functional classification and variant-level annotation of the NPM1 gene
NPM1 updated from Tumor Suppressor gene (TSG) to both Oncogene (OG) and TSG
Biological effect of annotated variants updated from Loss-of-function to Switch-of-function
Updated Therapeutic Implications:
Promotion of tumor type-specific level of evidence for an alteration
Level 1: ESR1 V422del in breast cancer promoted from Level 2 to Level 1 based on FDA approval of imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer (PMID: 39660834)
Level 2 sensitivity-associated evidence currently in OncoKB™ for ESR1 V422del in breast cancer: Elacestrant
Level 1: ESR1 S463F in breast cancer promoted from Level 3A to Level 1 based on FDA approval of imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer (PMID: 39660834)
Level 3A sensitivity-associated evidence currently in OncoKB™ for ESR1 S463F in breast cancer: Fulvestrant
Level 1: NPM1 Susceptible Mutations in acute myeloid leukemia promoted from Level 3A to Level 1 based on FDA approvals of revumenib and ziftomenib for relapsed or refractory acute myeloid leukemia with a susceptible NPM1 mutation (PMID: 40332046, 40997296)
NPM1 susceptible mutations were defined per the FDA label and include the following mutations:
Truncating mutations in Exon 5, Truncating mutations in Exon 9, Truncating mutations in Exon 11
Select exon 5 indels: K134delinsQLLSGL, L135insALELGN, L136_137insAEDVKLL, K141_142insLSALSISGK
Select NPM1 fusions (NPM1-CCDC28A Fusion, NPM1-HAUS1 Fusion, NPM1-MLF1 Fusion, NPM1-RPP30 Fusion)
Addition of drug(s) associated with a tumor type-specific leveled alteration(s) currently in OncoKB™ (without changing the alteration's highest level of evidence)
Level 1: Addition of Imlunestrant to ESR1 S463P, L469V, L536, Y537, D538 and E380 in breast cancer based on FDA approval of imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer (PMID: 39660834)
Level 1 sensitivity-associated therapeutics currently in OncoKB™ for ESR1 S463P, L469V, L536, Y537, D538 and E380 in breast cancer: Elacestrant
Gene Curation:
Addition of 10 new genes:
AIM2, AURKC, CAV1, COL5A1, GSTO1, HERPUD1, LZTS1, PICALM, PTK7, YWHAE
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