A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies

Authors

Curtis A Lachowiez
Sanam Loghavi
Zhihong Zeng
Tomoyuki Tanaka
Yi June Kim
Hidetaka Uryu
Sven Turkalj
Niels Asger Jakobsen
Marlise R Luskin
Dzifa Y Duose
Rebecca S S Tidwell
Nicholas J Short
Gautam Borthakur
Tapan M Kadia
Lucia Masarova
George D Tippett
Prithviraj Bose
Elias J Jabbour
Farhad Ravandi
Naval G Daver
Guillermo Garcia-Manero
Hagop Kantarjian
Jacqueline S Garcia
Paresh Vyas
Koichi Takahashi
Marina Konopleva
Courtney D DiNardo

Publication Date

7-5-2023

Journal

Blood Cancer Discovery

Abstract

UNLABELLED: The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were 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 versus IVO + VEN was 90% versus 83%. Among measurable residual disease (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 event-free survival and overall survival were 36 [94% CI, 23-not reached (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 cooccurring mutations, antiapoptotic 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.

SIGNIFICANCE: IVO + VEN + AZA is safe and active in patients with IDH1-mutated myeloid malignancies. Combination therapy appears to overcome resistance mechanisms observed with single-agent IDH-inhibitor use, with high MRD-negative remission rates. Single-cell DNA ± protein and time-of-flight mass-cytometry analysis revealed complex resistance mechanisms at relapse, highlighting key pathways for future therapeutic intervention. This article is highlighted in the In This Issue feature, p. 247.

Keywords

Humans, Neoplasm Recurrence, Local, Antineoplastic Agents, Azacitidine, Isocitrate Dehydrogenase

Comments

See commentary "Highlighted research articles" in volume 4 on page 247.

Supplementary Materials

PMID: 37102976