Ivosidenib Combo Shows Preliminary Activity in IDH1-Mutated AML

Combining ivosidenib (Tibsovo) with azacitidine (Vidaza) showed early real-world activity that was comparable with prior clinical trial results among patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), according to findings from the phase 3b ALIDHE trial (NCT05907057) presented in a poster session at the 2025 American Society of Hematology Annual Meeting and Exhibition.¹

Among 89 patients who received the ivosidenib combination in the ALIDHE trial, the objective response rate (ORR) was 58.4%. These responses included complete responses (CRs) in 41.6% of patients, CR with hematologic recovery (CRh) in 3.4%, CR with incomplete hematologic recovery in 7.9%, and partial responses (PRs) in 4.5%. According to the investigators, these outcomes were comparable to those reported in the phase 3 AGILE trial (NCT03173248), in which ivosidenib and azacitidine yielded an ORR of 62.5% among 72 evaluable patients.²

“Preliminary findings from ALIDHE are consistent with the AGILE pivotal trial; ivosidenib [plus] azacitidine shows similar safety results, and efficacy outcomes are promising. Data from ALIDHE will enrich knowledge on safety and help translate efficacy to effectiveness, bridging the gap between clinical trials and clinical practice,” lead study author Paresh Vyas, MRCP, FRCP, FRCPath, from the MRC Molecular Haematology Unit in the Radcliffe Department of Medicine of Weatherall Institute of Molecular Medicine at the University of Oxford, wrote with coauthors in the poster.¹ “ALIDHE is still enrolling; future analyses will focus on safety outcomes from extended follow-up, effectiveness, and quality of life.”

The FDA previously approved ivosidenib plus azacitidine for patients with newly diagnosed AML harboring IDH1 mutations in May 2022 based on data from the AGILE trial.³ Investigators of the ongoing post-approval ALIDHE study are assessing the safety and efficacy of the ivosidenib combination in a real-world setting that is inclusive of all patients with IDH1-mutated disease who are ineligible for intensive induction chemotherapy. Patients were assigned to receive oral ivosidenib at 500 mg once daily plus azacitidine at 75 mg/m² intravenously or subcutaneously for 7 days in each 28-day cycle.

The study’s primary end points include treatment-emergent adverse effects (TEAEs), serious AEs (SAEs), AEs of special interest, transfusion requirements, and infection rates. Secondary end points include event-free survival, responses, patient- or caregiver-reported outcomes, length of hospital stay, outpatient visits, and emergency room visits.

Patients 18 years and older with newly diagnosed, previously untreated AML harboring a documented IDH1 R132 mutation are eligible for inclusion. Other eligibility criteria include being unsuitable to receive intensive chemotherapy and having an ECOG performance status of 0 to 2.

As of the data cutoff date of May 5, 2025, 89 patients were evaluable for safety and efficacy, with 68 (76.4%) still receiving treatment at the time of analysis. The median duration of therapy was 5.1 months (range, 0.2-14.9).

The median patient age was 75.0 years (range, 51-84), and most patients were female (57.3%). Additionally, most patients had de novo disease (58.4%) and an ECOG performance status of 1 (42.7%). Data showed that the most common IDH1 mutation allele variants were R132C and R132H, with the most frequent co-occurring mutations being those located in genes associated with epigenetics, chromatin regulation, differentiation, and splicing. Overall, 25% of patients had at least 1 RTK/RAS pathway mutation; these findings were comparable to those observed in the AGILE trial.

In the AGILE trial and ALIDHE trial, respectively, any TEAEs occurred in 98.6% and 93.3% of patients, with 93.0% vs 80.9% having grade 3 or higher events. Common TEAEs in each population included neutropenia (28.2% vs 32.6%), nausea (42.3% vs 29.2%), QT prolongation (19.7% vs 23.6%), and anemia (31.0% vs 20.2%). Across both trials, safety data revealed TEAEs leading to interruption of ivosidenib/azacitidine (52.1% vs 23.6%), discontinuation of ivosidenib/azacitidine (26.8% vs 4.5%), dose reduction of ivosidenib/azacitidine (5.6% vs 1.1%), and death (14.1% vs 6.7%).

References

1. Vyas P, Recher C, Döhner H, et al. ALIDHE: An ongoing open-label phase 3b study investigating ivosidenib with azacitidine in clinical practice in adult patients with newly diagnosed mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy (IC). Presented at the 2025 American Society of Hematology Annual Meeting and Exhibition; December 6-9, 2025; Orlando, FL. Abstract 3443.
2. Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344.
3. Servier announces FDA approval of TIBSOVO® (ivosidenib tablets) in combination with azacitidine for patients with newly diagnosed IDH1-mutated acute myeloid leukemia. News release. Servier. May 25, 2022. Accessed December 23, 2025. https://prn.to/3wMibQh