Reference Detail

Ref Type

Journal Article

PMID

(37102976)

Authors

Lachowiez CA, Loghavi S, Zeng Z, Tanaka T, Kim YJ, Uryu H, Turkalj S, Jakobsen NA, Luskin MR, Duose DY, Tidwell RSS, Short NJ, Borthakur G, Kadia TM, Masarova L, Tippett GD, Bose P, Jabbour EJ, Ravandi F, Daver NG, Garcia-Manero G, Kantarjian H, Garcia JS, Vyas P, Takahashi K, Konopleva M, DiNardo CD

Title

A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated myeloid malignancies.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood cancer discovery			2023 Apr 27	276-293	Blood Cancer Discov

URL

Abstract Text

The safety and efficacy of combining the IDH1 inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO+VEN) +/- azacitidine (AZA; IVO+VEN+AZA) was evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n=31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO+VEN+AZA vs. IVO+VEN was 90% vs. 83%. Among MRD-evaluable patients (N=16) 63% attained MRD-negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N=14). Median EFS and OS were 36 (95% CI: 23-NR) and 42 (95% CI: 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked co-occurring mutations, anti-apoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH1 mutant	myeloid neoplasm	predicted - sensitive	Ivosidenib + Venetoclax	Phase Ib/II	Actionable	In a Phase Ib/II trial, combination treatment with Tibsovo (ivosidenib) and Venclexta (venetoclax) demonstrated safety and efficacy in patients with advanced myeloid malignancies harboring IDH1 mutations, and led to a CRc (complete response (CR) + CR with partial hematologic recovery + CR with incomplete hematologic recovery) rate of 83% (10/12), median event-free survival (EFS) of 11 mo, 12-mo EFS rate of 50%, median overall survival (OS) of 42.1 mo, and 24-mo OS rate of 58% (PMID: 37102976; NCT03471260).	37102976
IDH1 mutant	myeloid neoplasm	predicted - sensitive	Azacitidine + Ivosidenib + Venetoclax	Phase Ib/II	Actionable	In a Phase Ib/II trial, Tibsovo (ivosidenib) in combination with Vidaza (azacitidine) and Venclexta (venetoclax) demonstrated safety and efficacy in patients with IDH1-mutant advanced myeloid malignancies, and led to a CRc (complete response (CR) + CR with partial hematologic recovery + CR with incomplete hematologic recovery) rate of 90% (17/19), 12-mo event-free survival (EFS) rate of 84%, 24-mo overall survival (OS) rate of 75%, and median EFS and OS were not reached (PMID: 37102976; NCT03471260).	37102976