Data from A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in <i>IDH1</i>-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.
<div>Abstract<p>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 <i>IDH1</i>-mutated myeloid malignancies (<i>n</i> = 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 (<i>N</i> = 16), 63% attained MRD-negative remissions; <i>IDH1</i> mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (<i>N</i> = 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 <i>IDH1</i>-mutated clones. No IDH isoform switching or second-site <i>IDH1</i> mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.</p>Significance:<p>IVO + VEN + AZA is safe and active in patients with <i>IDH1</i>-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.</p></div>