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

by Selleckchem | Jul 23 2023

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.

Comments:

The study evaluated the safety and effectiveness of combining the IDH1 inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN), with or without azacitidine (AZA), in patients with IDH1-mutated myeloid malignancies. The study included a total of 31 patients across four cohorts.

The results showed that the combination therapy was generally well-tolerated, with the majority of adverse events being grade 1 or 2, indicating mild to moderate side effects. The study did not reach the maximal tolerated dose, suggesting that the combination therapy may be administered at higher doses if necessary.

The composite complete remission rate with the triple combination of IVO+VEN+AZA was 90%, while the combination of IVO+VEN alone resulted in a remission rate of 83%. Among patients who were evaluable for minimal residual disease (MRD), 63% achieved MRD-negative remissions, indicating a substantial reduction in cancer cells. Additionally, 64% of patients who received at least five treatment cycles showed clearance of the IDH1 mutation.

The median event-free survival (EFS) was 36 months, with a confidence interval (CI) of 23 to not reached (NR), indicating that the median EFS was not reached within the study duration. The median overall survival (OS) was 42 months, with a CI of 42 to NR, suggesting that the median OS was also not reached within the study period. These findings indicate that the combination therapy may provide durable responses and prolonged survival in patients with IDH1-mutated myeloid malignancies.

Patients with signaling gene mutations appeared to derive particular benefits from the triplet regimen, indicating that the combination therapy may be especially effective in this subgroup of patients.

The study also employed longitudinal single-cell proteogenomic analyses, which revealed associations between co-occurring mutations, expression of anti-apoptotic proteins, cell maturation, and therapeutic sensitivity of IDH1-mutated clones. This information provides insights into the mechanisms underlying the therapeutic response to the combination therapy.

Importantly, the study did not observe any IDH isoform switching or second-site IDH1 mutations, indicating that the combination therapy may overcome established resistance pathways that can occur with single-agent ivosidenib.

Overall, these findings suggest that the combination of ivosidenib, venetoclax, and azacitidine shows promising safety and efficacy in patients with IDH1-mutated myeloid malignancies. The study highlights the potential of combination therapies to improve outcomes and overcome resistance pathways associated with single-agent treatments.