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