Reference Detail

Ref Type

Journal Article

PMID

(34994649)

Authors

Eder JP, Doroshow DB, Do KT, Keedy VL, Sklar JS, Glazer P, Bindra R, Shapiro GI

Title

Clinical Efficacy of Olaparib in IDH1/IDH2-Mutant Mesenchymal Sarcomas.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JCO precision oncology	5		2021 Nov	466-472	JCO Precis Oncol

URL

Abstract Text

Tumors with neomorphic mutations in IDH1/2 have defective homologous recombination repair, resulting in sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. The Olaparib Combination trial is a phase II, open-label study in which patients with solid tumors harboring IDH1/2 mutations were treated with olaparib as monotherapy, with objective response and clinical benefit rates as the primary end points.Ten patients with IDH1/2-mutant tumors by next-generation sequencing were treated with olaparib 300 mg twice daily.Three of five patients with chondrosarcomas had clinical benefit, including one patient with a partial response and two with stable disease lasting > 7 months. A patient with pulmonary epithelioid hemangioendothelioma had stable disease lasting 11 months. In contrast, clinical benefit was not observed among four patients with cholangiocarcinoma.These results indicate preliminary activity of PARP inhibition in patients with IDH1/2-mutant chondrosarcoma and pulmonary epithelioid hemangioendothelioma. Further studies of PARP inhibitors alone and in combination in this patient population are warranted.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
IDH2	V305M	missense	unknown	IDH2 V305M does not lie within any known functional domains of the Idh2 protein (UniProt.org). V305M has been identified in the scientific literature (PMID: 34994649), but has not been biochemically characterized and therefore, its effect on Idh2 protein function is unknown (PubMed, Apr 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH1 R132C	chondrosarcoma	predicted - sensitive	Olaparib	Case Reports/Case Series	Actionable	In a Phase II trial (OLAPCO), Lynparza (olaparib) treatment resulted in a partial response with 59% tumor reduction lasting 14 months in one patient and stable disease lasting 7.5 months in one patient out of four patients with chondrosarcoma harboring IDH1 R132C (PMID: 34994649, NCT02576444).	34994649
IDH2 V305M	malignant epithelioid hemangioendothelioma	predicted - sensitive	Olaparib	Case Reports/Case Series	Actionable	In a Phase II trial (OLAPCO), Lynparza (olaparib) treatment resulted in stable disease lasting 11 months in a patient with pulmonary epithelioid hemangioendothelioma harboring IDH2 V305M (PMID: 34994649, NCT02576444).	34994649
IDH1 R132S	chondrosarcoma	predicted - sensitive	Olaparib	Case Reports/Case Series	Actionable	In a Phase II trial (OLAPCO), Lynparza (olaparib) treatment resulted in stable disease lasting 10 months in a patient with chondrosarcoma harboring IDH1 R132S (PMID: 34994649, NCT02576444).	34994649