A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Hematologic Malignancies: A 2024 Update

Background: Ivosidenib (IVO) is an effective and well-tolerated targeted small molecule inhibitor of mutant IDH1. In combination with azacitidine (AZA) in the AGILE trial, patients (pts) with newly diagnosed (ND) IDH1^MUT acute myeloid leukemia (AML) experienced a complete remission (CR)/CR with incomplete count recovery (CRi) rate of 53% and a median overall survival (mOS) of 29 months. Venetoclax (VEN) + AZA is also efficacious in IDH1^MUT AML with CR/CRi rate of 66% and mOS of 10 months in VIALE-A. Combining IVO, VEN, and AZA into one regimen may improve durability of long-term remission. Herein, we report updated results from the multisite Phase Ib/II study of VEN + IVO ± AZA for IDH1^MUT hematologic malignancies.

Methods: Eligible pts were ≥ 18 years old with IDH1^MUT relapsed/refractory (R/R) AML, ND AML not eligible for standard induction chemotherapy, or high-risk myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) (defined as ≥10% blasts or intermediate/high risk by IPSS, R-IPSS, or D-IPSS). Receipt of prior VEN or IVO was exclusionary.

The phase Ib portion evaluated four combination dose levels (DL) as previously described (Lachowiez et al., 2023). The phase 2 expansions for both ND and R/R patients are currently ongoing at DL3 (IVO 500mg + VEN 400mg + AZA 75mg/m2). Treatment cycles include VEN given on days 1-14, AZA on days 1-7, and IVO continuously. The primary objectives were to determine the safety and overall response rate (ORR = CR + CRi + CRh + MLFS + PR). Composite complete remission (CRc) was defined as CR + CRi + CRh. OS and event free survival (EFS), defined as lack of response to frontline treatment, relapse, or death, were evaluated by Kaplan-Meier method.

Results: From March 2018, to March 2024, 56 pts initiated study treatment (Phase 1b: 31, Phase II: 25). The median age at enrollment was 69 years (range: 43 – 86) and 35 pts (63%) were male. Most participants had ND AML (31 [70%]), while 13 (30%) had R/R AML, and 12 (21%) had MDS or MPN. Sixteen (27%) pts had received prior treatment (range: 1-5 lines) including 3 pts (5%) with a prior IDH1 inhibitor other than IVO.

The median number of cycles received was 4 (range: 1 – 75) with 16 pts (29%) still on study treatment. Median cycle length was 34 days (range: 24-111). The most common reasons for stopping treatment were SCT (22, 55%) or relapse (10, 25%). No patients discontinued treatment due to intolerance. Two dose limiting toxicities (DLTs) occurred in DL3: grade 3 (G3) tumor lysis syndrome (TLS) and G3 QTc prolongation, both managed with supportive care and with IVO dose reduction in the latter case. Fifteen of 56 (27%) pts experienced ≥G3 non-hematologic adverse event (AE), with febrile neutropenia the most common (6/56, 11%). G3 or higher differentiation syndrome occurred in 4 (7%) of pts, all reversible with protocol-guided management.

The ORR was 94% (51 of 54 evaluable pts) with 93% (50/54) achieving CRc within 5 cycles. Response rates did not differ by diagnosis (p=0.40) or by DL (p=0.30). The median time to best response was 53 days (range: 23 – 171). Measurable residual disease (MRD) negativity by flow cytometry (limit of detection (LOD) <0.1%) was achieved in 77% (37/48) pts. More pts treated with the triplet regimen achieved MRD negativity compared to the doublet (86% vs 50%, p=0.037). Mutated IDH1 was undetectable by next-generation sequencing (LOD VAF <5%) in 62% of pts (28/45) and was not different between DLs (p=0.5).

With a median follow-up of 36 months (95% CI: 22.6 to 46.8 months), mOS has not been reached. The overall 3-year OS was 70.5% (95% CI: 57.7 – 86.1%). Pts who received SCT had a 3-year OS of 94.7% (95% CI: 85.2 – 100%) compared to 52.8% (25.6 – 78.2%) in those who did not. For MDS or MPN (n=12), ND AML (n=31), and R/R AML (n=13) subsets, the 3-year OS was 81.5% (95% CI: 61.1 – 100%), 71.4% (53.2 – 95.8%), and 52.1% (28.8 – 94.3%), respectively. The mEFS was 50.4 months with a 3-year EFS of 67.3% (95% CI: 54.4 – 83.3%). EFS did not differ between diagnosis groups (p=0.52) but was lower in those who received an IVO + VEN doublet compared to an IVO + VEN + AZA triplet (HR 0.37, 95% CI: 0.14 – 0.95, p=0.033). mDOR was 43.4 months, with an estimated 3-year DOR of 58.5% (95 CI: 39.8 – 86.0%).

Conclusions: Triplet therapy with IVO + VEN ± AZA was safe, efficacious, and demonstrates durable responses with long term follow up compared to doublet therapy. Accrual is ongoing (NCT03471260) and prospective trials comparing “triplet” vs “doublet” regimens for IDH1^MUT AML are needed.